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MicroRNA-9 inhibits the proliferation of oral squamous cell carcinoma cells by suppressing expression of CXCR4 via the Wnt/β-catenin signaling pathway

Oncogene volume 33, pages 5017–5027 (2014)Cite this article

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Abstract

Aberrant expression of microRNAs (miRNAs) has been involved in the development and progression of malignancy. MicroRNA-9 (miR-9) has been confirmed to be underexpressed in many types of cancers. However, the relationship between miR-9 and the Wnt/β-catenin signaling pathway in oral squamous cell carcinoma (OSCC) remains largely unknown. Here we showed that the miR-9 was underexpressed in patients with OSCC and several OSCC cell lines. Lentivirus-mediated miR-9 overexpression in highly aggressive (Tca8113 and SCC-9) tumor cells significantly inhibited proliferation of the two cell lines in vitro and in vivo. Furthermore, we found that the CXC chemokine receptor 4 (CXCR4) gene was a direct target of miR-9. RNA interference silencing of CXCR4 proved that miR-9 underexpression led to constitutive activation of β-catenin through activation of CXCR4 expression in OSCC cells. Finally, we also analyzed the possible relationship between miR-9 and the genes downstream of the Wnt/β-catenin pathway in OSCC development and progression. These results provide new evidence of miR-9 as a promising tumor gene therapeutic target for OSCC patients.

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References

  1. Kademani D . Oral cancer. Mayo Clin Proc 2007; 82: 878–887.

    Article  Google Scholar 

  2. Petersen PE . The World Oral Health Report 2003: continuous improvement of oral health in the 21st century- the approach of WHO Global Programme. Commun Dent Oral Epidemiol 2003; 31: 3–23.

    Article  Google Scholar 

  3. Yu T, Wang XY, Gong RG, Li A, Yang S, Cao YT et al. 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; 13: 64.

    Article  Google Scholar 

  4. Kessler P, Grabenbauer G, Leher A, Bloch-Birkholz A, Vairaktaris E, Neukam FW . Neoadjuvant and adjuvant therapy in patients with oral squamous cell carcinoma: long-term survival in a prospective, non-randomized study. Br J Oral Maxillofac Surg 2008; 46: 1–5.

    Article  Google Scholar 

  5. Hu J, He Y, Yan M, Zhu C, Ye W, Zhu H et al. Dose dependent activation of retinoic acid-inducible gene-I promotes both proliferation and apoptosis signals in human head and neck squamous cell carcinoma. PLoS One 2013; 8: e58273.

    Article  CAS  Google Scholar 

  6. Uchida F, Uzawa K, Kasamatsu A, Takatori H, Sakamoto Y, Ogawara K et al. Overexpression of CDCA2 in human squamous cell carcinoma: correlation with prevention of G1 phase arrest and apoptosis. PLoS One 2013; 8: e56381.

    Article  CAS  Google Scholar 

  7. Ambros V . The functions of animal microRNAs. Nature 2004; 431: 350–355.

    Article  CAS  Google Scholar 

  8. Bartel DP . MicroRNAs: genomics, biogenesis, mechanism and function. Cell 2004; 116: 281–297.

    Article  CAS  Google Scholar 

  9. Calin GA, Croce CM . MicroRNA-cancer connection: the beginning of a new tale. Cancer Res 2006; 66: 7390–7394.

    Article  CAS  Google Scholar 

  10. Bandyopadhyay S, Mitra R, Maulik U, Zhang MQ . Development of the human cancer microRNA network. Silence 2010; 1: 6.

    Article  Google Scholar 

  11. Selcuklu SD, Donoghue MTA, Spillane C . MiR-21 as a key regulator of oncogenic processes. Biochem Soc T 2009; 37: 918–925.

    Article  CAS  Google Scholar 

  12. Li JS, Huang HZ, Sun LJ, Yang M, Pan CB, Chen WL et al. MiR-21 indicates poor prognosis in tongue squamous cell carcinomas as an apoptosis inhibitor. Clin Cancer Res 2009; 15: 3998–4008.

    Article  CAS  Google Scholar 

  13. Avissar M, McClean MD, Kelsey KT, Marsit CJ . MicroRNA expression in head and neck cancer associates with alcohol consumption and survival. Carcinogenesis 2009; 30: 2059–2063.

