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Published in: Cancer Cell International 1/2013

Open Access 01-12-2013 | Primary research

MiR-145 inhibits oral squamous cell carcinoma (OSCC) cell growth by targeting c-Myc and Cdk6

Authors: Yuan Shao, Yiping Qu, Siwen Dang, Bowen Yao, Meiju Ji

Published in: Cancer Cell International | Issue 1/2013

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Abstract

Background

MicroRNAs (miRNAs) are a large group of negative gene regulators that potentially play a critical role in tumorigenesis. Increasing evidences indicate that miR-145 acts a tumor suppressor in numerous human cancers. However, its role in oral carcinogenesis remains poorly defined. The aim of this study is to determine expression levels of miR-145 in oral squamous cell carcinomas (OSCCs) and normal mucosa tissues, and explore its biological functions in OSCCs.

Methods

Reverse transcription quantitative real-time PCR (RT-qPCR) assay was used to evaluate expression levels of miR-145. The biological functions of miR-145 were determined by cell proliferation and colony formation, cell cycle and apoptosis, as well as cell invasion assay.

Results

MiR-145 was frequently down-regulated in OSCCs compared with normal mucosa tissues. Restoring miR-145 expression in OSCC cells dramatically suppressed cell proliferation and colony formation, and induced G1 phase arrest and cell apoptosis. Importantly, our data showed that miR-145 downregulated the expression of c-Myc and Cdk6, which have previously been identified as two direct targets of miR-145.

