The important roles of mir 205 in normal physiology, cancers and as a potential therapeutic target

Send Orders for Reprints to reprints@benthamscience.net Current Cancer Drug Targets, 2014, 14, 621-637 621 The Important Roles of miR-205 in Normal Physiology, Cancers and as a Potential Therapeutic Target Haleh Vosgha, Ali Salajegheh, Robert Anthony Smith and Alfred King-Yin Lam* Cancer Molecular Pathology, School of Medicine and Griffith Health Institute, Griffith University, Gold Coast, Queensland, Australia Abstract: Evidences have demonstrated key mediatory roles of microRNA-205 (miR-205) in normal physiology and its aberrant expression in many cancers Indeed, miR-205 has been identified as both a tumour suppressive and oncogenic miRNA playing crucial roles in tumourigenesis through regulating different cellular pathways such as cell survival, apoptosis, angiogenesis and metastasis As a tumour suppressor, miR-205 acts as an inhibitor of cell proliferation, migration and invasion On the other hand, as an oncogene, miR-205 promotes tumour initiation and development All these functions act through different target genes in various types of cancers Also, miR-205 displays potential as a therapeutic target for different cancers To conclude, miR-205 has important clinical and pathological correlations in different cancers and may act as a diagnostic and prognostic marker as well as new molecular target for cancer therapy Keywords: Carcinoma, cancer, miRNA-205, microRNA, oncogene, tumour suppressor gene INTRODUCTION microRNAs (miRNAs) have been described as pivotal gene regulatory factors that could play an important role in the majority of key cellular processes, including cell differentiation, cell proliferation, cell death and embryonic development in a broad range of invertebrate and vertebrate organisms, in particular humans [1] Structurally, mature miRNAs are small (composed of approximately 19-23 nucleotides), non-protein-coding and single-stranded RNAs that act as post-transcriptional gene regulators, which target more than 30% of human coding genes [2] To date, more than 1000 miRNAs have been detected in humans Each miRNA can target several mRNAs and a single gene can be regulated by many miRNAs [3] The abnormal expression of miRNAs has been observed in a many human disorders such as cardiovascular [4], neurological diseases [5], diabetes [6] and cancers [7] miRNAs may act either as tumour suppressors or oncogenes during the progression of tumour, depending on which kind of gene(s) they target [8] Due to their known targeting of cancer related genes, improving our understanding of miRNAs and their targets would not only be useful for determining patient diagnosis and prognosis but it may also be a promising method for gene therapy [9] microRNA-205 (miR-205), as a highly conserved microRNA, has homologs in diverse species [10] Using computational methods, the existence of miR-205 was initially predicted based on the conservation with mouse and Fugu rubripes sequences [11] Consequently, the expression of miR-205 has been established in zebra fish and humans [12, 13] Human miR-205 is encoded within the sequence of *Address correspondence to this author at the Head of Pathology, Griffith Medical School, Gold Coast Campus, Gold Coast QLD 4222, Australia; Tel: +61 56780718; Fax: +61 56780303; E-mail: a.lam@griffith.edu.au 1873-5576/14 $58.00+.00 a hypothetical gene termed LOC642587 which is located in the chromosome 1q32.2 region The pre-miR-205 exists in the connecting position of the second intron and the third exon of LOC642587 Cell-specific expression of miR-205 was located and reported in the epithelial tissues by several studies [11, 14, 15] In zebra fish, miR-205 is mainly expressed in epidermis of the skin [14] In the mouse, miR205 expression was noted in squamous epithelium in footpad, tongue, skin epidermis, hair follicle and corneal epithelium and not detected in small intestine, brain, heart, liver, kidney, or spleen [16] In human, expression of miR-205 was identified in breast, prostate and thymus, suggesting that these organs require miR-205 for their development In human cancer, miR-205 in malignancies plays a dual function as a tumour suppressor and sometimes as an oncogene To date, the only logical interpretation for this dual action has been associated with the cancer tissue-type, morphology and the target genes [15] miR-205 IN NORMAL PHYSIOLOGY Studies have examined the potential ability of miR-205 to regulate normal physiology [17-22] Yu et al demonstrated that miR-205 could play an important role in wound-healing as well as keratinocyte migration via suppressing Src Homology 2-containing phosphoinositide 5’-phosphatase (SHIP2) and altering F-actin organization [19] Consequently, this could accelerate the process of wound healing as a result of activation protein kinase B (AKT) signalling in human epidermal keratinocytes and corneal epithelial keratinocytes Upon SHIP2 suppression, cell-substrate adhesion decreased and cell mobility was promoted In addition, miR-184 was identified as an antagomiR of miR-205, which negatively affects this process by inhibiting the interaction between miR-205 and SHIP2, leading to reduced capability of cells to repair scratch wounds [18, 19] In another study, KIR4.1 (KCNJ10), a critical member of the KIR (inward rectifier© 2014 Bentham Science Publishers 622 Current Cancer Drug Targets, 2014, Vol 14, No type potassium channel) family in regulating cell membrane potential [23, 24], was shown to be modulated by miR-205 in wound-healing [20] Over-expressed miR-205 during an injury could bring about repression of KCNJ10 in human corneal epithelial cells, resulting in inactivation of potassium channel activity and subsequent stimulation of the healing process [20] miR-205 has also been found to be implicated in regulation of primary human trophoblast development and changes in hypoxia such as hypo-perfusion and placental injury [21] In this situation, the expression of miR-205 is elevated which enables the suppression of the regulator of placental development, mediator of RNA polymerase II transcription subunit (MED1) Such suppression could be useful for adaptation to injuries during pregnancy [21] Another important physiological role of miR-205 is regulation of adipogenesis differentiation through targeting glycogen synthase kinase beta (GSK-3β) in pre-adipocytes [22] A study has shown that over-expression of miR-205 suppressed the expression of GSK-3β, thus leading to dephosphorylation of β -catenin, activation of the Wnt signalling pathway and inhibition of adipogenesis In addition, high expression of miR-205 and active nonphosphorylated β -catenin increased the expression of cyclin D and c-Myc They are cell-cycle progression inducers, and promoted pre-adipocyte cells proliferation Also, miR-205 is itself regulated by peroxisome proliferator-activated receptor γ (PPAR γ), which up-regulates miR-205 expression during adipogenesis [22] Altogether, miR-205 acts as a regulatory factor of adipogenesis differentiation and pre-adipocyte cell growth by affecting GSK-3β and the Wnt pathway [22] In embryonic development, miR-205 has been detected as one of the key regulators of two physiological processes namely extra-embryonic endoderm differentiation and spermatogenesis under inactivation of Arf (alternate reading frame) as a main regulator of those processes [25] It has been shown that induced expression of miR-205 could stimulate formation and adhesion of extra-embryonic endoderm cells from pluripotent embryonic stem cells or trigger pluripotent cell progenitors and modulate spermatogenesis [25] Elevated expression of miR-205 has also been identified in mammary epithelial cell progenitors which could target the PTEN (Phosphatase and tensin homolog) tumour suppressor and Zeb1/2 (zinc finger E-box binding homeobox 1/ 2) as epithelial-to-mesenchymal transition-inducing repressor genes, resulting in increased cell proliferation [26] In addition, when miR-205 was over-expressed in these cells, many morphological changes including progenitor cell expansion, reduced cell size and increased potential of colony-formation occurred miR-205 was involved in neonatal expansion and proliferation of skin stem cells through targeting SHIP-2 and Phlda-3 (Pleckstrin homology-like domain, family A, member 3) which are negative regulators of the PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) pathway [27] The experiment showed that reduction of miR-205 expression led to neonatal fatality along with defecting epidermal and hair follicle growth in mouse Finally, Vosgha et al miR-205 controls two positive regulators of cell migration genes, Arhgap5 (Rho GTPase-activating protein 5) and Cxcl12 (Chemokine [C-X-C Motif] Ligand 12), which are involved in skin stem cell migration and adhesion [27] Therefore, disruption to the normal expression pattern of miR-205 can be observed in initiation and development of abnormalities in physiological events in addition to initiation of different disorders, potentially including a number of epithelial cancers miR-205 AND BREAST CANCER Nearly all breast cancers are adenocarcinomas, mostly ductal or