Clinical and Translational Oncology

, Volume 18, Issue 5, pp 427–436 | Cite as

Non-coding RNAs deregulation in oral squamous cell carcinoma: advances and challenges

  • T. YuEmail author
  • C. Li
  • Z. Wang
  • K. Liu
  • C. Xu
  • Q. Yang
  • Y. Tang
  • Y. WuEmail author
Review Article


Oral squamous cell carcinoma (OSCC) is a common cause of cancer death. Despite decades of improvements in exploring new treatments and considerable advance in multimodality treatment, satisfactory curative rates have not yet been reached. The difficulty of early diagnosis and the high prevalence of metastasis associated with OSCC contribute to its dismal prognosis. In the last few decades the emerging data from both tumor biology and clinical trials led to growing interest in the research for predictive biomarkers. Non-coding RNAs (ncRNAs) are promising biomarkers. Among numerous kinds of ncRNAs, short ncRNAs, such as microRNAs (miRNAs), have been extensively investigated with regard to their biogenesis, function, and importance in carcinogenesis. In contrast to miRNAs, long non-coding RNAs (lncRNAs) are much less known concerning their functions in human cancers especially in OSCC. The present review highlighted the roles of miRNAs and newly discovered lncRNAs in oral tumorigenesis, metastasis, and their clinical implication.


Non-coding RNAs microRNAs Long non-coding RNAs Oral squamous cell carcinoma 



This paper was supported by the Fund of the Department of Science and Technology of Sichuan Province (grant no. 2014JY0033) and Fund of the Sichuan Provincial Bureau of Health (grant no. 130231).

Compliance with ethical standards

Informed consent

All authors are in agreement with the content of this manuscript and gave their informed consent prior to their inclusion in this study.

Conflict of interest

There were no human participants and/or animal experiments in this review. So, there is no conflict of interest in this study.