Conclusions

Our data suggest that miR-145 exerts its tumor suppressor function by targeting c-Myc and Cdk6, leading to the inhibition of OSCC cell growth. MiR-145 rescue may thus be a rational for diagnostic and therapeutic applications in OSCC.
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Literature
2.
go back to reference de Araújo RF, Jr BCA, Clebis NK, de Moura SA, Lopes Costa Ade L: Prognostic significance of the anatomical location and TNM clinical classification in oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal. 2008, 13: E344-347.PubMed de Araújo RF, Jr BCA, Clebis NK, de Moura SA, Lopes Costa Ade L: Prognostic significance of the anatomical location and TNM clinical classification in oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal. 2008, 13: E344-347.PubMed
3.
go back to reference Scully C, Bagan J: Oral squamous cell carcinoma overview. Oral Oncol. 2009, 45: 301-308. 10.1016/j.oraloncology.2009.01.004.CrossRefPubMed Scully C, Bagan J: Oral squamous cell carcinoma overview. Oral Oncol. 2009, 45: 301-308. 10.1016/j.oraloncology.2009.01.004.CrossRefPubMed
4.
go back to reference Ha PK, Califano JA: Promoter methylation and inactivation of tumour-suppressor genes in oral squamous-cell carcinoma. Lancet Oncol. 2006, 7: 77-82. 10.1016/S1470-2045(05)70540-4.CrossRefPubMed Ha PK, Califano JA: Promoter methylation and inactivation of tumour-suppressor genes in oral squamous-cell carcinoma. Lancet Oncol. 2006, 7: 77-82. 10.1016/S1470-2045(05)70540-4.CrossRefPubMed
5.
go back to reference Leemans CR, Braakhuis BJ, Brakenhoff RH: The molecular biology of head and neck cancer. Nat Rev Cancer. 2011, 11: 9-22. 10.1038/nrc2982.CrossRefPubMed Leemans CR, Braakhuis BJ, Brakenhoff RH: The molecular biology of head and neck cancer. Nat Rev Cancer. 2011, 11: 9-22. 10.1038/nrc2982.CrossRefPubMed
6.
go back to reference Ambros V: microRNAs: tiny regulators with great potential. Cell. 2001, 107: 823-826. 10.1016/S0092-8674(01)00616-X.CrossRefPubMed Ambros V: microRNAs: tiny regulators with great potential. Cell. 2001, 107: 823-826. 10.1016/S0092-8674(01)00616-X.CrossRefPubMed
7.
go back to reference Lee RC, Ambros V: An extensive class of small RNAs in Caenorhabditis elegans. Science. 2001, 294: 862-864. 10.1126/science.1065329.CrossRefPubMed Lee RC, Ambros V: An extensive class of small RNAs in Caenorhabditis elegans. Science. 2001, 294: 862-864. 10.1126/science.1065329.CrossRefPubMed
8.
go back to reference Lai EC: Micro RNAs are complementary to 3’ UTR sequence motifs that mediate negative post-transcriptional regulation. Nat Genet. 2002, 30: 363-364. 10.1038/ng865.CrossRefPubMed Lai EC: Micro RNAs are complementary to 3’ UTR sequence motifs that mediate negative post-transcriptional regulation. Nat Genet. 2002, 30: 363-364. 10.1038/ng865.CrossRefPubMed
9.
go back to reference Calin GA, Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 2006, 6: 857-866. 10.1038/nrc1997.CrossRefPubMed Calin GA, Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 2006, 6: 857-866. 10.1038/nrc1997.CrossRefPubMed
10.
go back to reference Esquela-Kerscher A, Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006, 6: 259-269.CrossRefPubMed Esquela-Kerscher A, Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006, 6: 259-269.CrossRefPubMed
11.
go back to reference Kent OA, Mendell JT: A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene. 2006, 25: 6188-6196. 10.1038/sj.onc.1209913.CrossRefPubMed Kent OA, Mendell JT: A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene. 2006, 25: 6188-6196. 10.1038/sj.onc.1209913.CrossRefPubMed
12.
go back to reference Cordes KR, Sheehy NT, White MP, Berry EC, Morton SU, Muth AN, Lee TH, Miano JM, Ivey KN, Srivastava D: miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009, 460: 705-710.PubMedCentralPubMed Cordes KR, Sheehy NT, White MP, Berry EC, Morton SU, Muth AN, Lee TH, Miano JM, Ivey KN, Srivastava D: miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009, 460: 705-710.PubMedCentralPubMed