lobular carcinomas The cancer has a profile of abnormal miR-205 expression which is able to change cell proliferation as well as cell cycle regulation [28] In 2007, using in situ hybridization, Sempere et al initially reported that miR-205 is restrictedly expressed in myoepithelial/basal cells of normal mammary ducts and lobules [29] They also found that expression of this miRNA is reduced or totally abolished in breast cancer samples To obtain insight into expression profiling of miRNAs in normal and different breast cancer tissues, they examined the expression of the miRNA in several different molecular subtypes of breast cancers Triple negative breast carcinoma is an aggressive type of carcinomas with negative expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER-2 or ErbB-2) Interestingly, they observed elevated expression of miR-205 in triple negative breast carcinomas implying that there is a correlation between miR-205 and this aggressive molecular subtype of breast cancer The result was in concurrence with low miR-205 expression in breast cancer cell lines in comparison with non-tumorigenic ones [29] This result was attributed to the negative-regulatory role of miR-205 in epithelial-to-mesenchymal transition [30] Several reports have indicated that the levels of miR-205 are decreased in invasive breast cancer cell lines that had undergone epithelial-to-mesenchymal transition in response to transforming TGF-beta (transforming growth factorbeta), resulting in up-regulation of Zeb-1 and Zeb-2 [30, 31] These factors are then capable of binding to E-cadherin and cell polarity genes, leading to suppression of E-cadherin and loss of cell-cell junction Therefore, miR-205 has a potential role in epithelial mesenchymal transition, which may explain its negative correlation to invasion of breast cancer through its targeting Zeb-1 and Zeb-2 [30, 31] On investigating putative targets of miR-205, Iorio et al., found ErbB-3 or HER-3 tyrosine-protein kinase receptor could be regulated by miR-205 in breast cancer [32] They showed that miR-205 expression decreased in breast carcinomas compared to non-cancer samples, whereas HER3 is frequently up-regulated in breast cancers, suggesting that there is an inverse link between miR-205 and HER-3 protein level This function of miR-205 can impair the activation of downstream mediator Akt in the PI3K/Akt cell survival pathway and subsequently inhibit breast cancer cell growth [32] Moreover, this study described the introduction of miR205 in breast cancer cells could enhance the responsiveness to tyrosine kinase inhibitor (TKI) therapies such as Gefitinib and Lapatinib through annihilating HER3-mediated resistance miR-205 in Normal Physiology and Cancer and repairing pro-apoptotic activity [32] Similar results were reported by Wang et al in 2013, showing that overexpression of miR-205 was able to enhance apoptosis and decrease the migration capacity of breast cancer cells through targeting HER-3 [33] Another study carried out by Wu et al indicated that miR-205 was as a potential tumour suppressor and the down-regulation of miR-205 was observed in breast cancer cells compared with the normal breast epithelial cell line [34] They also reported that transfection of miR-205 can repress proliferation, clonogenic survival, anchorage–independent growth and aggressiveness [34] Apart from HER-3, VEGF-A (vascular endothelin growth factor –A), was identified as another potent target for miR205, implying that inhibition of breast cancer and blood vessel growth could also be mediated by miR-205 and emphasising the multiple targeting potentials of this miRNA [10, 34] In 2011, Adachi et al observed for the first time the reduction of miR-205 as a result of over-expression of ErbB2 (HER-2) in breast epithelial cells, indicating that it may be a major event for ErbB-2-induced breast carcinogenesis [35] Cyclin D1 and cyclin E are two key downstream molecules in the ErbB-2 signalling pathway, which are required for breast carcinogenesis mediated by ErbB-2 ErbB-2overexpressing breast epithelial cells transfected by precursor miR-205 showed significantly lower expression of cyclin E, but not cyclin D1 This finding suggested the mediatory role of miR-205 in activation of cyclin E induced and provided further evidence that this mediation might be integral to ErbB-2-induced breast carcinogenesis [35] Further information on the role of miR-205 in breast carcinogenesis was provided when p53 was observed to be a positive regulatory factor of miR-205 in triple negative breast carcinomas cells p53 can directly bind to a responsive element located up-stream of miR-205, resulting in increased expression of miR-205 [36] LAMC1 (laminin, gamma 1) and E2F1 (E2F transcription factor 1) regulators of cell proliferation, migration, adhesion and cell cycle, were two novel target genes of miR-205 which were also identified in this research, confirming the tumour suppressive role of miR-205 in breast cancer Reintroduction of miR-205 into the triple negative breast cancer cell line was dramatically able to reduce cell proliferation, cell cycle progression as well as clonogenic potentiality both in vitro and in a xenograft model, attributed to targeting of LAMC1 and E2F1 [36, 37] Le Quesne and colleagues reported that miR-205 expression was found to be a grade- and stage-independent predictor of survival of patients with ductal carcinoma of breast [38] However, when lymph node status of ductal carcinomas was entered into this model, the predictor potential of miR-205 was lost It was proposed that an antimetastatic effect might mediate the correlation of miR-205 and survival They also noted that AFF1 (AF4/FMR2 family, member 1), a transcriptional factor was highly expressed in lobular carcinomas [39], and was a predicted target gene of miR-205 This finding showed that the overall transcriptional profile, morphology and biological behaviour of lobular breast carcinoma might be contributed by the loss of miR205 and its AFF1 interaction [38] Current Cancer Drug Targets, 2014, Vol 14, No 623 By studying 59 breast carcinomas patients in three different molecular groups (ER- and/or PR+; Group I), (HER2+; Group II) and (ER/ PR/ HER2; Group III), Savad et al observed that miR-205 down regulated in all these groups [40] However, there was a significant down-regulation only in Group III cancers, which had also been reported by other studies [29, 41] Therefore, down regulation of miR-205 is a feature for triple negative breast cancer [40] Liu et al used RT-PCR to analyse expression of miR-205 in archived serum of 30 participants including 20 breast cancer patients and 10 healthy people They stated that there was significant miR-205 down-regulation in serum of patients compared to healthy individuals [42] Other than that, there was no significant association between miR-205 expression and clinicopathological parameters of patients with breast cancer [42] In 2013, Wang et al reported that Entinostat (a class I Histone Deacetylase [HDAC] inhibitor in clinical trials of treatment of various cancers) could induce apoptosis in ErbB-2-overexpressing breast cancer cells by causing upregulation of miR-205 whose main targets are ErbB-2/ ErbB-3 receptors [43] Based on this information, epigenetic approaches such as inhibition of HDAC via Entinostat in concert with exogenous dosing of ErbB-2/ ErbB-3- targeting miRNAs could be promising strategies in the hope of treating the breast cancer patients with ErbB-2 overexpression [43] Taken together, the above-mentioned findings show the function of miR-205 in breast cancer formation and its aggressiveness through involvement in specific signalling pathways which can be likely dependent on the stage of tumour and origin of cells miR-205 AND PROSTATE CANCER Nearly all prostatic carcinomas are adenocarcinomas In 2007, Porkka and colleagues had found from oligonucleotide array hybridization method in cells lines, xenografts and carcinomas samples that down-regulation of miR-205 linked to tumour progression in prostatic carcinoma [44] In 2009, Gandellini et al found significant down-regulation of miR205 in prostate cancer cell lines and prostate cancer tissues compared to normal samples [45] They demonstrated for the first time that miR-205 had a tumour-suppressive role in prostate cancer through inhibiting epithelial mesenchymal transition process and repressing cell migration and invasion partly by suppression of protein kinase C miR-205 has also been implicated in sustaining epithelial cell phenotype and tissue organization due to targeting several factors (specifically E2F-1, E2F-5, Zeb-2 and N-chimaerin) involved in regulation of cell motility, invasion properties and cellcell adhesion [45] This possibility could be used as a treatment strategy using miR-205 in order to reprogram the phenotype of prostate cancer cells to a less invasive form [45] In 2010, the tumour suppressive role of miR-205 in prostate cells was also recognized by Majid et al through promoting the expression of two other tumour suppressor genes; interleukins 24 (IL- 24) and interleukin 32 (IL-32) by targeting their promoters [46] Also, metastatic prostate cancer cells transfected