MicroRNA Profiles of HPV-Associated Oropharyngeal Squamous Cell Carcinoma (OPSCC)

  • Daniel Lee MillerEmail author
  • M. Sharon Stack


The tumorigenesis pathways and molecular etiologies of head and neck squamous cell carcinoma (HNSCC) have been studied extensively, however it remains a very difficult disease to treat and cure. Further, there is a paucity of clinically applicable diagnostic platforms that significantly improve detection rates and patient outcomes. Early detection of locally confined cancers promises the ability to improve patient outcomes by providing less invasive surgical treatments. Indeed, patients at high risk of treatment failure should be appropriately stratified and treated compared to those with relatively low-risk profiles. This promise, together with the ability to classify disease according to a panel of phenotypic and genotypic markers in order to select the optimal treatment modality, is the fundamental premise of the emerging field of “precision medicine.” In this chapter, we summarize recent data on microRNA profiling of human papillomavirus positive (HPV+) HNSCC, predominantly localized in the oropharynx (OPSCC), discuss potential targets of these microRNAs, and examine the potential utility of microRNAs as biomarkers and therapeutic targets in HPV+ OPSCC.


HPV Microrna Immune system Biomarker 



This work was supported in part by research grant RO1085870 (MSS) from the National Institutes of Health/National Cancer Institute, a RL Kirschstein National Research Service Award F31 DE021926 (DLM) from the National Institute of Dental and Craniofacial Research, and an Advancing Basic Cancer research grant from the Walther Cancer Foundation (MSS).


  1. Albers A, Abe K, Hunt J, Wang J, Lopez-Albaitero A, Schaefer C, Gooding W, Whiteside TL, Ferrone S, DeLeo A, Ferris RL (2005) Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck. Cancer Res 65:11146–11155PubMedCrossRefGoogle Scholar
  2. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363(1):24–35PubMedCentralPubMedCrossRefGoogle Scholar
  3. Avery JK, Steele PF, Avery N (2002) Oral development and histology, 3rd edn. Thieme Medical Publishers, StuttgartGoogle Scholar
  4. Avissar M, Christensen BC, Kelsey KT, Marsit CJ (2009) A microRNA expression ratio is predictive of head and neck squamous cell carcinoma. Clin Can Res 15(08):2850–2855CrossRefGoogle Scholar
  5. Bader AG (2012) miR-34, a microRNA replacement therapy headed to the clinic. Front Genet 3:120Google Scholar
  6. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297PubMedCrossRefGoogle Scholar
  7. Bazzoni F, Rossato M, Fabbri M, Gaudiosi D, Mirolo M, Mori L, Tamassia N, Mantovani A, Cassatella MA, Locati M (2009) Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc Natl Acad Sci USA 106(13):5282–5287PubMedCentralPubMedCrossRefGoogle Scholar
  8. Bourguignon LY, Spevak CC, Wong G, Xia W, Gilad E (2009) Hyaluronan-CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the Production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J Biol Chem 284(39):26533–26546PubMedCentralPubMedCrossRefGoogle Scholar
  9. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM (2002) Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99(24):15524–15529PubMedCentralPubMedCrossRefGoogle Scholar
  10. Cervigne NK, Reis PP, Machado J, Sadikovic B, Bradley G, Galloni NN, Pintilie M, Jurisica I, Perez-Ordonez B, Gilbert R, Gullane P, Irish J, Kamel-Reid S (2009) Identification of a microRNA signature associated with progression of leukoplakia to oral carcinoma. Hum Mol Genet 18(24):4814–4829CrossRefGoogle Scholar