  1. 1.
    Yu T, Liu K, Wu Y. MicroRNA-9 inhibits the proliferation of oral squamous cell carcinoma cells by suppressing expression of CXCR4 via the Wnt/beta-catenin signaling pathway. Oncogene. 2014;33:5017–27.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61:212–36.CrossRefPubMedGoogle Scholar
  3. 3.
    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 Max Surg. 2008;46:1–5.CrossRefGoogle Scholar
  4. 4.
    Gonzalez-Ramirez I, Irigoyen-Camacho ME, Ramirez-Amador V. Association between age and high-risk human papilloma virus in Mexican oral cancer patients. Oral Dis. 2013;19:796–804.CrossRefPubMedGoogle Scholar
  5. 5.
    Isayeva T, Li Y, Maswahu D, Brandwein-Gensler M. Human papillomavirus in non-oropharyngeal head and neck cancers: a systematic literature review. Head Neck Pathol Suppl. 2012;1:S104–20.CrossRefGoogle Scholar
  6. 6.
    Towle R, Garnis C. Methylation-mediated molecular dysregulation in clinical oral malignancy. J Oncol. 2012;2012:170172.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mascolo M, Siano M, Ilardi G. Epigenetic disregulation in oral cancer. Int J Mol Sci. 2012;13:2331–53.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Carninci P, Kasukawa T, Katayama S. The transcriptional landscape of the mammalian genome. Science. 2005;309:1559–63.CrossRefPubMedGoogle Scholar
  9. 9.
    Zhu E, Zhao F, Xu G. mirTools: microRNA profiling and discovery based on high-throughput sequencing. Nucl Acids Res. 2010;38:392–7.CrossRefGoogle Scholar
  10. 10.
    Chang SS, Jiang WW, Smith I. MicroRNA alterations in head and neck squamous cell carcinoma. Int J Cancer. 2008;123:2791–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Denaro N, Russi EG, Adamo V, Merlano MC. State-of-the-art and emerging treatment options in the management of head and neck cancer: news from 2013. Oncology. 2014;86:212–29.PubMedGoogle Scholar
  12. 12.
    Gonzalez-Ramirez I, Soto-Reyes E, Sanchez-Perez Y, Herrera LA, Garcia-Cuellar C. Histones and long non-coding RNAs: the new insights of epigenetic deregulation involved in oral cancer. Oral Oncol. 2014;50:691–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Gasche JA, Goel A. Epigenetic mechanisms in oral carcinogenesis. Future Oncol. 2012;8:1407–25.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kugel JF, Goodrich JA. Non-coding RNAs: key regulators of mammalian transcription. Trends Biochem Sci. 2012;37:144–51.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ge XS, Ma HJ, Zheng XH. HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF-1 expression and activates Wnt pathway. Cancer Sci. 2013;104:1675–82.CrossRefPubMedGoogle Scholar
  16. 16.
    Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Fu W, Pang L, Chen Y, Yang L, Zhu J, Wei Y. The microRNAs as prognostic biomarkers for survival in esophageal cancer: a meta-analysis. Sci World J. 2014;2014:523979.Google Scholar
  18. 18.
    Bandyopadhyay S, Mitra R, Maulik U, Zhang MQ. Development of the human cancer microRNA network. Silence. 2010;1:6.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Li J, Huang H, Sun L. MiR-21 indicates poor prognosis in tongue squamous cell carcinomas as an apoptosis inhibitor. Clin Cancer Res. 2009;15:3998–4008.CrossRefPubMedGoogle Scholar
  20. 20.
    Wu BH, Xiong XP, Jia J, Zhang WF. MicroRNAs: new actors in the oral cancer scene. Oral Oncol. 2011;47:314–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Hebert C, Norris K, Scheper MA, Nikitakis N, Sauk JJ. High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma. Mol Cancer. 2007;6:5.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wong TS, Liu XB, Chung-Wai Ho A, Po-Wing Yuen A, Wai-Man Ng R, Ignace Wei W. Identification of pyruvate kinase type M2 as potential oncoprotein in squamous cell carcinoma of tongue through microRNA profiling. Int J Cancer. 2008;123:251–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Wong TS, Liu XB, Wong BY, Ng RW, Yuen AP, Wei WI. Mature miR-184 as potential oncogenic microRNA of squamous cell carcinoma of tongue. Clin Cancer Res. 2008;14:2588–92.CrossRefPubMedGoogle Scholar
  24. 24.
    Kozaki K, Mogi S, Omura K, Inazawa J. Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res. 2008;68:2094–105.CrossRefPubMedGoogle Scholar
  25. 25.
    Ramdas L, Giri U, Ashorn CL. miRNA expression profiles in head and neck squamous cell carcinoma and adjacent normal tissue. Head Neck. 2009;31:642–54.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Yu T, Wang XY, Gong RG. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Jung HM, Phillips BL. Patel RS (2012) Keratinization-associated miR-7 and miR-21 regulate tumor suppressor reversion-inducing cysteine-rich protein with kazal motifs (RECK) in oral cancer. J Biol Chem. 2012;287:29261–72.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Liu CJ, Shen WG, Peng SY. miR-134 induces oncogenicity and metastasis in head and neck carcinoma through targeting WWOX gene. Int J Cancer. 2014;134:811–21.CrossRefPubMedGoogle Scholar
  29. 29.
    Eis PS, Tam W, Sun L. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA. 2005;102:3627–32.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wang X, Tang S, Le SY. Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One. 2008;3:e2557.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Jiang S, Zhang HW, Lu MH. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 2010;70:3119–27.CrossRefPubMedGoogle Scholar