with miR-205 showed the reduction of cell invasive properties and migratory abilities which was consistent with previous reports [44, 45] Hence, miR-205- 624 Current Cancer Drug Targets, 2014, Vol 14, No induced IL-24/32 activation may be beneficial as a new method for prostate cancer therapy Moreover, it has been shown that pro-apoptotic genes such as BAK (bcl-2 associated killer), BAX (bcl-2 associated X) and BID (BH3 interacting domain death agonist) were considerably upregulated as a result of miR-205 over-expression in prostate cancer, resulting in inhibition of cancer cell proliferation [46] In other research in 2010, apoptosis regulation of prostate cancer cells was investigated through miR-205induced BCL2L2 repression [47] BCL2L2 is an antiapoptotic protein which can be targeted by miR-205 in prostate cancer miR-205 was able to enhance prostate cancer cell apoptosis induced by chemotherapeutic agents via down-regulating BCL2L2 However, hypermethylation of miR-205 promoter in advanced prostate cancers led to repression of the miRNA, preventing this effect Thus, low expression of miR-205 could directly promote prostate cancer progression into more invasive and chemo-resistant states [47] Taking the advantages of next generation sequencing technology, Watahiki et al identified different expression patterns of miRNAs in metastatic prostatic cancer cells compared to a non-metastatic prostate cancer in mice models Of these miRNAs, miR-205 was found to be down regulated in the metastatic cells, showing a potential significant role in prostate cancer metastasis [48] miR-205 could also play an important role in a pathway involving ∆Np63 [49] ∆Np63, a protein exclusively expressed by basal cells of prostatic glands [50], is required for lineage commitment and differentiation in prostate development [51, 52] It has been determined that an interaction between miR-205 and ∆Np63 is essential for maintenance of the basement membrane which surrounds normal prostate glands and preserves tissue integrity Invasion of basement membrane is one of the key events in invasive carcinoma ∆Np63 was capable of enhancing miR205 expression by binding to its promoter, while miR-205 could indirectly decrease the amount of ∆ Np63 protein mainly through its proteasomal degradation At the functional level, miR-205 modulates basement membrane assembly and maintains tissue integrity by regulating laminin-332 deposition and its receptor integrinβ4 Therefore, pathological reduction of miR-205 can increase the chance of carcinogenesis by creating gaps in the basement membrane [49] Another study in 2012 noted that miR-205 expression could be regulated by isoforms of p63 - ∆Np63 and Tap63 [53] It has been found that both p63 and miR-205 are down-regulated in metastatic prostate cancer According to this study, ∆Np63 has an inhibitory role in the epithelial mesenchymal transition process through reduction of Zeb-1, which can be abolished by the use of an anti-miR205 In addition, mutated p53 was introduced as a key factor to reduce the expression of ∆Np63 and miR-205 in prostate cells, resulting in increased cell migration [53] Puhr et al highlighted the correlation between reduced expression of miR-205 and docetaxel insensitivity in prostate carcinoma [54] Docetaxel is a standard chemotherapy for patients with metastatic prostate carcinoma The authors reported that the level of miR-205 was diminished in Vosgha et al docetaxel-resistant cells, resulting in increased expression of E-cadherin and promoting the epithelial mesenchymal transition process These findings demonstrated that prostate cancer cell survival and drug resistance during chemotherapy are directly associated with the level of miR-205 [54] Epigenetic regulation of miR-205, leading to reduction of its expression in prostate cancer cells has been highlighted [47, 55, 56] In 2013, Hulf et al showed the association between epigenetic mechanisms such as DNA methylation and histone H3K9-deacetylation of miR-205 locus and MED-1 (mediator of RNA polymerase II transcription subunit 1) gene deregulation in prostate cancer [57] They found silencing and reduced expression of miR-205 in prostate cancer cells through hyper-methylation and histone deacetylation Moreover, MED-1, an androgen receptor coactivator and an important factor for transcription of androgen receptor target genes [58], was observed to be over-expressed in prostate cancer and could be regulated by miR-205 Therefore, reduced expression of miR-205 through epigenetic mechanisms can up-regulate MED-1 in prostate cancer On analysing 111 archival prostate carcinoma samples, Verdoodt and colleagues indicated that miR-205 expression was reduced in the majority of cancer samples compared to benign ones [59] miR-205 expression diminished with increasing size of the carcinoma Additionally, the antiapoptotic protein BCL-2, is highly expressed in primary prostate cancer and is a marker for poor prognosis in patients with prostatic cancer The marker was found to be a target of miR-205 Upon targeting BCL-2, miR-205 could increase apoptosis and inhibit proliferation in prostate cancer cells in response to chemotherapeutic agents namely cisplatin and doxorubicin [59] miR-205 expression was found to be inversely correlated with the incidence of metastases and decreased overall survival of patients with prostate carcinoma [60] The miRNA was noted to be mainly expressed in the basal cells of prostate glands Patients with prostatic cancer having higher tissue levels of miR-205 expression had better survival when compared to those who did not Furthermore, miR-205 was found to bind to and have an inverse link with serum levels of the androgen-regulated prostate-specific antigen, verifying miR-205’s potential role in targeting of androgen receptor signalling [60] It has also been shown that the MAPK (mitogen-activated protein kinase) pathway is one of the oncogenic pathways affected by miR-205 in prostate cancer cells MAPK is implicated in phosphorylation of androgen receptor which could promote the ligandindependent activation of the androgen receptor in response to androgen ablation treatment (castration) In addition, lower expression of miR-205 has been detected in castrationresistant patients who had up-regulation of androgen receptor Thus, miR-205 may be able to exert a therapeutic function, in particular for castration resistant prostate cancers [60] Another potential target for miR-205 was heterogeneous nuclear ribonucleoprotein K (hnRNP-K), a multifunctional protein and an inhibitor of androgen receptor known to be up-regulated in prostate cancer [61, 62] Indeed, Szczyrba et al demonstrated that hnRNP-K was a target of miR-205 [63] Higher levels of hnRNP-K expression caused enhancement miR-205 in Normal Physiology and Cancer of the angiogenic and migratory functions of prostate carcinoma cells The remarkable down-regulation of miR205 in prostate cancer tissues thus results in underexpression of androgen receptor through regulation of AKT/hnRNP-K/AR/β-catenin and MAP kinase signalling pathways [63, 64] In 2013, Gandellini et al reported that miR-205 was found to be the most suppressed miRNA in prostate cancer cells undergoing epithelial mesenchymal transition upon stimulation by cancer-associated fibroblasts [65] Epithelial mesenchymal transition-induced by down regulation of miR-205 was determined to occur in two different stages in prostate cancer cells First, matrix metalloproteases (MMP) -2 and secreted by cancer-associated fibroblasts caused activation of hypoxia-inducible factor 1-alpha (HIF-1 alpha) which was able to supress miR-205 Secondly, downregulated miR-205 resulted in promotion of Zeb1/2 and PKCε activity, stimulating epithelial mesenchymal transition and IL-6 secretion respectively Acquisition of stem cell properties, tumourigenicity and reactivity of cancer-associated fibroblasts via IL-6 secretion were the consequences of miR-205 repression in prostate cancer cells [65] Wang and co-workers have also showed a correlation between miR-205 expression in prostatic cancer with the clinicopathological stage of disease and total/free serum prostate-specific antigen level [66] Wang et al also observed that c-Src (sarcoma [Schmidt-Ruppin A-2] viral oncogene), a non-receptor tyrosine kinase and a key role-player in various cellsignalling pathways such as apoptosis, cell proliferation, invasion and adhesion [67, 68], has been determined to be a target of miR-205 Through repression of c-SRC, miR-205 affected downstream signalling molecules involved in proliferation such as FAK, p-FAK, ERK1/2, p-ERK1/2, c-MYC and cyclin D1, resulting in inhibited cell invasion and tumour growth [66] In high risk prostatic adenocarcinoma (Gleason score ≥ and/or pathological stage (T stage ≥ and/or PSA ≥ 20 ng/μL), down-regulation of miR-205 was noted which implied the tumour-suppressive role of miR-205 in this cancer [69] Since miR-205 expression reduced in lymph nodes with metastatic carcinomas when compared to the primary carcinomas, miR-206 might play a critical role in those processes leading to migration and metastatic traits in prostate carcinoma cells The dual tumour suppressive and oncogenic roles