  11. Chang SS, Jiang WW, Smith I, Poeta LM, Begum S, Glazer C, Shan S, Westra W, Sidransky D, Califano JA (2008) MicroRNA alterations in head and neck squamous cell carcinoma. Int J Can 123(12):2791–2807CrossRefGoogle Scholar
  12. Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, Jiang B, Goodman MT, Sibug-Saber M, Cozen W, Liu L, Lynch CF, Wentzensen N, Jordan RC, Altekruse S, Anderson WF, Rosenberg PS, Gillison ML (2011) Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 29(32):4294–4301PubMedCentralPubMedCrossRefGoogle Scholar
  13. Chen Z, Jin Y, Yu D, Wang A, Mahjabeen I, Wang C, Liu X, Zhou X (2012) Down-regulation of the microRNA-99 family members in head and neck squamous cell carcinoma. Oral Oncol 48(8):686–691PubMedCentralPubMedCrossRefGoogle Scholar
  14. Childs G, Fazzari M, Kung G, Kawachi N, Brandwein-Gensler M, McLemore M, Chen Q, Burk RD, Smith RV, Prystowsky MB, Belbin TJ, Schlecht NF (2009) Low-level expression of microRNAs let-7d and miR-205 are prognostic markers of head and neck squamous cell carcinoma. Am J Pathol 174(3):736–745PubMedCentralPubMedCrossRefGoogle Scholar
  15. Ding Y, Tang Y, Kwok CK, Zhang Y, Bevilacqua PC, Assmann SM (2014) In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features. Nature 505(7485):696–700PubMedCrossRefGoogle Scholar
  16. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, Forastiere A, Gillison ML (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100(4):261–269PubMedCrossRefGoogle Scholar
  17. Fletcher AM, Heaford AC, Trask DK (2008) Detection of metastatic head and neck squamous cell carcinoma using the relative expression of tissue-specific miR-205. Transl Oncol 1(4):202–208PubMedCentralPubMedCrossRefGoogle Scholar
  18. Gao G, Gay HA, Chernock RD, Zhang TR, Luo J, Thorstad WL, Lewis JSJ, Wang X (2013a) A microRNA expression signature for the prognosis of oropharyngeal squamous cell carcinoma. Cancer 119:72–80Google Scholar
  19. Gao F, Zhao ZL, Zhao WT, Fan QR, Wang SC, Li J, Zhang YQ, Shi JW, Lin XL, Yang S, Xie RY, Liu W, Zhang TT, Sun YL, Xu K, Yao KT, Xiao D (2013b) miR-9 modulates the expression of interferon-regulated genes and MHC class I molecules in human nasopharyngeal carcinoma cells. Biochem Biophys Res Commun 431(3):610–616Google Scholar
  20. Gillison ML, Castellsague X, Chaturvedi A, Goodman MT, Snijders P, Tommasino M, Arbyn M, Franceschi S (2014) Eurogin Roadmap: comparative epidemiology of HPV infection and associated cancers of the head and neck and cervix. Int J Cancer 134:497–507PubMedCrossRefGoogle Scholar
  21. Gounden V, Zhao Z (2013) MicroRNAs as potential biomarkers: Is the future here? In: The American Association for Clinical Chemistry. 22nd of January 2013. NACB Scientific shorts.
  22. He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM (2005) A microRNA polycistron as a potential human oncogene. Nature 435(7043):828–833PubMedCrossRefGoogle Scholar
  23. Henson BJ, Bhattacharjee S, O’Dee DM, Feingold E, Gollin SM (2009) Decreased expression of miR-125b and miR-100 in oral cancer cells contributes to malignancy. Genes Chromosom Cancer 48:569–582Google Scholar
  24. Hoffmann TK, Arsov C, Schirlau K, Bas M, Friebe-Hoffmann U, Klussmann JP, Scheckenbach K, Balz V, Bier H, Whiteside TL (2006) T cells specific for HPV16 E7 epitopes in patients with squamous cell carcinoma of the oropharynx. Int J Cancer 118:1984–1991PubMedCrossRefGoogle Scholar
  25. Hu H, Li S, Cui X, Lv X, Jiao Y, Yu F, Yao H, Song E, Chen Y, Wang M, Lin L (2013) The overexpression of hypomethylated miR-663 induces chemotherapy resistance in human breast cancer cells by targeting heparin sulfate proteoglycan 2 (HSPG2). J Biol Chem 288(16):10973–10985PubMedCentralPubMedCrossRefGoogle Scholar
