mir 134 a human cancer suppressor

Accepted Manuscript MiR-134: a human cancer suppressor? Jing-Yu Pan, Feng Zhang, Cheng-Cao Sun, Shu-Jun Li, Guang Li, Feng-Yun Gong, Tao Bo, Jing He, Rui-Xi Hua, Wei-Dong Hu, Zhan-Peng Yuan, De-Jia Li PII: S2162-2531(16)30360-2 DOI: 10.1016/j.omtn.2016.11.003 Reference: OMTN To appear in: Molecular Therapy: Nucleic Acid Please cite this article as: Pan J-Y, Zhang F, Sun C-C, Li S-J, Li G, Gong F-Y, Bo T, He J, Hua R-X, Hu W-D, Yuan Z-P, Li D-J, MiR-134: a human cancer suppressor?, Molecular Therapy: Nucleic Acid (2017), doi: 10.1016/j.omtn.2016.11.003 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT MiR-134: a human cancer suppressor? Jing-Yu Pan1,#, Feng Zhang1,#, Cheng-Cao Sun1,#,*, Shu-Jun Li1,2, Guang Li3, and De-Jia Li1,* RI PT Feng-Yun Gong4, Tao Bo4, Jing He5, Rui-Xi Hua6, Wei-Dong Hu7, Zhan-Peng Yuan8, Department of Occupational and Environmental Health, School of Public Health, SC Wuhan University, 430071 Wuhan, Hubei, P R China; Wuhan Hospital for the Prevention and Treatment of Occupational Diseases, 430015 M AN U Wuhan, Hubei, P R China; Department of Oncology, Wuhan Pu-Ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430034 Wuhan, Hubei, P R China; Department of Infectious Diseases, Wuhan Medical Treatment Center, 430023 Wuhan, Hubei, P R China; Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou TE D Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, Guangdong, P R China; Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, EP 510080 Guangzhou, Guangdong, P R China; Department of Oncology, ZhongNan Hospital of Wuhan University, 430071 Wuhan, AC C Hubei, P R China; Department of toxicology, School of Public Health, Wuhan University, 430071 Wuhan, P R China # Jing-Yu Pan, Feng Zhang, Cheng-Cao Sun contribute equal to this work; * Corresponding Author Corresponding author: De-Jia Li; No.115 Donghu Road, Wuchang District, Wuhan, China; Tel: (86) ACCEPTED MANUSCRIPT 18271470520; E-mail address: lodjlwhu@sina.com Cheng-Cao Sun; No.115 Donghu Road, Wuchang District, Wuhan, China; Tel: (86) SC RI PT 18162634120; E-mail address: chengcaosun@whu.edu.cn Abstract: MicroRNAs (miRNAs) are small noncoding RNAs with approximately 20 M AN U to 25 nucleotides in length, which play crucial roles through directly binding to corresponding 3’-UTR of targeted mRNAs It has been reported that miRNAs involve in numerous of diseases, including cancers Recently, miR-134 has been identified to dysregulate in handles of human cancers, such as lung cancer, glioma, breast cancer, TE D colorectal cancer and so on Increasing evidence indicates that miR-134 is essential for human carcinoma and participates in tumor cell proliferation, apoptosis, invasion and metastasis, drug resistance as well as cancer diagnosis, treatment and prognosis EP Nevertheless, its roles in human cancer are still ambiguous, and its mechanisms are sophisticated as well, referring to a variety of targets and signal pathways, such as AC C STAT5B, KRAS, MAPK/ERK signal pathway, Notch pathway, etc Herein, we review the crucial roles of miR-134 in scores of human cancers via analyzing latest investigations, which might provide evidence for cancer diagnose, treatment, prognosis or further investigations Keywords: miR-134; human cancer; microRNA ACCEPTED MANUSCRIPT Abbreviations EMT: Epithelial-mesenchymal transition MAPK: Mitogen-activated protein kinase; MPE: Malignant pleural effusion; ROC: receiver operating characteristic; NSCLC: non-small cell lung cancer; TGF-β1: transforming growth factor-β1; SCLC: small cell lung cancer; RI PT PARP：poly (ADP-ribose) polymerase; region; miRNA: microRNA; M AN U KRAS: Kirsten rat sarcoma viral oncogene; 3’-UTR: 3’-untranslated SC WWOX: WW domain-containing oxidoreductase HNSCC: head and neck squamous cell carcinomas; 5-FU: 5-fluorouracil; EGFR: epidermal growth factor receptor kinases RTK: receptor tyrosine TE D STAT3: signal transducer and activator of transcription ERK: signal-regulated kinase Bcl-2: B-cell lymphoma-2 AUC: area under the curve DPD: dihydropyrimidine dehydrogenase 1; EP ABCC1: ATP Binding Cassette C1 APE1: Apurinic/apyrimidinic endonuclease AC C DLK1-DIO3: delta-like homolog gene and the type III iodothyronine deiodinase gene RI PT ACCEPTED MANUSCRIPT Introduction SC Cancers, the leading part of death-related diseases in humans, have long been severely threated to human health Multitudes of people are diagnosed or dead from M AN U cancers every year In America, cancers have been the second major death