    Article  CAS  Google Scholar 

  14. Wong TS, Liu XB, Ho ACW, Yuen APW, Ng RWM, Wei WI . Identification of pyruvate kinase type M2 as potential oncoprotein in squamous cell carcinoma of tongue through microRNA profiling. Int J Cancer 2008; 123: 251–257.

    Article  CAS  Google Scholar 

  15. Jiang L, Liu XQ, Kolokythas A, Yu JS, Wang AX, Heidbreder CE et al. Downregulation of the Rho GTPase signaling pathway is involved in the microRNA-138-mediated inhibition of cell migration and invasion in tongue squamous cell carcinoma. Int J Cancer 2010; 127: 505–512.

    Article  CAS  Google Scholar 

  16. Gao F, Zhao ZL, Zhao WT, Fan QR, Wang SC, Li J et al. miR-9 modulates the expression of interferon-regulated genes and MHC class I molecules in human nasopharyngeal carcinoma cells. Biochem Biophys Res Commun 2013; 431: 610–616.

    Article  CAS  Google Scholar 

  17. Bandres E, Agirre X, Bitarte N, Ramirez N, Zarate R, Roman-Gomez J et al. Epigenetic regulation of microRNA expression in colorectal cancer. Int J Cancer 2009; 125: 2737–2743.

    Article  CAS  Google Scholar 

  18. Selcuklu SD, Donoghue MT, Rehmet K, de Souza Gomes M, Fort A, Kovvuru P et al. MicroRNA-9 inhibition of cell proliferation and identification of novel miR-9 targets by transcriptome profiling in breast cancer cells. J Biol Chem 2012; 287: 29516–29528.

    Article  CAS  Google Scholar 

  19. Liu S, Kumar SM, Lu H, Liu A, Yang R, Pushparajan A et al. MicroRNA-9 up-regulates E-cadherin through inhibition of NF-κB1-Snail1 pathway in melanoma. J Pathol 2012; 226: 61–72.

    Article  CAS  Google Scholar 

  20. Sun Z, Han Q, Zhou N, Wang S, Lu S, Bai C et al. MicroRNA-9 enhances migration and invasion through KLF17 in hepatocellular carcinoma. Mol Oncol 2013; S1574-7891: 00068–00069.

    Google Scholar 

  21. Nass D, Rosenwald S, Meiri E, Gilad S, Tabibian-Keissar H, Schlosberg A et al. MiR-92b and miR-9/9* are specifically expressed in brain primary tumors and can be used to differentiate primary from metastatic brain tumors. Brain Pathol 2009; 19: 375–383.

    Article  CAS  Google Scholar 

  22. Leucci E, Zriwil A, Gregersen LH, Jensen KT, Obad S, Bellan C et al. Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo. Oncogene 2012; 31: 5081–5089.

    Article  CAS  Google Scholar 

  23. Teicher BA, Fricker SP . CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin. Cancer Res 2010; 16: 2927–2931.

    CAS  Google Scholar 

  24. Burger JA, Kipps TJ . CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood 2006; 107: 1761–1767.

    Article  CAS  Google Scholar 

  25. Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC . Structural basis of Wnt recognition by Frizzled. Science 2012; 337: 59–64.

    Article  CAS  Google Scholar 

  26. Garzon R, Calin GA, Croce CM . MicroRNAs in Cancer. Annu Rev Med 2009; 60: 167–179.

    Article  CAS  Google Scholar 

  27. Garzon R, Marcucci G, Croce CM . Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov 2010; 9: 775–789.

    Article  CAS  Google Scholar 

  28. Esquela-Kerscher A, Slack FJ . Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 2006; 6: 259–269.

    Article  CAS  Google Scholar 

  29. Liu N, Sun Q, Chen J, Li J, Zeng Y, Zhai S et al. MicroRNA-9 suppresses uveal melanoma cell migration and invasion through the NF-κB1 pathway. Oncol Rep 2012; 28: 961–968.

    PubMed  Google Scholar 

  30. Jing L, Jia Y, Lu J, Han R, Li J, Wang S et al. MicroRNA-9 promotes differentiation of mouse bone mesenchymal stem cells into neurons by Notch signaling. Neuroreport 2011; 22: 206–211.

    Article  CAS  Google Scholar 

  31. Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res 2005; 65: 7065–7070.

    Article  CAS  Google Scholar 

  32. Lehmann U, Hasemeier B, Christgen M, Müller M, Römermann D, Länger F et al. Epigenetic inactivation of microRNA gene hsa-miR-9-1 in human breast cancer. J Pathol 2008; 214: 17–24.