  26. Hu X, Schwarz JK, Lewis JS Jr, Huettner PC, Rader JS, Deasy JO, Grigsby PW, Wang X (2010) A microRNA expression signature for cervical cancer prognosis. Cancer Res 70(4):1441–1448PubMedCentralPubMedCrossRefGoogle Scholar
  27. Hui AB, Lenarduzzi M, Krushel T, Waldron L, Pintilit M, Shi W, Perez-Ordonez B, Jurisica I, O’Sullivan B, Waldron J, Gullane P, Cummings B, Liu FF (2010) MicroRNA profiling for head and enck squamous cell carcinomas. Clin Can Res 16(4):1129–1139CrossRefGoogle Scholar
  28. Hui AB, Lin A, Xu W, Waldron L, Perez-Ordonez B, Weinreb I et al (2013) Potentially Prognostic miRNAs in HPV-Associated Oropharyngeal Cancer. Clin Cancer Res 19:2154–2162PubMedCrossRefGoogle Scholar
  29. Hunt JL, Barnes L, Lewis JS Jr, Mahfouz ME, Slootweg PJ, Thompson LD, Cardesa A, Devaney KO, Gnepp DR, Westra WH, Rodrigo JP, Woolgar JA, Rinaldo A, Triantafyllou A, Takes RP, Ferlito A (2014) Molecular diagnostic alterations in squamous cell carcinoma of the head and neck and potential diagnostic applications. Eur Arch Otorhinolaryngol 271(2):211–223PubMedCrossRefGoogle Scholar
  30. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patick AK, Chen A, Zhou Y, Persson R, King BD, Kauppinen S, Levin AA, Hodges T (2013) Treatment of HCV infection by targeting microRNA. New Engl J Med 368:1685–1694PubMedCrossRefGoogle Scholar
  31. Kim SH, Juhn YS, Kang S, Park SW, Sung MW, Bang YJ, Song YS (2006) Human papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ ERK1,2 and PI3 K/Akt. Cell Mol Life Sci 63:930–938PubMedCrossRefGoogle Scholar
  32. Kim SH, Koo BS, Kang S, Park K, Kim H, Lee KR, Lee MJ, Kim JM, Choi EC, Cho NH (2007) HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formation. Int J Cancer 120:1418–1425PubMedCrossRefGoogle Scholar
  33. Kim YK, Kim VN (2007) Processing of intronic microRNAs. EMBO J 26(3):775–783PubMedCentralPubMedCrossRefGoogle Scholar
  34. Kozomara A, Griffiths-Jones S (2014) miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 42(Database issue):D68–D73Google Scholar
  35. Lagos-Quintana M et al (2001) Identification of novel genes coding for small expressed RNAs. Science 294(5543):853–858PubMedCrossRefGoogle Scholar
  36. Lajer CB, Nielsen FC, Friis-Hansen L, Norrild B, Borup R, Garnaes E, Rossing M, Specht L, Therkildsen MH, Nauntofte B, Dabelsteen S, von Buchwald C (2011) Different miRNA signatures of oral and pharyngeal squamous cell carcinomas: a prospective translational study. Br J Cancer 104:830–840PubMedCentralPubMedCrossRefGoogle Scholar
  37. Lau NC et al (2001) An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294(5543):858–862PubMedCrossRefGoogle Scholar
  38. Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854PubMedCrossRefGoogle Scholar
  39. Lee RC, Ambros V (2001) An extensive class of small RNAs in Caenorhabditis elegans. Science 294(5543):862–864PubMedCrossRefGoogle Scholar
  40. Leucht C, Stigloher C, Wizenmann A, Lkafke R, Folchert A, Bally-Cuif L (2008) MicroRNA-9 directs late organizer activity of the midbrain-hindbrain boundary. Nature Neurosci 11:641–648PubMedCrossRefGoogle Scholar
  41. Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R, Oggionni M, Rossini C, Cantù G, Squadrelli M, Quattrone P, Locati LD, Bergamini C, Olmi P, Pierotti MA, Pilotti S (2006) High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 24(36):5630–5636PubMedCrossRefGoogle Scholar
  42. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435(7043):834–838PubMedCrossRefGoogle Scholar
  43. Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, Bruno TC, Richmon JD, Wang H, Bishop JA, Chen L, Drake CG, Topalian SL, Pardoll DM, Pai SI (2013) Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res 73(6):1733–1741PubMedCentralPubMedCrossRefGoogle Scholar