reason, which are barely inferior to heart diseases Siegel et al reported that there might be newly diagnosed 1,658,370 cancer patients and 589,430 cancer deaths in 2015.1 In China, Chen et al collected information of 72 cancer registries which indicated about TE D 12,000 new cancer cases occur every day, and it would be increased to approximately 4,292,000 new cases in 2015.2 Moreover, cancers lead to increase in severe disease burthen and hamper economy development.3 Therefore, it is imperative to investigate EP the correlation between cancers and its risk factors, especially the molecular mechanisms of cancers, which might contribute to develop novel and effective AC C pharmaceutics or treatments MicroRNAs (miRNAs) are characterized as a group of small noncoding RNAs with approximately 20 to 25 nucleotides in length, which play key roles by binding to cor responding 3’-UTR of targeted mRNAs.4-6 MiRNAs regulate approximately 30%-50% human genes expression.7,8 Recently, numerous of researches have reported the roles of miRNAs in several human diseases, especially in cancers Massive ACCEPTED MANUSCRIPT evidence indicates miRNAs could function as modulators in multiple pathological and biological progressions, such as cancer cell differentiation, proliferation and apoptosis, RI PT etc Additionally, miRNAs are described as a kind of emerging clinical, diagnostic, and prognostic biomarkers, as well as treatment approaches.9,10 Sun et al have explored the association between miRNAs and non-small cell lung cancer (NSCLC), miR-139-5p, miR-187, miR-206, miR-326, and miR-329 were SC revealing down-regulated in lung cancer cell lines and tissues, and played tumor-suppressive M AN U roles by targeting specific 3’-UTR of mRNAs for several oncogenes.11-15 However, there are also scores of miRNAs over-expressed in various cancers, including gastric cancer, bladder carcinoma, NSCLC, and breast cancer and so on, which might promote cancer development and malignancy.16-20 Moreover, investigations suggested TE D that miRNAs functioned as vital modulators in DNA damage with ionizing irradiation engendered, and what’s more, a subset of miRNAs signature has been verified that could response to radiotherapy in HNSCC.21 Chen and colleagues found no more than EP a few miRNA-based treatments were applied for clinical trial, which was not appropriate to glioblastoma.22 However, we suppose that miRNA-based medicine AC C might be a novel and promising method to against various tumors in the future with unknown fields between miRNAs and cancer discovered MiR-134 belongs to chromosome 14q32 miRNAs clusters, and it has been reported that DLK1-DIO3 appears differentially methylated region leads to abnormal expression of 14q32 gene clusters.23,24 MiR-134 was found to regulate dendritic spine development through targeting Limk1 mRNA in rat hippocampal neurons.25 Recently, ACCEPTED MANUSCRIPT it has been reported that miR-134 also plays a crucial role in enhancing hippocampal memory and synaptic plasticity through RI PT 2,3,5,4’-tetrahydroxystilbene-2-O-β-D-glucoside treatment in normal mice.26 Fiore et al discovered miR-134 acted as a vital regulator in homeostatic synaptic repression by targeting Pumilio-2.27 Furthermore, miR-134 was monitored to involve in condition of SC epilepticus, as evidenced by the fact that miR-134 protected neuro and decreased epilepticus seizure.28 Recently, miR-134 has been reported to participate in a mass of M AN U carcinomas and tumors Upregulation of miR-134 was observed in lung tumor, pancreatic cancer, colon cancer and prostate cancer, whereas down-regulation of it was also found in a variety of cancers, including NSCLC, glioblastomas, breast cancer, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, osteosarcoma, etc TE D (Table 1) These findings suggested miR-134 might present some characters in tumor progression Consistently, it has been reported that miR-134 played a critical role in cancer cell proliferation, apoptosis, invasion and metastasis, drug resistance as well as EP cancer diagnosis, treatment and prognosis For instance, Liu et al found miR-134 markedly decreased in renal cell carcinoma cells and tissues, and restoration of its AC C expression was able to refrain cell proliferation by silencing G0/G1 phase.41 Over-expressed miR-134 could also refrain cell metastasis in endometrial tumor.50 Furthermore, miR-134 could also regulate drug resistance through targeting ABCC1 in breast cancer cells, meanwhile it also participated in drug