of miR-205 are the reason for its expression to be ups and downs at different stages of prostate cancer [69] In 2013, Srivastava et al signified for the first time the remarkably lower expression of miR-205 in urine samples of prostate cancer patients in comparison to the urine of healthy individuals, introducing that miR-205 could be used for screening urine for prostate cancer [70] In addition, utilizing PCR array in formalin-fixed, paraffin embedded prostate cancer tissue, they also reported significant reduction of miR-205 expression in cancer samples compared to noncancer ones [70] Investigating the potential role of miRNAs in arsenicinduced malignancy for prostate cancer, Nghalame et al Current Cancer Drug Targets, 2014, Vol 14, No 625 in 2014 showed the down-regulation of miR-205 in arsenictransformed epithelial prostate cells [71] The authors found the same result after analysing the miRNA’s expression in cancer stem cells transformed by arsenic It has been reported that miR-205 is among those miRNAs whose aberrant expression is involved in regulation of RAS/ERK and PI3K/PTEN/AKT pathways and controlling cell proliferation and cell death in these transformed cells [71] Therefore, regulatory actions of miR-205 through different molecular factors and also various roles of this miRNA in prostate cancer initiation, progression and metastasis may suggest that miR-205 can be utilized as a hopeful therapeutic target in this particular type of cancer miR-205 AND LUNG CANCER Lung cancer, the major cause of cancer mortality in the world, can be divided into two groups: small cell lung carcinoma and non-small cell lung carcinoma (NSCLC) The latter type of lung cancer also contains the two most prevalent histological types of lung cancer, namely squamous cell carcinoma and adenocarcinoma Multiple groups have demonstrated the critical role of miR-205 in lung cancer progression, most of which found up-regulation of miR-205 in non-small cell carcinoma [72] In 2008, Markou and colleagues performed quantitative real-time polymerase chain reaction to measure miR-205 expression in non-small cell carcinoma [73] It has been reported that miR-205 was up-regulated in 65% (31 of 48) fresh frozen non-small cell carcinoma samples compared to their adjacent non-cancerous specimens Nonetheless, they could not find any correlation between miR-205 expression and survival rates of patients with non-small cell carcinoma [73] miR-205 as one of the miRNAs was found to be differentially expressed in squamous cell lung carcinoma in comparison to lung adenocarcinoma was noted in a study in 2006 [74] In 2009, another group further reported that miR205 could be used as a marker for squamous cell carcinoma of lung [75] Consistent with this study, Hamamoto et al in 2013 determined that miR-205 expression could assist in the discrimination of non-small cell carcinoma histological subtypes through its up-regulation in squamous cell carcinoma compared to adenocarcinoma [76] In 2010, Bishop et al compared the classification of 102 non-small cell carcinoma small biopsies samples based on two different approaches; standard pathologic methods (microscopic examination and immunohistochemistry) and a novel miR-205 expression-based method [77] They could distinguish 52 resected lung carcinomas as squamous cell carcinomas and 50 as adenocarcinomas by using both techniques, implying that miR-205 can be taken up as a diagnostic tool for an accurate differentiation of squamous cell carcinoma from non-small cell carcinomas [77] Similarly, when comparing miRNA expression profiling between squamous cell carcinoma and adenocarcinoma in stage I lung cancer patients, Lu et al observed significant over-expression of miR-205 in squamous cell carcinoma compared to adenocarcinoma [78] 626 Current Cancer Drug Targets, 2014, Vol 14, No More recently, Haung et al found over-expression of miR-205 in squamous cell carcinoma of lung compared with adenocarcinoma and small cell carcinoma of lung [72] In addition, the authors identified 11 significant target genes of miR-205, among which target genes (ACSL1, PRKAG3, RUNX1, SMAD4, STK3 and TBL1XR1) were reported for the first time to be involved in lung cancer progression [72] In contrast to other studies, Del Vescovo et al in 2011 found that miR-205 expression in lung cancer tissue was not a reliable morphological marker to differentiate squamous cell carcinoma from adenocarcinoma in lung [79] In 2012, performing microarray and laser-capture microdissection methods, Huang et al investigated the ability of miR-205 to discriminate lung squamous cell carcinoma and adenocarcinomas in bronchial brushing samples [80] They suggested that miR-205 has an oncogenic function in squamous cell carcinoma due to its higher expression compared to adenocarcinoma [80] miR-205 was shown to be over-expressed in different non-small cell lung carcinomas tissues, resulting in increased cell proliferation and activated angiogenesis both in vitro and in vivo through directly targeting PTEN and PHLPP2 (PH domain and Leucine rich repeat Protein Phosphatases 2) tumour suppressor genes and subsequently activating AKT/FOXO3a and AKT/mTOR pathways [81] Activated AKT signalling, a common event in non-small cell lung carcinomas, leads to phosphorylation of FOXO3a (Forkhead box O3) and mTOR (mammalian target of rapamycin), whose abnormal expression are involved in tumour angiogenesis promotion by affecting p21, VEGF-A and cyclin D1 Moreover, Cai et al identified a novel mechanism for NFκB which has a putative binding sequence located upstream of the miR-205 gene locus, implying that NF-κB can transactivate miR-205 in cells from non-small cell lung carcinomas including adenocarcinoma, squamous cell carcinoma, large cell carcinoma and adenosquamous carcinoma Therefore, miR-205 repression as well as PTEN and PHLPP2 restoration that can inhibit the activity of AKT/FOXO3a and AKT/mTOR pathways provides potential targets to treat non-small cell lung carcinomas [81] Another independent study compared for the first time the significance and potential diagnostic and prognostic role of miR-205-5p and miR-205-3p in tissue and serum of patients with non-small cell lung carcinomas, benign pulmonary diseases and healthy individuals [82] They revealed that whilst high levels of miR-205-5p and miR-2053p were noticed in squamous cell carcinoma, miR-205-5p alone was significantly overexpressed in non-small cell lung carcinomas They concluded that miR-205-5p could be used to discriminate squamous cell carcinoma from other nonsmall cell lung carcinomas [82] Aushev et al with the aim of finding novel method for early detection of squamous cell carcinoma of lung, analysed plasma miRNA profiles in these patients before and after lung cancer surgery [83] They demonstrated that expression of miR-205 considerably diminished in the blood of patients after r removal of lung cancers They also compared miRNA profiling in exosomal and exosome-free fractions of serum from patients with squamous cell carcinoma, showing a Vosgha et al higher level of miR-205 in tumour-specific exosomes These findings indicated that miR-205 could be used as a marker of squamous cell carcinoma of lung both in plasma and tumourspecific exosomes [83] Contrary to other studies, a potential tumour suppressive role of miR-205 to inhibit lung cancer cell migration was reported by Song et al in 2009 [84] They indicated that low-density lipoprotein receptor-related protein (LRP1), which is a crucial factor in cancer cell migration [85], could be suppressed by miR-205, causing a reduction in ability of tumour cells to migrate [84] Larzabal and co-workers have also reported significant down-regulation of miR-205 in nonsmall cell lung carcinoma compared with non-cancerous lung epithelial cells, describing it as a tumour suppressor miRNA [86] For clarification of this contradictory finding, they investigated a novel molecular signalling pathway in which miR-205 has an ability to regulate cancer cell migration and metastases by making connection between TMPRSS4 (transmembrane protease, serine 4) and integrin α5 TMPRSS4 has been known as a membrane-anchored proteases implicated in cell invasion and motility Upon knockdown of TMPRSS4, they found miR-205 was upregulated, resulting in increased E-cadherin expression, reduction of fibronectin and inhibition of epithelialmesenchymal transition They further found that integrin α5 which is involved in cell motility and invasion and also is a direct target for miR-205, was down-regulated due to upregulation of miR-205 Eventually, they found a hindrance in cell migration and reduction in cell proliferation Thus, their result proposed a new insight into the molecular connection of these two membrane-anchored proteins and miR-205 and a possibility of an effective therapeutic method for targeting this axis in patients with non-small cell lung carcinoma [86] Tellez et al used immortalized human bronchial epithelial cells to expose to tobacco carcinogens for 12 weeks until markers of stemness, enriched with CD44High/CD24 Low, as detected by flow cytometry were highly presented [87] The morphological appearance of epithelial-mesenchymal