  44. Ma L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D, Teruya-Feldstein J, Reinhardt F, Onder TT, Valastyan S, Westermann F, Speleman F, Vandesompele J, Weinberg RA (2010) Mir9, a YC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 12(3):247–256PubMedCentralPubMedGoogle Scholar
  45. Melar-New M, Laimins LA (2010) Human papillomaviruses modulate expression of microRNA 203 upon epithelial differentiation to control levels of p63 proteins. J Virol 84:5212–5221PubMedCentralPubMedCrossRefGoogle Scholar
  46. Mendell JT (2008) miRiad roles for the miR-17-92 cluster in development and disease. Cell. 2008 Apr 18; 133(2):217–22.Google Scholar
  47. Mendell JT, Olson EN (2012) MicroRNAs in stress signaling and human disease. Cell 148(6):1172–1187PubMedCentralPubMedCrossRefGoogle Scholar
  48. Miller DL, Davis JW, Taylor KH, Johnson J, Shi Z, Williams R, Atasoy U, Lewis JS, Stack MS (2015) Identification of a human papillomavirus-associated oncogenic miRNA panel in human oropharyngeal squamouse cell carcinoma validated by bioinformatics analysis of the cancer genome atlas. Am J Pathol 185(3):679–692PubMedCrossRefGoogle Scholar
  49. Miller DL, Puricelli MD, Stack MS (2012) Virology and molecular pathogenesis of HPV-associated oropharyngeal squamous cell carcinoma. Biochem J 443:339–353PubMedCentralPubMedCrossRefGoogle Scholar
  50. Mironov AS, Gusarov I, Rafikov R, Lopez LE, Shatalin K, Kreneva RA, Perumov DA, Nudler E (2002) Sensing small molecules by nascent RNA: a mechanism to control transcription in bacteria. Cell 111(5):747–756PubMedCrossRefGoogle Scholar
  51. Molinolo AA, Marsh C, El Dinali M, Gangane N, Jennison K, Hewitt S, Patel V, Seiwert TY, Gutkind JS (2012) mTOR as a molecular target in HPV-associated oral and cervical squamous carcinomas. Clin Cancer Res 18:2558–2568PubMedCentralPubMedCrossRefGoogle Scholar
  52. Mroz EA, Forastiere AA, Rocco JW (2011) Implications of the oropharyngeal cancer epidemic. J Clin Oncol 29(32):4222–4223PubMedCentralPubMedCrossRefGoogle Scholar
  53. Nahvi A, Sudarsan N, Ebert MS, Zou X, Brown KL, Breaker RR (2002) Genetic control by a metabolite binding mRNA. Chem Biol 9(9):1043PubMedCrossRefGoogle Scholar
  54. O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435(7043):839–843PubMedCrossRefGoogle Scholar
  55. Pai SI, Westra WH (2009) Molecular pathology of head and neck cancer: implications for diagnosis, prognosis, and treatment. Annu Rev Pathol 4:49–70PubMedCentralPubMedCrossRefGoogle Scholar
  56. Pai SI (2013) Adaptive immune resistance in HPV-associated head and neck squamous cell carcinoma. Oncoimmunology. 2013 May 1; 2(5):e24065Google Scholar
  57. Park NJ, Zhou H, Elashoff D, Henson BS, Kastratovic DA, Abemayor E, Wong DT (2009) Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res 15(17):5473–5477PubMedCentralPubMedCrossRefGoogle Scholar
  58. Perry ME (1994) The specialised structure of crypt epithelium in the human palatine tonsil and its functional significance. J Anat 185:111–127PubMedCentralPubMedGoogle Scholar
  59. Qian K, Pietilä T, Rönty M, Michon F, Frilander MJ, Ritari J, Tarkkanen J, Paulín L, Auvinen P, Auvinen E (2013) Identification and Validation of Human Papillomavirus Encoded microRNAs. PLoS ONE 8(7):e70202PubMedCentralPubMedCrossRefGoogle Scholar
  60. Qu C, Liang Z, Huang J, Zhao R, Su C, Wang S, Wang X, Zhang R, Lee MH, Yang H (2012) MiR-205 determines the radioresistance of human nasopharyngeal carcinoma by directly targeting PTEN. Cell Cycle 11(4):785–796PubMedCentralPubMedCrossRefGoogle Scholar