  32. 32.
    Wang B, Majumder S, Nuovo G. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology. 2009;50:1152–61.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Raponi M, Dossey L, Jatkoe T. MicroRNA classifiers for predicting prognosis of squamous cell lung cancer. Cancer Res. 2009;69:5776–83.CrossRefPubMedGoogle Scholar
  34. 34.
    Gironella M, Seux M, Xie MJ. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc Natl Acad Sci USA. 2007;104:16170–5.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Nikiforova MN, Tseng GC, Steward D, Diorio D, Nikiforov YE. MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J Clin Endocrinol Metabo. 2008;93:1600–8.CrossRefGoogle Scholar
  36. 36.
    Shi LJ, Zhang CY, Zhou ZT. MicroRNA-155 in oral squamous cell carcinoma: overexpression, localization, and prognostic potential. Head Neck. 2014;37:970–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Winter SC, Buffa FM, Silva P. Relation of a hypoxia metagene derived from head and neck cancer to prognosis of multiple cancers. Cancer Res. 2007;67:3441–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Gee HE, Camps C, Buffa FM. hsa-mir-210 is a marker of tumor hypoxia and a prognostic factor in head and neck cancer. Cancer. 2010;116:2148–58.PubMedGoogle Scholar
  39. 39.
    Sun Q, Zhang J, Cao W. Dysregulated miR-363 affects head and neck cancer invasion and metastasis by targeting podoplanin. Int J Biochem Cell Biol. 2013;45:513–20.CrossRefPubMedGoogle Scholar
  40. 40.
    Cervigne NK, Reis PP, Machado J. Identification of a microRNA signature associated with progression of leukoplakia to oral carcinoma. Hum Mol Genet. 2009;18:4818–29.CrossRefPubMedGoogle Scholar
  41. 41.
    Yang CC, Hung PS, Wang PW. miR-181 as a putative biomarker for lymph-node metastasis of oral squamous cell carcinoma. J Oral Pathol Med. 2011;40:397–404.CrossRefPubMedGoogle Scholar
  42. 42.
    Boldrup L, Coates PJ, Laurell G, Wilms T, Fahraeus R, Nylander K. Downregulation of miRNA-424: a sign of field cancerisation in clinically normal tongue adjacent to squamous cell carcinoma. Br J Cancer. 2015;112:1760–5.CrossRefPubMedGoogle Scholar
  43. 43.
    Liao L, Wang J, Ouyang S, Zhang P, Wang J, Zhang M. Expression and clinical significance of microRNA-1246 in human oral squamous cell carcinoma. Med Sci Monit. 2015;21:776–81.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Zahran F, Ghalwash D, Shaker O, Al-Johani K, Scully C. Salivary microRNAs in oral cancer. Oral Dis. 2015;21:739–47.CrossRefPubMedGoogle Scholar
  45. 45.
    Shiiba M, Shinozuka K, Saito K. MicroRNA-125b regulates proliferation and radioresistance of oral squamous cell carcinoma. Br J Cancer. 2014;108:1817–21.CrossRefGoogle Scholar
  46. 46.
    Chang CC, Yang YJ, Li YJ. MicroRNA-17/20a functions to inhibit cell migration and can be used a prognostic marker in oral squamous cell carcinoma. Oral Oncol. 2013;49:923–31.CrossRefPubMedGoogle Scholar
  47. 47.
    Fish JE, Santoro MM, Morton SU. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 2008;15:272–84.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Wang S, Aurora AB, Johnson BA. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 2008;15:261–71.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Liu B, Peng XC, Zheng XL, Wang J, Qin YW. MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo. Lung Cancer. 2009;66:169–75.CrossRefPubMedGoogle Scholar
  50. 50.
    Miko E, Margitai Z, Czimmerer Z. miR-126 inhibits proliferation of small cell lung cancer cells by targeting SLC7A5. FEBS Lett. 2011;585:1191–6.CrossRefPubMedGoogle Scholar
  51. 51.
    Zhu N, Zhang D, Xie H. Endothelial-specific intron-derived miR-126 is down-regulated in human breast cancer and targets both VEGFA and PIK3R2. Mol Cell Biochem. 2011;351:157–64.CrossRefPubMedGoogle Scholar
  52. 52.
    Otsubo T, Akiyama Y, Hashimoto Y, Shimada S, Goto K, Yuasa Y. MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis. PLoS One. 2011;6:e16617.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Donnem T, Lonvik K, Eklo K. Independent and tissue-specific prognostic impact of miR-126 in nonsmall cell lung cancer: coexpression with vascular endothelial growth factor-A predicts poor survival. Cancer. 2011;117:3193–200.CrossRefPubMedGoogle Scholar
  54. 54.
    Watahiki A, Wang Y, Morris J. MicroRNAs associated with metastatic prostate cancer. PLoS One. 2011;6:e24950.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Sasahira T, Kurihara M, Bhawal UK. Downregulation of miR-126 induces angiogenesis and lymphangiogenesis by activation of VEGF-A in oral cancer. Br J Cancer. 2012;107:700–6.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Xu Q, Sun Q, Zhang J, Yu J, Chen W, Zhang Z. Downregulation of miR-153 contributes to epithelial-mesenchymal transition and tumor metastasis in human epithelial cancer. Carcinogenesis. 2013;34:539–49.CrossRefPubMedGoogle Scholar
  57. 57.
    Huang WC, Chan SH, Jang TH. miRNA-491-5p and GIT1 serve as modulators and biomarkers for oral squamous cell carcinoma invasion and metastasis. Cancer Res. 2014;74:751–64.CrossRefPubMedGoogle Scholar
  58. 58.