resistant in ovarian carcinoma and SCLC cells Suggesting the mechanisms of miR-134 in different carcinomas might be diverse In addition, miR-134 targeted multiple genes in tumors, ACCEPTED MANUSCRIPT such as KRAS, STAT5B, Nanog, FOXM1, EGFR, etc (Table 1) Despite functioning as modulators in cancers, miR-134 affected abundant and complicated signal RI PT pathways, including MAPK/ERK signal pathway, EGFR pathway, Notch pathway, etc In this review, we synthesize the roles and mechanisms of miR-134 in cancer cell SC proliferation, apoptosis, invasion and metastasis, drug resistance, cancer diagnosis as well as patients’ survival and prognosis, to provide intuitionistic evidence for clinical MiR-134 in cell proliferation M AN U applications and further investigations in the future Increasing evidence indicates miR-134 associates with various genes mediating TE D cancer cell proliferation Cyclin D and CDK4 are discovered to be upregulated in a variety of human cancer cells.60 P21 gene, a cell growth regulator, is found to involve in cancerous cell cycle arrest at G1 phase.61,62 Sun et al disclosed that miR-134 EP increased p21 expression and suppressed cyclin D1, cyclin D2 and CDK4 proteins expression in SPC-A1 and A549 cells, which indicated miR-134 could repress AC C NSCLC cells proliferation.30 In another study, increasing miR-134 expression suppressed lung cancer cells proliferation by down-regulating EGFR.32 It has been reported that EGFR possessed effect of resistance to cancer procession and development.63 MiR-134 was also found to associate with cancer treatment as well as trigger numerous pathways, such as MAPK pathway, PI3K–AKT–mTOR pathway.64 Qin et al found EGFR was an appropriate target of miR-134 in NSCLC cells, and ACCEPTED MANUSCRIPT upregulation of miR-134 inhibited EGFR-correlated signal pathway After being transfected mimics of miR-134, protein level of p-Akt was downregulated in H1299, RI PT H520 as well as A549 cell lines; pERK1/2 yield was reduced in A549, H520 and H1975 cell lines; p-STAT3 expression was decreased in H1299 and H520 cells These data suggested miR-134 repressed NSCLC cells proliferation via targeting EGFR and SC activating corresponding pathways.32 Consistently, that evidence uncovered mutant KRAS played a critical modulator in the EGFR signaling cascade through repressing M AN U miR-4689 to modulate both PI3K/AKT and RAS/ MAPK pathways in colorectal cancer.65 In addition, miR-134 was also demonstrated to downregulate in glioma tumor and overexpressed miR-134 inhibited glioma cell growth through targeting KRAS and TE D activating the ERK pathway.33 Overexpression of miR-134 significantly repressed cell proliferation and xenograft development in another investigation of glioblastoma tumor 36 Zhang et al confirmed that miR-134 expression was remarkably decreased in EP glioblastoma, and had an opposite correlation with MET, and other proteins, including RTKs EGFR and PDGFR.36 Additionally, miR-134 also functioned as a tumor AC C suppressor via downregulating KRAS and STAT5B expression.36 It was also verified in another study about glioblastoma that miR-134 suppressed tumor progression and proliferation in vivo and in vitro.37 Liu et al found miR-134 expression markedly decreased in renal cell carcinoma cells and tissues compared with that of normal cells and tissues, and restoration of its expression was able to refrain cell proliferation by silencing G0/G1 phase.41 In addition, miR-134 expression was discovered to increase ACCEPTED MANUSCRIPT in colon cancer patients’ stool,56 whereas it was found to appear an opposite outcome of expression in colorectal tumor that remarkably decreased in tumor tissues and cell RI PT lines Overexpression of miR-134 resulted in repression of colorectal cancer cell proliferation and growth.43,44 It has been reported that 1,25-(OH)2D3 involved in prostate carcinoma and played an inhibitory role in tumor cells proliferation After SC transfecting it into cancer cells, miR-134 expression was noticeably upregulated, which verified 1,25-(OH)2D3/miR-134 cascade might be a novel point in therapy M AN U cancer.57 C/EBPα gene, a tumor suppressor, was verified to crosstalk with miR-134 in breast cancer, and they were both decreased in cancer tissues as well as repressed tumor cell growth.38 Moreover miR-134 refrained cell growth through targeting POGLUT1 in endometrial tumor cells.50 Another investigation revealed that TE D epidermal growth factor receptor was determined as a corresponding target of miR-134.39 