13.
go back to reference Ostenfeld MS, Bramsen JB, Lamy P, Villadsen SB, Fristrup N, Sørensen KD, Ulhøi B, Borre M, Kjems J, Dyrskjøt L: miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors. Oncogene. 2010, 29: 1073-1084. 10.1038/onc.2009.395.CrossRefPubMed Ostenfeld MS, Bramsen JB, Lamy P, Villadsen SB, Fristrup N, Sørensen KD, Ulhøi B, Borre M, Kjems J, Dyrskjøt L: miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors. Oncogene. 2010, 29: 1073-1084. 10.1038/onc.2009.395.CrossRefPubMed
14.
go back to reference Ozen M, Creighton CJ, Ozdemir M, Ittmann M: Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2008, 27: 1788-1793. 10.1038/sj.onc.1210809.CrossRefPubMed Ozen M, Creighton CJ, Ozdemir M, Ittmann M: Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2008, 27: 1788-1793. 10.1038/sj.onc.1210809.CrossRefPubMed
15.
go back to reference Ichimi T, Enokida H, Okuno Y, Kunimoto R, Chiyomaru T, Kawamoto K, Kawahara K, Toki K, Kawakami K, Nishiyama K: Identification of novel microRNA targets based on microRNA signatures in bladder cancer. Int J Cancer. 2009, 125: 345-352. 10.1002/ijc.24390.CrossRefPubMed Ichimi T, Enokida H, Okuno Y, Kunimoto R, Chiyomaru T, Kawamoto K, Kawahara K, Toki K, Kawakami K, Nishiyama K: Identification of novel microRNA targets based on microRNA signatures in bladder cancer. Int J Cancer. 2009, 125: 345-352. 10.1002/ijc.24390.CrossRefPubMed
16.
go back to reference Akao Y, Nakagawa Y, Naoe T: MicroRNA-143 and −145 in colon cancer. DNA Cell Biol. 2007, 26: 311-320. 10.1089/dna.2006.0550.CrossRefPubMed Akao Y, Nakagawa Y, Naoe T: MicroRNA-143 and −145 in colon cancer. DNA Cell Biol. 2007, 26: 311-320. 10.1089/dna.2006.0550.CrossRefPubMed
17.
go back to reference Akao Y, Nakagawa Y, Kitade Y, Kinoshita T, Naoe T: Downregulation of microRNAs-143 and −145 in B-cell malignancies. Cancer Sci. 2007, 98: 1914-1920. 10.1111/j.1349-7006.2007.00618.x.CrossRefPubMed Akao Y, Nakagawa Y, Kitade Y, Kinoshita T, Naoe T: Downregulation of microRNAs-143 and −145 in B-cell malignancies. Cancer Sci. 2007, 98: 1914-1920. 10.1111/j.1349-7006.2007.00618.x.CrossRefPubMed
18.
go back to reference Villadsen SB, Bramsen JB, Ostenfeld MS, Wiklund ED, Fristrup N, Gao S, Hansen TB, Jensen TI, Borre M, Ørntoft TF: The miR-143/-145 cluster regulates plasminogen activator inhibitor-1 in bladder cancer. Br J Cancer. 2012, 106: 366-374. 10.1038/bjc.2011.520.PubMedCentralCrossRefPubMed Villadsen SB, Bramsen JB, Ostenfeld MS, Wiklund ED, Fristrup N, Gao S, Hansen TB, Jensen TI, Borre M, Ørntoft TF: The miR-143/-145 cluster regulates plasminogen activator inhibitor-1 in bladder cancer. Br J Cancer. 2012, 106: 366-374. 10.1038/bjc.2011.520.PubMedCentralCrossRefPubMed
19.
go back to reference Chiyomaru T, Enokida H, Tatarano S, Kawahara K, Uchida Y, Nishiyama K, Fujimura L, Kikkawa N, Seki N, Nakagawa M: miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer. Br J Cancer. 2010, 102: 883-891. 10.1038/sj.bjc.6605570.PubMedCentralCrossRefPubMed Chiyomaru T, Enokida H, Tatarano S, Kawahara K, Uchida Y, Nishiyama K, Fujimura L, Kikkawa N, Seki N, Nakagawa M: miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer. Br J Cancer. 2010, 102: 883-891. 10.1038/sj.bjc.6605570.PubMedCentralCrossRefPubMed
20.
go back to reference Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS: MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell. 2009, 137: 647-658. 10.1016/j.cell.2009.02.038.CrossRefPubMed Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS: MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell. 2009, 137: 647-658. 10.1016/j.cell.2009.02.038.CrossRefPubMed
21.