transition appeared after a sustained silencing of tumour suppressive miRNAs including miR-200b and 200c and miR-205 This study demonstrated that, miRNAs and transcriptional regulators are essential in the formation of mesenchymal characteristics in cancer cells, and this association is not always harmonized towards the epithelialmesenchymal transition [87] Overall, these findings can infer that miR-205 has a complex role and may function both as a tumour suppressor and an oncogene in non-small cell lung carcinoma Also the classifier ability and tissue specificity of miR-205 in nonsmall cell lung carcinoma may suggest that this miRNA is one the most important miRNAs to distinguish squamous cell lung carcinoma and lung adenocarcinoma miR-205 AND MELANOMA miR-205 was significantly suppressed in metastatic melanoma specimens in comparison to primary tumours or nevi [88] Dar et al further reported E2F1 and E2F5, two oncogenic cell cycle regulators, as putative target genes of miR-205 in Normal Physiology and Cancer miR-205, whose expression level had an inverse correlation with that of miR-205 in melanoma cell lines Expression of miR-205 in melanoma cell lines and in xenografts decreased protein levels of E2F1 and E2F5, leading to induction of apoptosis via reducing AKT-phosphorylation regulated by E2F over-expression This apoptosis mediated by overexpressed miR-205 could occur through either suppression of caspase-9 and BAD (bcl-2 associated death promoter) phosphorylation or caspase-3 and PARP (Poly [ADP-ribose] polymerase) cleavage and cytochrome c release Moreover, an implication of miR-205 in human melanoma cell senescence mediated by up-regulation of p16INK4a and repression of Retinoblastoma (Rb) phosphorylation was revealed for the first time in this study [88] Looking for molecular mechanisms in control of apoptosis-induced dysregulated E2F1 in melanoma, Alla et al stated that miR-205 was a potent target of p73, whose expression is abrogated after being exposed to genotoxic stress by endogenous DNp73 [89] They indicated that there were two molecular strategies that could be used in order to rescue metastatic cells from drug resistance, thus promoting apoptosis and reducing tumour cell proliferation in vivo [89] These strategies were knockdown of DNp73, or overexpression of miR-205 in cells with no p73 expression Upregulation of miR-205 can enhance its inhibitory function on the expression of Bcl-2 and ATP-binding cassette transporters A2 (ABCA2) and (ABCA5), leading to reduced drug resistance of melanoma cells and malignant progression These results introduced the E2F1-p73/DNp73-miR-205 axis as a significant mechanism of drug resistance as well as a potential preventive target for metastases [89] Noguchi et al employed a synthetic miR-205, miR205BP/S3, was generated by benzene-pyridine modification to find its effects on melanoma cancer both in vitro and in vivo [90] They reported that miR-205BP/S3 was able to act as a tumour suppressor similar to miR-205 by directly targeting E2F1, BCL2 and VEGF genes, leading to inhibition of tumour cell proliferation and promoting cell death [90] They also showed that miR-205BP/S3 was a more effective tumour suppressor in vivo compared to premiR-205 due it high resistance to RNase This indicates that chemically modified synthetic miR-205 could be used as a helpful therapeutic agent for melanoma [90] Using a luciferase activity assay, Noguchi et al found ErbB-3, a member of the epidermal growth factor family of receptor tyrosine kinases and an activator of cell proliferation signalling could be targeted by miR-205 in melanoma In vitro experiments illustrated that induced expression of miR-205 in human malignant melanoma and canine malignant melanoma cells could result in inhibition of cell proliferation [91] These results confirmed the potential role of miR-205 as a tumour suppressor in both human melanoma and canine melanoma cells [91] Performing miRNA microarrays and qRT-PCR, Liu et al indicated that miR-205 as a tumour suppressor had the largest differential down-expression in various melanoma samples with different stages, being remarkably decreased in disease progression [92] Ten-fold lower miR-205 expression in primary melanomas compared to benign nevi was Current Cancer Drug Targets, 2014, Vol 14, No 627 reported, which then dropped an additional 100-fold from primary melanomas to metastatic melanomas Ectopic expression of miR-205 could also impede the migratory and invasive properties of melanoma cell lines both in vitro and in vivo through targeting and Zeb-2 and consequently increasing E-cadherin This was the first study providing experimental evidence about the crucial regulatory role of miR-205 in enhancing epithelial mesenchymal transition in melanoma progression [92] Hanna and co-workers confirmed the tumour suppressive role of miR-205 in tissue microarray, whose expression was reduced in metastatic and primary melanomas when compared to nevi [93] In vivo experiments showed that reintroduction of miR-205 could inhibit tumour growth, promote senescence and decrease cell proliferation through E2F1 down-regulation which was in concordance with the findings of Dar et al [93] In 2013, Kozubek et al used next-generation sequencing to analyse the miRNA transcriptome both in tissue sample and cell lines of melanoma They verified reduction of miR205 expression in 19 melanoma tissue samples and in different melanoma cell lines versus non-cancer controls This result also reinforced a potential diagnostic role for miR-205 in order to categorize melanoma from nevus [94] In another study, Dahmke and colleagues reported for the first time the effect of curcumin, an anti-inflammatory and anti-carcinogenic compound, through its effects on miRNA profile in murine melanoma, indicating that mmu-miR-205-5p was greatly up-regulated in response to curcumin exposure [95] It has been shown that mmu-miR-205-5p was a potential therapeutic target and biomarker to detect the aggressiveness and metastatic behaviour of melanomas [95] Information obtained from mentioned studies indicate that miR-205 can stop melanoma through targeting different oncogenes and critical signalling pathways Thus, manipulation of these pathways mainly through miR-205 can offer a novel gene therapy method for this disease miR-205 AND URINARY BLADDER CANCER The majority of urinary bladder cancer is papillary urothelial carcinoma In 2007, Gottardo et al found for the first time that miR205 expression was significantly up-regulated in bladder carcinoma tissues compared to adjacent normal mucosa [96] A study carried out by Wiklund et al also showed that although miR-205 expression was up-regulated in the bladder carcinomas, it was found to be reduced in invasive compared to non-invasive carcinomas [97] This indicated that regardless of the oncogenic role of miR-205 in a given tissue, it could impede tumour invasion and metastases Furthermore, promoter hyper-methylation of miR-205 has been detected in muscle invasive bladder carcinomas and high-grade bladder carcinoma cell lines, implying that aberrant epigenetic silencing of miR-205 and consequently the loss of expression could be a promising prognostic factor in bladder carcinoma They also found that the mesoderm specific transcription factor TWIST1 could be a transcriptional inhibitor of miR-205, resulting in promotion of epithelial-mesenchymal transition [97] 628 Current Cancer Drug Targets, 2014, Vol 14, No Similar to the finding in prostate adenocarcinoma, miR205 and its interaction with ΔNp63 for its role in epithelialmesenchymal transition in bladder cancer has also been investigated [98] A p63 isoform, ΔNp63α, itself a member of the p53 family, has been shown to modulate the expression of miR-205 and eventually assist in the promotion of epithelial-mesenchymal transition [98] ΔNp63α controls the expression of miR-205 via activation of the starting codon of miR-205, recruitment of RNA Pol II and coordination of the transcription of the miR-205 In addition, elevated miR-205 expression in parallel with expression of the known activators of epithelial-mesenchymal transition, Zeb-1/2 was mutually associated with the poor clinical outcomes in patients with bladder carcinoma [98] Unlike previous studies which indicated that miR-205 was down-regulated in invasive bladder carcinoma due to aberrant DNA methylation, Dip et al showed a higher level of miR-205 expression in 30 samples with high grade, invasive bladder carcinoma which was not explainable by its inhibitory role in epithelial-mesenchymal transition [99] Like other studies, they noticed under-expression of miR205 in bladder carcinomas of lower grade and of noninvasive types [99] Therefore, authors finally suggested it needs to have further research to explain these discrepancies about miR-205 expression Lower expression of miR-205 in high grade papillary urothelial carcinomas compared to low grade papillary urothelial carcinoma of bladder on study on 100 cases of bladder carcinoma [100] Low expression of miR-205 along with cancer progression was associated with high expression of Zeb-1 The result confirmed the importance of miR-205 in controlling the expression