    Article  CAS  Google Scholar 

  33. Nie K, Gomez M, Landgraf P, Garcia JF, Liu Y, Tan LH et al. MicroRNA-mediated downregulation of PRDM1/Blimp-1 in Hodgkin/Reed-Sternberg cells: a potential pathogenetic lesion in Hodgkin lymphomas. Am J Pathol 2008; 173: 242–252.

    Article  CAS  Google Scholar 

  34. Rotkrua P, Akiyama Y, Hashimoto Y, Otsubo T, Yuasa1 Y . MiR-9 downregulates CDX2 expression in gastric cancer cells. Int J Cancer 2011; 129: 2611–2620.

    Article  CAS  Google Scholar 

  35. Omura N, Li CP, Li A, Hong SM, Walter K, Jimeno A et al. Genomewide profiling at methylated promoters in pancreatic adenocarcinoma. Cancer Biol Ther 2008; 7: 1146–1156.

    Article  CAS  Google Scholar 

  36. Luo H, Zhang H, Zhang Z, Zhang X, Ning B, Guo J et al. Downregulated miR-9 and miR-433 in human gastric carcinoma. J Exp Clin Cancer Res 2009; 28: 82.

    Article  Google Scholar 

  37. Laios A, O'Toole S, Flavin R, Martin C, Kelly L, Ring M et al. Potential role of miR-9 and miR-223 in recurrent ovarian cancer. Mol Cancer 2008; 7: 35.

    Article  Google Scholar 

  38. Caruz A, Samsom M, Alonso JM, Alcami J, Baleux F, Virelizier JL et al. Genomic organization and promoter characterization of human cxcr4 gene. FEBS Lett 1998; 426: 271–278.

    Article  CAS  Google Scholar 

  39. Balkwill F . Cancer and the chemokine network. Nat Rev Cancer 2004; 4: 540–550.

    Article  CAS  Google Scholar 

  40. Peifer M, Polakis P . Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus. Science 2000; 287: 1606–1609.

    Article  CAS  Google Scholar 

  41. Lowy AM, Fenoglio-Preiser C, Kim OJ, Kordich J, Gomez A, Knight J et al. Dysregulation of beta-catenin expression correlates with tumor differentiation in pancreatic duct adenocarcinoma. Ann Surg Oncol 2003; 10: 284–290.

    Article  Google Scholar 

  42. Al-Aynati MM, Radulovich N, Riddell RH, Tsao MS . Epithelialcadherin and beta-catenin expression changes in pancreatic intraepithelial neoplasia. Clin Cancer Res 2004; 10: 1235–1240.

    Article  CAS  Google Scholar 

  43. Jin Z, Zhao C, Han X, Han Y . Wnt5a promotes ewing sarcoma cell migration through upregulating CXCR4 expression. BMC Cancer 2012; 12: 480.

    Article  CAS  Google Scholar 

  44. Choe Y, Pleasure SJ . Wnt signaling regulates intermediate precursor production in the postnatal dentate gyrus by regulating CXCR4 expression. Dev Neurosci 2012; 34: 502–514.

    Article  CAS  Google Scholar 

  45. Fracalossi AC, Silva Mde S, Oshima CT, Ribeiro DA . Wnt/beta-catenin signalling pathway following rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide. Exp Mol Pathol 2010; 88: 176–183.

    Article  CAS  Google Scholar 

  46. Farr GH, Ferkey DM, Yost C, Pierce SB, Weaver C, Kimelman D . Interaction among GSK-3, GBP, axin, and APC in Xenopus axis specification. J Cell Biol 2000; 148: 691–702.

    Article  CAS  Google Scholar 

  47. Chiyomaru T, Enokida H, Tatarano S, Kawahara K, Uchida Y, Nishiyama K et al. miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer. Br J Cancer 2010; 102: 883–891.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Head and Neck Oncology Surgery, Sichuan Cancer Hospital, Chengdu, People's Republic of China

    T Yu, K Liu, J Fan, J Chen, C Li, Q Yang & Z Wang

  2. State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, People’s Republic of China

    Y Wu

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  1. T Yu
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Correspondence to T Yu or Z Wang.

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Yu, T., Liu, K., Wu, Y. et al. MicroRNA-9 inhibits the proliferation of oral squamous cell carcinoma cells by suppressing expression of CXCR4 via the Wnt/β-catenin signaling pathway. Oncogene 33, 5017–5027 (2014). https://doi.org/10.1038/onc.2013.448

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