    Harris T, Jimenez L, Kawachi N. Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. Am J Pathol. 2012;180:917–28.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Peng CH, Liao CT, Peng SC. A novel molecular signature identified by systems genetics approach predicts prognosis in oral squamous cell carcinoma. PLoS One. 2011;6:e23452.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Peng SC, Liao CT, Peng CH. MicroRNAs MiR-218, MiR-125b, and Let-7g predict prognosis in patients with oral cavity squamous cell carcinoma. PLoS One. 2014;9:e102403.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Lee SA, Kim JS, Park SY. miR-203 downregulates Yes-1 and suppresses oncogenic activity in human oral cancer cells. J Biosci Bioeng. 2015;S1389–S1723:00063–8.Google Scholar
  62. 62.
    Chi H. miR-194 regulated AGK and inhibited cell proliferation of oral squamous cell carcinoma by reducing PI3K-Akt-FoxO3a signaling. Biomed Pharmacother. 2015;71:53–7.CrossRefPubMedGoogle Scholar
  63. 63.
    Deng L, Liu H. MicroRNA-506 suppresses growth and metastasis of oral squamous cell carcinoma via targeting GATA6. Int J Clin Exp Med. 2015;8:1862–70.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Zheng M, Jiang YP, Chen W. Snail and Slug collaborate on EMT and tumor metastasis through miR-101-mediated EZH2 axis in oral tongue squamous cell carcinoma. Oncotarget. 2015;6:6797–810.CrossRefPubMedGoogle Scholar
  65. 65.
    Pan YF, Feng L, Zhang XQ. Role of long non-coding RNAs in gene regulation and oncogenesis. Chin Med J. 2011;124:2378–83.PubMedGoogle Scholar
  66. 66.
    Struhl K. Transcriptional noise and the fidelity of initiation by RNA polymerase II. Nat Struct Mol Biol. 2007;14:103–5.CrossRefPubMedGoogle Scholar
  67. 67.
    Clark MB, Mattick JS. Long noncoding RNAs in cell biology. Semin Cell Dev Biol. 2011;22:366–76.CrossRefPubMedGoogle Scholar
  68. 68.
    Denaro N, Merlano MC, Russi EG, Lo Nigro C. Non coding RNAs in head and neck squamous cell carcinoma (HNSCC): a clinical perspective. Anticancer Res. 2014;34:6887–96.PubMedGoogle Scholar
  69. 69.
    Yang QQ, Deng YF. Long non-coding RNAs as novel biomarkers and therapeutic targets in head and neck cancers. Int J Clin Exp Pathol. 2014;7:1286–92.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Maruyama R, Suzuki H. Long noncoding RNA involvement in cancer. BMB reports. 2012;45:604–11.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discov. 2011;1:391–407.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Ernst C, Morton CC. Identification and function of long non-coding RNA. Front Cell Neurosci. 2013;7:168.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Gupta RA, Shah N, Wang KC. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Yang Z, Zhou L, Wu LM. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 2011;18:1243–50.CrossRefPubMedGoogle Scholar
  75. 75.
    Gutschner T, Diederichs S. The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol. 2012;9:703–19.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 2011;10:38.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Li X, Wu Z, Mei Q. Long non-coding RNA HOTAIR, a driver of malignancy, predicts negative prognosis and exhibits oncogenic activity in oesophageal squamous cell carcinoma. Br J Cancer. 2013;109:2266–78.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Li CH, Chen Y. Targeting long non-coding RNAs in cancers: progress and prospects. Int J Biochem Cell Biol. 2013;45:1895–910.CrossRefPubMedGoogle Scholar
  79. 79.
    Popov N, Gil J. Epigenetic regulation of the INK4b-ARF-INK4a locus: in sickness and in health. Epigenetics. 2010;5:685–90.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Gibb EA, Vucic EA, Enfield KS. Human cancer long non-coding RNA transcriptomes. PLoS One. 2011;6:e25915.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Jia LF, Wei SB, Gan YH. Expression, regulation and roles of miR-26a and MEG3 in tongue squamous cell carcinoma. Int J Cancer. 2014;135:2282–93.CrossRefPubMedGoogle Scholar
  82. 82.
    Li D, Feng J, Wu T. Long intergenic noncoding RNA HOTAIR is overexpressed and regulates PTEN methylation in laryngeal squamous cell carcinoma. Am J Pathol. 2013;182:64–70.CrossRefPubMedGoogle Scholar
  83. 83.
    Fang Z, Wu L, Wang L, Yang Y, Meng Y, Yang H. Increased expression of the long non-coding RNA UCA1 in tongue squamous cell carcinomas: a possible correlation with cancer metastasis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117:89–95.CrossRefPubMedGoogle Scholar
  84. 84.
    Gibb EA, Enfield KS, Stewart GL. Long non-coding RNAs are expressed in oral mucosa and altered in oral premalignant lesions. Oral Oncol. 2011;47:1055–61.CrossRefPubMedGoogle Scholar
  85. 85.
    Gao W, Chan JY, Wong TS. Long non-coding RNA deregulation in tongue squamous cell carcinoma. BioMed Res Int. 2014;2014:405860.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Wu Y, Zhang L, Zhang L. Long non-coding RNA HOTAIR promotes tumor cell invasion and metastasis by recruiting EZH2 and repressing E-cadherin in oral squamous cell carcinoma. Int J Oncol. 2015;46:2586–94.PubMedGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2015

Authors and Affiliations

  1. 1.Department of Head and Neck Oncology SurgerySichuan Cancer HospitalChengduPeople’s Republic of China
  2. 2.State Key Laboratory of Oral Diseases, West China School of StomatologySichuan UniversityChengduPeople’s Republic of China

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