of Zeb-1 and impeded epithelial mesenchymal transition processes and cancer invasiveness [100] Although these studies verified a pivotal role for miR-205 in bladder carcinoma, more in-depth investigations are required to clarify the effect of different expression patterns and mechanisms in how this miRNA regulates the progression of bladder carcinoma miR-205 AND HEAD/NECK CANCERS Head/neck cancers are often squamous cell carcinomas The only exception is nasopharynx cancer which is often undifferentiated carcinoma In 2007, Tran et al noticed an up-regulation of miR-205 in head and neck carcinomas using an array platform on cancer cell lines from tongue, hypopharyngeal and tonsil carcinoma [101] Authors summarized that the exclusive overexpression of miR-205 could be a unique event in head and neck carcinomas [101] Then, Fletcher and co-workers observed no significant variation in miR-205 expression in different stages of head and neck carcinomas [102] They used different cell lines from primary squamous cell carcinoma and tissues from 12 head and neck squamous cell carcinoma and lymph nodes with metastatic head and neck squamous cell carcinoma In this study, miR-205 expression could not be used as a biomarker to discriminate head and neck squamous cell carcinoma from normal squamous epithelium However, the authors found that high expression of miR-205 may be capable of detecting those carcinomas with lymph node metastases [102] Vosgha et al Contrary to former results, low expression of miR-205 in head and neck squamous cell carcinoma was observed by Childs et al, reflecting the tumour suppressive function of this miRNA Childs et al also indicated that in 104 primary tumour samples, miR-205 was a prognostic biomarker which was independent of treatment, stage of cancer and anatomical region [103] Dihydrofolate reductase (DHFR), an oncogene involved in p14ARF pathway, was also identified as a potential target of miR-205 in this study, having a reverse correlation with expression level of miR-205 in head and neck squamous cell carcinomas [103] In agreement with previous findings regarding miR-205 effects on epithelial mesenchymal transition, Zidar et al showed the down-regulation of miR-205 in spindle cell carcinoma (a type of poorly-differentiated squamous cell carcinoma) [104] miR-205 down-regulation has also been found to be associated with up-regulation of Zeb-2 and E-cadherin down-regulation, which have a crucial function in spindle cell carcinomas of the head and neck pathogenesis [104] Correlation between miR-205 expression and radiosensitivity of human nasopharyngeal carcinoma was noted [105] It has been shown that radio-resistant nasopharyngeal carcinoma cell lines had increased expression levels of miR205, which were able to repress the tumour suppressor gene, PTEN This suppression was associated with activation of the PI3K/Akt pathway and, in turn, apoptosis reduction Hence, these results suggested a significant prognostic capability of miR-205/PTEN pathway, which could be considered for a new treatment approach for patients with nasopharyngeal carcinoma [105] In 2013, Wang et al introduced SZ-685C, which is an anti-cancer chemical isolated from fungus, as an inhibitor of tumour cell proliferation through inactivation of Akt and reduction of miR-205 and eventually elevation of PTEN expression level in nasopharyngeal carcinoma cells [106] They indicated that SZ-685C played an integral role to induce apoptosis, suggesting it can be used as a valuable anti-cancer drug for patients with nasopharyngeal carcinoma [106] Kim et al also revealed the tumour suppressive role of miR-205 in human oral cancer cells in which miR-205 expression was significantly decreased in comparison to normal oral keratinocytes [107] In addition, the proapoptotic function of over-expressed miR-205 in oral cancer cells has been detected through caspase-3 and -7 activation and directly up-regulating of IL-24, which is an important tumour suppressor and apoptosis stimulator [107] In other work carried out by this group, axis inhibitor protein (Axin2) was detected as novel target of miR-205, which was significantly up-regulated in oral cancer cells relative to normal keratinocytes due to miR-205 reduction, leading to inhibited apoptosis [108] They noted that Axin2 acts as an oncogene in this type of cancer and has an integral regulatory role in Wnt/β-catenin signalling pathway which is a well-known pathway regulating various cellular processes such as cell proliferation and apoptosis [108] Therefore, miR-205 should be considered as a potential target for oral cancer treatment [107, 108] Although higher expression of miR-205 in laryngeal squamous cell carcinoma has been detected, reduced levels miR-205 in Normal Physiology and Cancer of the miRNA have also been identified in such tissues [109] Tian and colleagues showed that miR-205 acted as a tumour suppressor in laryngeal squamous cell carcinoma tissues through promoting cell apoptosis [110] Advanced pathological or T stages, but not lymph node metastases, have been shown to have lower expression of miR-205, implying its tumour suppressive function occurs in the early stages of laryngeal squamous cell carcinomas Bcl-2 was found as a major target of miR-205 in laryngeal squamous cell carcinoma, which is down-regulated upon ectopic expression of this miRNA, resulting in suppression of cell proliferation [110] Furthermore, the cell-proliferationinhibitory role of miR-205 has been shown in vitro and in xenograft via significant repression of two important proliferative markers; dihydrofolate reductase and proliferating cell nuclear antigen (PCNA) [111, 112] Based on these findings, miR-205 could be a therapeutic target with a potential capability to regulate cell cycle and cell proliferation in this cancer [110] Current Cancer Drug Targets, 2014, Vol 14, No 629 In 2010 and 2011, Matsushima and colleagues reported that miR-205 was over-expressed in well or moderately differentiated human oesophageal squamous cell carcinoma when compared to non-cancerous tissue Similar to studies in other cancers, miR-205 was also identified as a regulatory factor to impede cell migration and epithelial mesenchymal transition by suppressing of Zeb-2 which is a repressor of E-cadherin [119, 120] A miRNA array study done by Fassen et al analysed the expression of miRNAs in tissue samples from Barrett’s mucosa including low grade and high grade, oesophageal adenocarcinoma as well as normal squamous epithelium [121] Thirteen miRNAs were detected as the “progression signature”, indicating Barrett’s mucosa progression to malignancy Of these, miR-205 was identified to be downregulated in the pathogenesis [121] The two most common oesophageal cancers are squamous cell carcinomas and adenocarcinomas Many of the studies on miR-205 were on the oesophageal adenocarcinoma Saad and colleagues compared the expression of the 21 most deregulated miRNAs in normal squamous mucosa, Barrett’s mucosa, high grade glandular dysplasia, oesophageal adenocarcinoma, gastric adenocarcinoma and normal gastric tissue samples [122] Lower expression of miR-205 was found in oesophageal adenocarcinoma compared to Barrett’s mucosa but not in gastric adenocarcinoma [122] Feber et al in 2008 analysed expression of microRNA in 35 oesophageal tissues samples including adenocarcinoma, squamous cell carcinoma, normal oesophageal epithelium, Barrett’s oesophagus and Barrett’s oesophagus with high grade glandular dysplasia They found that miR-205 was down-regulated in adenocarcinoma and squamous cell carcinoma in comparison to normal samples [113] However, in another study done by Kimura et al miR-205 has been found to be notably over-expressed in normal and cancerous squamous epithelia of the oral cavity including oesophageal squamous cell carcinoma, suggesting the ability of this microRNA to distinguish squamous cell carcinoma from other carcinomas and it may also be a promising marker for normal samples [114] Based on the real time RT-PCR assay, Dijckmeester at al showed the expression of miR-205 was significantly decreased in Barrett’s oesophagus compared to normal squamous epithelium [115] Two studies for miR-205 were based on oesophageal squamous cell carcinoma Fifty-five tissues samples from patients diagnosed with oesophageal squamous cell carcinoma were used by Akagi et al in order to analyse the expression level of miR-205 using real-time PCR [123] It was shown that over-expressed miR-205 was linked to lymph node metastasis in patients with oesophageal squamous cell carcinoma, implying that miR-205 expression could indicate the progression of oesophageal squamous cell carcinoma [123] In the other study, Zhao et al noted that miR-205 was among those miRNAs which was over-expressed in oesophageal squamous cell carcinoma samples from patients with better prognosis [124] Collectively, oncogenic role of miR-205 has been indicated in oesophageal carcinoma Furthermore, the altered expression level of miR-205 can be useful to classify different types of oesophageal carcinomas, suggesting the specific biomarker potential of miR-205 Profiling the expression of 470 human miRNAs in tissue samples ranging