go back to reference Sachdeva M, Zhu S, Wu F, Wu H, Walia V, Kumar S, Elble R, Watabe K, Mo YY: p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc Natl Acad Sci USA. 2009, 106: 3207-3212. 10.1073/pnas.0808042106.PubMedCentralCrossRefPubMed Sachdeva M, Zhu S, Wu F, Wu H, Walia V, Kumar S, Elble R, Watabe K, Mo YY: p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc Natl Acad Sci USA. 2009, 106: 3207-3212. 10.1073/pnas.0808042106.PubMedCentralCrossRefPubMed
22.
go back to reference Shi B, Sepp-Lorenzino L, Prisco M, Linsley P, de Angelis T, Baserga R: Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells. J Biol Chem. 2007, 282: 32582-32590. 10.1074/jbc.M702806200.CrossRefPubMed Shi B, Sepp-Lorenzino L, Prisco M, Linsley P, de Angelis T, Baserga R: Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells. J Biol Chem. 2007, 282: 32582-32590. 10.1074/jbc.M702806200.CrossRefPubMed
23.
go back to reference Sachdeva M, Mo YY: MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. Cancer Res. 2010, 70: 378-387. 10.1158/0008-5472.CAN-09-2021.PubMedCentralCrossRefPubMed Sachdeva M, Mo YY: MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. Cancer Res. 2010, 70: 378-387. 10.1158/0008-5472.CAN-09-2021.PubMedCentralCrossRefPubMed
24.
go back to reference Gregersen LH, Jacobsen AB, Frankel LB, Wen J, Krogh A, Lund AH: MicroRNA-145 targets YES and STAT1 in colon cancer cells. PLoS One. 2010, 5: e8836-10.1371/journal.pone.0008836.PubMedCentralCrossRefPubMed Gregersen LH, Jacobsen AB, Frankel LB, Wen J, Krogh A, Lund AH: MicroRNA-145 targets YES and STAT1 in colon cancer cells. PLoS One. 2010, 5: e8836-10.1371/journal.pone.0008836.PubMedCentralCrossRefPubMed
25.
go back to reference Xu Q, Liu LZ, Qian X, Chen Q, Jiang Y, Li D, Lai L, Jiang BH: MiR-145 directly targets p70S6K1 in cancer cells to inhibit tumor growth and angiogenesis. Nucleic Acids Res. 2012, 40: 761-774. 10.1093/nar/gkr730.PubMedCentralCrossRefPubMed Xu Q, Liu LZ, Qian X, Chen Q, Jiang Y, Li D, Lai L, Jiang BH: MiR-145 directly targets p70S6K1 in cancer cells to inhibit tumor growth and angiogenesis. Nucleic Acids Res. 2012, 40: 761-774. 10.1093/nar/gkr730.PubMedCentralCrossRefPubMed
26.
go back to reference Spizzo R, Nicoloso MS, Lupini L, Lu Y, Fogarty J, Rossi S, Zagatti B, Fabbri M, Veronese A, Liu X: miR-145 participates with TP53 in a death-promoting regulatory loop and targets estrogen receptor-alpha in human breast cancer cells. Cell Death Differ. 2010, 17: 246-254. 10.1038/cdd.2009.117.PubMedCentralCrossRefPubMed Spizzo R, Nicoloso MS, Lupini L, Lu Y, Fogarty J, Rossi S, Zagatti B, Fabbri M, Veronese A, Liu X: miR-145 participates with TP53 in a death-promoting regulatory loop and targets estrogen receptor-alpha in human breast cancer cells. Cell Death Differ. 2010, 17: 246-254. 10.1038/cdd.2009.117.PubMedCentralCrossRefPubMed
27.
go back to reference Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H: MicroRNA signatures in human ovarian cancer. Cancer Res. 2007, 67: 8699-8707. 10.1158/0008-5472.CAN-07-1936.CrossRefPubMed Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H: MicroRNA signatures in human ovarian cancer. Cancer Res. 2007, 67: 8699-8707. 10.1158/0008-5472.CAN-07-1936.CrossRefPubMed
28.
go back to reference Suh SO, Chen Y, Zaman MS, Hirata H, Yamamura S, Shahryari V, Liu J, Tabatabai ZL, Kakar S, Deng G: MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer. Carcinogenesis. 2011, 32: 772-778. 10.1093/carcin/bgr036.PubMedCentralCrossRefPubMed Suh SO, Chen Y, Zaman MS, Hirata H, Yamamura S, Shahryari V, Liu J, Tabatabai ZL, Kakar S, Deng G: MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer. Carcinogenesis. 2011, 32: 772-778. 10.1093/carcin/bgr036.PubMedCentralCrossRefPubMed
29.
go back to reference Kent OA, Chivukula RR, Mullendore M, Wentzel EA, Feldmann G, Lee KH, Liu S, Leach SD, Maitra A, Mendell JT: Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway. Genes Dev. 2010, 24: 2754-2759. 10.1101/gad.1950610.PubMedCentralCrossRefPubMed Kent OA, Chivukula RR, Mullendore M, Wentzel EA, Feldmann G, Lee KH, Liu S, Leach SD, Maitra A, Mendell JT: Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway. Genes Dev. 2010, 24: 2754-2759. 10.1101/gad.1950610.PubMedCentralCrossRefPubMed