However, the role of miR-134 in breast cancer has not been further investigated EP Nevertheless, Chen et al discovered miR-134 exerted reverse role in SCLC cells, and after transfecting miR-134 mimics and its negative control into H69 cell, the AC C ability of cell proliferation was enhanced The opposite phenomenon was observed after transfecting miR-134 inhibitor and its negative control to cells.66 The ERK signaling pathway, a crucial downstream signal, was found to participate in cell development and progression.67-69 Chen et al also explored the mechanisms of miR-134 in SCLC cells, observing WWOX was a qualified target of miR-134.66 Moreover, enhancing miR-134 expression led to lower expression of pERK,70 which ACCEPTED MANUSCRIPT 48 Zha R, Guo W, Zhang Z, Qiu Z, Wang Q, Ding J, et al (2014) Genome-wide screening identified that miR-134 acts as a metastasis 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Dziadek J TE D 108 and Strapagiel D (2015) Genetic variation of the ABC transporter gene ABCC1 (Multidrug resistance protein 1-MRP1) in the Polish population BMC 109 EP Genet 16:114 Leschziner G, Zabaneh D, Pirmohamed M, Owen A, Rogers J, Coffey AJ, et AC C al (2006) Exon sequencing and high resolution haplotype analysis of ABC transporter genes implicated in drug resistance Pharmacogenet Genomics 16:439-50 110 Guo L, Liu Y, Bai Y, Sun Y, Xiao F and Guo Y (2010) Gene expression profiling of drug-resistant small cell lung cancer cells by combining microRNA and cDNA expression analysis Eur J Cancer 46:1692-702 38 ACCEPTED MANUSCRIPT 111 Rho JK, Choi YJ, Lee JK, Ryoo BY, Na, II, Yang SH, et al (2009) Epithelial to mesenchymal transition derived from repeated exposure to gefitinib cancer cell line Lung Cancer 63:219-26 112 RI PT determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung Kitamura K, Seike M, Okano T, Matsuda K, Miyanaga A, Mizutani H, et al MiR-134/487b/655 cluster regulates TGF-beta-induced SC (2014) epithelial-mesenchymal transition and drug resistance to gefitinib by targeting AC C EP TE D M AN U MAGI2 in lung adenocarcinoma cells Mol Cancer Ther 13:444-53 39 ACCEPTED MANUSCRIPT Table miR-134 deregulates in various cancers and its target genes Cancer type Target genes reference Down Lung cancer DPD gene 29 NSCLCa oncogenic 30 FOXM1 NSCLC EGFR gliomas KRAS gliomas glioblastomas 31 M AN U NSCLC 32 SC CCND1 RI PT miR-134 33 … 34, 35 KRAS 、 36 STAT5B Nanog 37 Breast cancer C/EBPα 38 Breast cancer HER2 39 Breast cancer … 40 KRAS 41 Renal Cell Carcinoma … 42 colorectal cancer EGFR 、 43 EP TE D glioblastomas AC C Renal Cell Carcinoma 40 PIK3CA colorectal cancer … 44 gastric cancer … 45, 46 ACCEPTED MANUSCRIPT Hepatocellular KRAS 47 ITGB1 48 Carcinoma Hepatocellular HNSCCb … endometrial cancer POGLUT1 49 50 … M AN U Lung tumors SC 51 osteosarcoma Up RI PT Carcinoma YKT6 53 WWOX gene 54 … 55 … 56 prostate cancer … 57 Uveal melanoma … 58 SCC of Tonguec … 59 NSCLC HNSCC Pancreatic cancer EP TE D colon cancer AC C NSCLCa: non-small cell lung cancer; HNSCCb: head and neck squamous cell carcinoma; SCC of Tonguec: Squamous Cell Carcinoma of Tongue 41 52 ACCEPTED MANUSCRIPT Figure legends Figure MiR-134 associates with various genes mediating cancer cell proliferation RI PT Upregulated-miR-134 inhibits the expression of cyclin D1/cyclin D2/CDK4, KRAS, EGFR, POGLUT1 and STAT5B repressing cell proliferation, while inhibits the expression of pERK and WWOX but increasing proliferation MiR-134 increases the suppression; Red arrows: indicate promotion SC expression of p21 resulting repressing cell proliferation Blue arrows: indicate M AN U Figure MiR-134 functions in cancer invasion and metastasis KRAS, Nanog mRNA, HNF4α, EGFR, ITGB1 and FOXM1 are all target genes of miR-134 and miR-134 inhibits their functions, which results repressing cell invasion and AC C EP TE D metastasis 42 AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ... 16:395-419 Hirata H, Takahashi A, Kobayashi S, Yonehara S, Sawai H, Okazaki T, et al AC C (1998) Caspases are activated in a branched protease cascade and control distinct downstream processes in Fas-induced... confirmed as a credible target of miR- 134, and further exploration indicated that miR- 134 regulated PIK3CA/AKT/mTOR signal pathway.43 Zha et al found miR- 134 was deregulated and EP inhibited carcinoma... osteosarcoma Genet Mol Res 52 TE D 14:16771-81 Mirzadeh Azad F, Naeli P, Malakootian M, Baradaran A, Tavallaei M, Ghanei M, et al (2016) Two lung development-related microRNAs, miR- 134 and 53 EP miR- 187,