from low grade, high grade dysplasia of Barrett’s oesophagus to oesophageal adenocarcinoma and normal samples, Yang et al demonstrated that while miR205 expression was not having any noticeable expression difference in low grade dysplasia, miR-205 expression was significantly lower in high grade dysplasia of Barrett’s oesophagus and oesophageal adenocarcinoma in comparison to normal tissues [116] Also, Wijnhoven and colleagues noted that 377 human miRNAs were interrogated in tissue samples of 16 individuals diagnosed with Barrett’s oesophagus, oesophageal adenocarcinoma and also their normal samples, among which miR-205 expression was found to be significantly reduced in Barrett’ s oesophagus and oesophageal adenocarcinoma when compared to normal tissues [117] In addition, there was another study in 2013 that confirmed this finding in 105 tissue samples of oesophageal carcinoma [118] miR-205 AND FEMALE GENITAL TRACT CANCERS miR-205 AND OESOPHAGEAL CANCERS Ovarian Cancer Epithelial ovarian cancer is the most common type of ovarian cancer in adult Many histological types of carcinomas are noted In a study of 15 normal and 69 snapfrozen malignant ovarian carcinomas of different histological types, Iorio and colleagues determined that DNA hypomethylation is associated with miR-205 up-regulation in ovarian carcinomas compared with normal ovarian tissues [125] In another study, endometrioid type of ovarian carcinomas showed overexpression of miR-205 [126] Chen et al investigated the role of miR-205 in the epithelial mesenchymal transition process of ovarian cancer cell lines, indicating that the expression of this miRNA was lower in moderately-differentiated papillary cystadenocarcinoma with mesenchymal properties compared 630 Current Cancer Drug Targets, 2014, Vol 14, No to poorly- differentiated papillary epithelial ovarian cancer cell characterized with epithelial features This result confirmed the usefulness of miR-205 as a biomarker of epithelial-mesenchymal transition [127] CD133+ spheroid-forming are reported to be one of the main features of ovarian stem cell miR-205 was determined to be significantly elevated in a CD133+ spheroid-forming subpopulation of ovarian cancer cells relative to the adherent culture condition, implying that miR-205 dysregulation could be a key player in the stem cell-like properties of ovarian cancer stem cells [128] Also, Zheng et al found that miR-205 had higher expression in plasma of cancer patients compared to unaffected patients [129] According to this finding, miR-205 could potentially act as a biomarker for early detection of ovarian cancer [129] ENDOMETRIAL CANCER While examining the role of miRNAs in carcinogenesis in endometrioid carcinoma, Wu et al noted that miR-205 expression was significantly elevated in cancerous tissue samples compared to normal counterparts [130] Also, in a study by Chung et al., the expression of miR-205 was found to be highly over-expressed in endometrioid carcinoma in comparison to normal samples [131] Moreover, it has been reported that the aberrant expression of miR-205 was linked to advanced staged endometrial carcinoma They further identified JPH-4 (junctophilin 4) as a novel target of miR205 and tumour suppressor in endometrioid carcinoma, whose ectopic expression was detected after miR-205 inhibition in endometrial cancer cell line [131] In agreement with former findings, Hiroki et al noted that miR-205 was up-regulated in endometrial serous carcinoma when compared to non-cancer tissue samples [132] They reported that this miRNA presented the highest level of over-expression amongst a total 66 miRNAs upregulated [132] In addition, Lee and colleague noted that miR-205 was highly elevated expressed in endometrial cancer relative to normal samples [133] Karaayvaz and co-workers identified significant overexpression of miR-205 in endometrial cancer, which was associated with poorer patient survival rate, suggesting the promising potential of this miRNA as a prognostic marker of endometrial cancer [134] Furthermore, PTEN expression was reduced in endometrial carcinoma This gene was shown to be a target of miR-205 in this cancer, as has been shown in other cancer types Oestrogen-related receptor γ (ESRRG) has also been determined to be another direct target of miR-205 in in endometrioid carcinoma [135] Over-expression of miR-205 could increase endometrial cell proliferation, migration and invasion through targeting ESRRGγ which is a tumour suppressor Therefore, a more extensive investigation of molecular mechanisms of oncogenesis by miR-205 and ESRRGγ may be useful for management of endometrioid carcinoma [135] CERVICAL CANCER The major type of cervical cancer is squamous cell carcinoma Vosgha et al Xie and colleagues demonstrated that miR-205 was overexpressed in cervical cancer tissues when compared with normal samples [136] The oncogenic role of miR-205 was confirmed by detection of increasing cell proliferation and migration of cervical cancer cells with increased miR-205 expression In addition, two members of the CCN (Cyr61, CTGF and Nov) family of growth regulators—cysteine-rich 61 (CYR61) and connective tissue growth factor (CTGF) are implicated in cell proliferation, metastasis and angiogenesis pathways These members have been shown to be downregulated in cervical cancer and were identified as targets for miR-205 Therefore, miR-205 along with its targets could be directly associated with cervical cancer pathogenesis [136] miR-205 can also be regulated by the E7 onco-protein of human papilloma virus type-16 (HPV-16) in human foreskin keratinocytes, which potentially affects proliferation and differentiation of human foreskin keratinocytes [137] It is speculated that E7 is able to release E2F through inactivation of Rb, leading to promoting the expression of miR-184 as an antagomiR of miR-205 Elevated miR-184 can suppress miR-205 expression and eventually impair human foreskin keratinocytes proliferation and differentiation [137] This control of miR-205 by the E7 oncoprotein may have implications for cervical carcinoma as well In summary, miR-205 not just can be considered as a diagnostic and prognostic biomarker of female genital tract cancers but also the therapeutic potential of miR-205 to hinder tumour progression can offer a new hope for cancer cure miR-205 AND LEUKEMIA Two studies performed by Dou and colleagues have demonstrated that miR-205 plays a vital role in an acute lymphoblastic leukaemia [138, 139] They indicated that MLL-AF4, an integral oncogene in tumourigenicity of acute lymphoblastic leukaemia, was found to be directly targeted by miR-205 This data was confirmed when the luciferase activity of a reporter plasmid containing the 3’-UTR sequence complementary to MLL-AF4 notably decreased upon over-expression of miR-205 In the following study, they reported that up-regulated miR-205 was involved in reduced MLL-AF4 expression at both mRNA and protein levels, resulting in cell proliferation repression and apoptosis induction In addition, miR-205 was found to be implicated in down-regulating two genes downstream of MLL-AF4, HOXA7 and HOXA9, suggesting the further regulatory function of this miRNA in acute lymphoblastic leukaemia [138, 139] Thus, miR-205 can exert a key role in the malignancy of leukemia cell lines by directly regulating its targets and propose a promising novel treatment for this type of cancer miR-205 AND BRAIN CANCER The most common brain cancer is different types of glioma Yue and colleagues showed for the first time the tumour suppressive role of miR-205 in human glioblastoma Significant miR-205 down-expression was detected in both miR-205 in Normal Physiology and Cancer Current Cancer Drug Targets, 2014, Vol 14, No glioma cell lines and tissue samples [140] They further found that induced expression of miR-205 inhibited cell growth, cell invasiveness and promoted cell apoptosis via down-regulating VEGF-A, implying the important roles of this miRNA in glioma and its potentially therapeutic ability Consistent with the finding of this study, Hou and colleagues reported the considerable down-regulation of miR-205 in human glioma tissue samples relative to normal counterparts [141] With regard to prognostic value of miR-205, the low miR-205 expression in gliomas was associated with poor prognosis observed in patients [140, 141] miR-205 has also been reported as a tumour suppressor in glioblastoma cell lines Expression of miR-215 could down-regulate the expression of low-density lipoprotein receptor-related protein (LRP-1) which is a crucial factor in human diseases pathogenesis, resulting in inhibition of tumour cell migration [84] Collectively, these results showed the direct association of low expression of miR-205 with glioma progression miR-205 AND RENAL CANCER The most common histological type of renal cancer is clear cell renal cell carcinoma In vitro experiments done by Majid et al demonstrated that miR-205 is significantly reduced in renal cancer cell lines as well as tumour tissues in comparison to normal samples [142] Src, Lyn and Yes, three members of Src family of protein kinases (SEK), were detected as direct targets of miR-205 in renal cancer