30.
go back to reference Yu T, Wang XY, Gong RG, Li A, Yang S, Cao YT, Wen YM, Wang CM, Yi XZ: The expression profile of microRNAs in a model of 7,12-dimethyl-benz[a]anthrance-induced oral carcinogenesis in Syrian hamster. J Exp Clin Cancer Res. 2009, 28: 64-10.1186/1756-9966-28-64.PubMedCentralCrossRefPubMed Yu T, Wang XY, Gong RG, Li A, Yang S, Cao YT, Wen YM, Wang CM, Yi XZ: The expression profile of microRNAs in a model of 7,12-dimethyl-benz[a]anthrance-induced oral carcinogenesis in Syrian hamster. J Exp Clin Cancer Res. 2009, 28: 64-10.1186/1756-9966-28-64.PubMedCentralCrossRefPubMed
31.
go back to reference Zhu H, Dougherty U, Robinson V, Mustafi R, Pekow J, Kupfer S, Li YC, Hart J, Goss K, Fichera A: EGFR signals downregulate tumor suppressors miR-143 and miR-145 in Western diet-promoted murine colon cancer: role of G1 regulators. Mol Cancer Res. 2011, 9: 960-975. 10.1158/1541-7786.MCR-10-0531.CrossRefPubMed Zhu H, Dougherty U, Robinson V, Mustafi R, Pekow J, Kupfer S, Li YC, Hart J, Goss K, Fichera A: EGFR signals downregulate tumor suppressors miR-143 and miR-145 in Western diet-promoted murine colon cancer: role of G1 regulators. Mol Cancer Res. 2011, 9: 960-975. 10.1158/1541-7786.MCR-10-0531.CrossRefPubMed
34.
go back to reference de Nigris F, Sica V, Herrmann J, Condorelli G, Chade AR, Tajana G, Lerman A, Lerman LO, Napoli C: c-Myc oncoprotein: cell cycle-related events and new therapeutic challenges in cancer and cardiovascular diseases. Cell Cycle. 2003, 2: 325-328.CrossRefPubMed de Nigris F, Sica V, Herrmann J, Condorelli G, Chade AR, Tajana G, Lerman A, Lerman LO, Napoli C: c-Myc oncoprotein: cell cycle-related events and new therapeutic challenges in cancer and cardiovascular diseases. Cell Cycle. 2003, 2: 325-328.CrossRefPubMed
35.
36.
37.
go back to reference Chen Z, Zeng H, Guo Y, Liu P, Pan H, Deng A, Hu J: miRNA-145 inhibits non-small cell lung cancer cell proliferation by targeting c-Myc. J Exp Clin Cancer Res. 2010, 29: 151-10.1186/1756-9966-29-151.PubMedCentralCrossRefPubMed Chen Z, Zeng H, Guo Y, Liu P, Pan H, Deng A, Hu J: miRNA-145 inhibits non-small cell lung cancer cell proliferation by targeting c-Myc. J Exp Clin Cancer Res. 2010, 29: 151-10.1186/1756-9966-29-151.PubMedCentralCrossRefPubMed
38.
go back to reference Larsson E, Fredlund Fuchs P, Heldin J, Barkefors I, Bondjers C, Genové G, Arrondel C, Gerwins P, Kurschat C, Schermer B: Discovery of microvascular miRNAs using public gene expression data: miR-145 is expressed in pericytes and is a regulator of Fli1. Genome Med. 2009, 1: 108-10.1186/gm108.PubMedCentralCrossRefPubMed Larsson E, Fredlund Fuchs P, Heldin J, Barkefors I, Bondjers C, Genové G, Arrondel C, Gerwins P, Kurschat C, Schermer B: Discovery of microvascular miRNAs using public gene expression data: miR-145 is expressed in pericytes and is a regulator of Fli1. Genome Med. 2009, 1: 108-10.1186/gm108.PubMedCentralCrossRefPubMed
39.
go back to reference Speranza MC, Frattini V, Pisati F, Kapetis D, Porrati P, Eoli M, Pellegatta S, Finocchiaro G: NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma. Oncotarget. 2012, 3: 723-734.PubMedCentralCrossRefPubMed Speranza MC, Frattini V, Pisati F, Kapetis D, Porrati P, Eoli M, Pellegatta S, Finocchiaro G: NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma. Oncotarget. 2012, 3: 723-734.PubMedCentralCrossRefPubMed
40.
go back to reference Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed
Metadata
Title
MiR-145 inhibits oral squamous cell carcinoma (OSCC) cell growth by targeting c-Myc and Cdk6
Authors
Yuan Shao
Yiping Qu
Siwen Dang
Bowen Yao
Meiju Ji
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2013
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/1475-2867-13-51

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