They found that ectopic expression of miR-205 could suppress the expression of these genes, leading to inhibited cancer cell proliferation and inducing apoptosis through inactivation of ERK1/2 and decreasing the expression of c-Myc and cyclin-D1 Src suppression via miR-205 over-expression could also repress the activity of focal adhesion kinase (FAK) and signal transducer and activator of transcription (STAT3) which significantly diminished cell migration and invasion Also, an in vivo experiment was done to confirm the cancer-cellgrowth inhibitory role of miR-205 in renal cancer [142] Therefore, the tumour suppressive regulatory function of miR-205 in renal cancer can be considered as a promising treatment method to reduce the tumour progression miR-205 AND CANCERS GASTROINTESTINAL TRACT Colon Cancer Colon cancer is mainly composed of adenocarcinoma Wang and colleagues revealed the down-regulation of miR-205 in nasopharyngeal carcinoma-associated gene (NGX6)-positive colon cancer cells when compared to negative ones [143] NGX6 is a tumour suppressor in colon cancer, which has a regulatory role in apoptosis, cell migration and in activation of JNK (c-Jun N-terminal kinases) and Notch pathways via mediatory function of miRNAs NGX6 was able to suppress the expression of miR-205 in colon cancer cell lines Furthermore, HEY2 (Hairy/enhancer-ofsplit related with YRPW motif protein 2) and NOTCH2, which are important factors in Notch pathways They are implicated in cell differentiation and tumour formation 631 and noted to targets of miR-205 in colon carcinoma cells [143] LIVER CANCERS The two main types of liver cancers are hepatocellular carcinomas and cholangiocarcinomas There are a few studies regarding the modulatory role of miR-205 in hepatocellular carcinoma [144-146] In 2013, Zhang et al showed the interaction between miR-205 and hepatitis B virus X protein (HBx) in development of hepatocellular carcinoma [144] The decreased expression of miR-205 was detected in hepatocellular carcinoma tissues compared with normal samples Moreover, HBx has been found as a direct target of miR-20 Induced expression was able to down-regulate the expression of HBx and to impede hepatoma cell proliferation both in vitro and in vivo They also indicated that the tumour suppressive function of miR205 could be affected by HBx-induced hyper-methylation of the miR-205 promoter Therefore, miR-205 might be considered as a potential therapeutic target of hepatocellular carcinoma [144] In another study from the same group to assess the mechanism of abnormal lipid metabolism in hepatocellular carcinoma, Cui et al found acyl-CoA synthesis long-chain family member and (ACSL1), as key factors in this process, could be targeted by miR-205 [145, 146] Down-regulated miR-205 in hepatocellular carcinoma was able to increase the expression of ACSL1 and 4, resulting in increasing the triglyceride and cholesterol levels in hepatoma cells which are involved in liver cancer progression [145, 146] Okamoto et al demonstrated that expression of miR-205 in cholangiocarcinoma cells could be applicable to enhance gemcitabine sensitivity to these cells, implying that different expression levels of miR-205 would be a beneficial diagnostic marker for gemcitabine therapy [147] PANCREATIC CANCER Pancreatic cancer is mainly composed of adenocarcinoma Pancreatic cancer has been found to have downregulation of miR-205 [148] Singh and co-workers showed that this reduced expression of miR-205 could increase chemo-resistance to gemcitabine in highly aggressive pancreatic adenocarcinoma cell lines This was done through targeting TUBB3 (tubulin, beta class III) which is a regulator of chemotherapy resistance in several cancers [148] Furthermore, they demonstrated that cancer stem cells were able to make cells more resistant to chemotherapy due to alcohol dehydrogenase activity Ectopic expression of miR-205 and down-regulated TUBB3 have been shown to diminish the expression of OCT3/4 and CD44 (stem cell markers), repress the cancer stem cells activity and subsequently restore gemcitabine sensitivity Hence, miR205 could be an option for pancreatic cancer therapy [148] Taken together, the results from the studies on gastrointestinal tract cancers illustrate that miR-205 has a role a tumour suppressor which can regulate cell proliferation and invasion through multiple pathways Thus, its capability in gastrointestinal cancer therapy could be possible 632 Current Cancer Drug Targets, 2014, Vol 14, No Vosgha et al TUMOUR SUP PPRESSOR ROLE miR-2 205 Zeb1, PKC E2F1, Epithelial mesenchymal transitiion Bcl2 Bcl2l2 C-SRC HBx TuBB3 Axiin2 PCNA DHFR LR RP-1 MED-1 ITG55 LAMC1 Her 2, hnRNP-K MLL-AF4 Apoptosis inhibition Cancer Cell Prolifeeration PHLPP-2 CTGF CYR61 ESRRRG VEGF-A A Angiogenesis P PTEN m miR-205 O Oncogene ONCO OGENIC ROLE TTumour suppresssor gene Fig (1) Tumour suppressor or oncogenic roles of miR-205 in malignancy miRNA 205 can control and inhibit the expression of oncogenes in normal situation Under-expression of miR-205 in cancer will let those oncogenes activate and promote different malignant pathways including cell proliferation, apoptosis inhibition, angiogenesis and epithelial mesenchymal transition miRNA 205 can also act as the moderator of tumour suppressor genes in normal situation The increased expression of this miRNA in some cancers caused inhibition of the tumour suppressors, therefore inhibition of their control over suppression of malignant pathways such as cancer cell proliferation miR-205 AND DERMATOFIBROSARCOMA PROTUBERANS Dermatofibrosarcoma protuberans is an uncommon neoplasm of the dermis layer of the skin The tumour suppressive role of miR-205 in dermatofibrosarcoma protuberans was identified by Kajihara et al They noted that miR-205 was down-regulated in dermatofibrosarcoma protuberans in comparison to normal skin and dermatofibroma [149] Low-density lipoprotein receptor-related protein-1 (LRP-1) has also been recognized as a target of miR-205 in this tumour Inhibition of miR-205 expression increased the expression of LRP-1 and activated cell proliferation through promoting ERK (extracellular signal-regulated kinase) phosphorylation Thus, activation of ERK and abnormal cell growth is a major role of miR-205 and LRP-1 correlation in dermatofibrosarcoma protuberans [149] Therefore, miR-205 as a tumour suppressor in this cancer can play an integral role as an effective therapeutic tool FUTURE PERSPECTIVE miR-205 is unlikely to be the sole controller of carcinogenesis including angiogenesis, proliferation, apoptosis and metastasis in cancer However, this review demonstrates miR-205 as a promising perspective in future miRNA-based treatment to affect cancer development Perhaps, future research involving more functional studies, investigating its role through cancer development in vivo, treatment aspect in those models will accelerate the transition of this application into clinical treatment Novel models can be built to help resolve the diversity in the roles of miR-205 in different cancers on the basis of biological findings, targeting specific functionality of this microRNA in each cancer CONCLUSION Accumulating evidence has demonstrated that dualfunctional miR-205 may contribute both in normal physiological processes, including wound healing and in development of pathological events such as cancers The tissue-type origin of the cancer and target genes therein is thus far the only logical determinant for the dual roles of miR-205 As a tumour suppressor or oncogene, miR-205 could effectively impair or promote cancer progression through a wide variety of cellular and molecular signalling pathways; cell proliferation, programmed cell death, miR-205 in Normal Physiology and Cancer epithelial-mesenchymal transition and angiogenesis to name a few (Fig 1) Down-regulation of miR-205 has been reported in a number of cancers, including cancer of breast, prostate, bladder and oesophagus On the other hand, miR205 has also been detected as up-regulated in ovarian, endometrial carcinoma, head and neck squamous carcinoma, bladder carcinoma and oesophageal squamous carcinoma The variation of miR-205 expression may act as a diagnostic and/or prognostic biomarker tool in human cancers, with different relationships in various cancers and their subtypes More importantly, appreciation of molecular function of miR-205 in initiation and progression of cancer via targeting numerous tumour suppressor genes and oncogenes could help us to address a cancer therapeutic issue and to open new avenues for gene therapy in those cancers where its tumour suppressive functions are dominant CONFLICT OF INTEREST The authors wish to state that they have no conflicts of interest or disclosures to make ACKNOWLEDGEMENTS All the authors were involved in writing the manuscript Haleh Vosgha did the first draft Ali Salajegheh contributed to the figure and the review Robert Anthony Smith & Alfred King-Yin Lam contributed to the final critical review and edit of the manuscript Current Cancer Drug Targets, 2014, Vol 14, No [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] REFERENCES [1] [2] 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