  61. Ramdas L, Giri U, Ashorn CL, Coombes KR, El-Naggar A, Ang KK, Story MD (2009) miRNA expression profiles in head and neck squamous cell carcinoma and adjacent normal tissue. Head Neck 31(5):642–654PubMedCentralPubMedCrossRefGoogle Scholar
  62. Rosenfeld N, Aharonov R, Meiri E, Rosenwald S, Spector Y, Zepeniuk M, Benjamin H, Shabes N, Tabak S, Levy A, Lebanony D, Goren Y, Silberschein E, Targan N, Ben-Ari A, Gilad S, Sion-Vardy N, Tobar A, Feinmesser M, Kharenko O, Nativ O, Nass D, Perelman M, Yosepovich A, Shalmon B, Polak-Charcon S, Fridman E, Avniel A, Bentwich I, Bentwich Z, Cohen D, Chajut A, Barshack I (2008) MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol 26(4):462–469PubMedCrossRefGoogle Scholar
  63. Rouskin S, Zubradt M, Washietl S, Kellis M, Weissman JS (2014) Genome-wide probing of RNA structure reveals active unfolding of mRNA structures in vivo. Nature 505(7485):701–705. doi: 10.1038/nature12894 PubMedCentralPubMedCrossRefGoogle Scholar
  64. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yuen ST, Chan TL, Kwong DL, Au GK, Liu CG, Calin GA, Croce CM, Harris CC (2008) MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299(4):425–436PubMedCentralPubMedCrossRefGoogle Scholar
  65. Schultz NA, Dehlendorff C, Jensen BV, Bjerregaard JK, Nielsen KR, Bojesen SE, Calatayud D, Nielsen SE, Yilmaz M, Holländer NH, Andersen KK, Johansen JS (2014) MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA 311(4):392–404Google Scholar
  66. Sempere LF (2012) Recent advances in miRNA-based diagnostic applications. Expert Rev Mol Diagn 12(6):557–559PubMedCrossRefGoogle Scholar
  67. Syrjanen S (2004) HPV infections and tonsillar carcinoma. J Clin Pathol 57:449–455PubMedCentralPubMedCrossRefGoogle Scholar
  68. Takwi AA, Wang YM, Wu J, Michaelis M, Cinatl J, Chen T (2013) miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells. Oncogene 33(28):3717–3729PubMedCentralPubMedCrossRefGoogle Scholar
  69. Tran N, McLean T, Zhang X, Zhao CJ, Thomson JM, O’Brien C, Rose B (2007) MicroRNA expression profiles in head and neck cancer cell lines. Biochem Biophys Res Commun 358(1):12–17PubMedCrossRefGoogle Scholar
  70. Ukpo OC, Thorstad WL, Lewis JS Jr (2013) B7-H1 expression model for immune evasion in human papillomavirus-related oropharyngeal squamous cell carcinoma. Head Neck Pathol 7(2):113–121PubMedCentralPubMedCrossRefGoogle Scholar
  71. Visone R, Rassenti LZ, Veronese A, Taccioli C, Costinean S, Aguda BD, Volinia S, Ferracin M, Palatini J, Balatti V, Alder H, Negrini M, Kipps TJ, Croce CM (2009) Karyotype-specific microRNA signature in chronic lymphocytic leukemia. Blood 114(18):3872–3879PubMedCentralPubMedCrossRefGoogle Scholar
  72. Wald AI, Hoskins EE, Wells SI, Feris RL, Khan SA (2011) Alteration of microRNA profiles in squamous cell carcinoma of the head and neck cell lines by human papillomavirus. Head Neck 33:504–512PubMedCentralPubMedCrossRefGoogle Scholar
  73. Wan Y, Qu K, Zhang QC, Flynn RA, Manor O, Ouyang Z, Zhang J, Spitale RC, Snyder MP, Segal E, Chang HY (2014) Landscape and variation of RNA secondary structure across the human transcriptome. Nature 505(7485):706–709PubMedCentralPubMedCrossRefGoogle Scholar
  74. Williams R, Lee DW, Elzey BD, Anderson ME, Hostager BS, Lee JH (2009) Preclinical models of HPV+ and HPV− HNSCC in mice: an immune clearance of HPV+ HNSCC. Head Neck 31:911–918PubMedCrossRefGoogle Scholar
  75. Winkler W, Nahvi A, Breaker RR (2002) Thiamine derivatives bindmessenger RNAs directly to regulate bacterial gene expression. Nature 419(6910):952–956PubMedCrossRefGoogle Scholar
  76. Wong TS, Liu XB, Chung-Wai Ho A, Po-Wing Yuen A, Wai-Man Ng R, Ignace Wei W (2008) Identification of pyruvate kinase type M2 as a potential oncoprotein in squamous cell carcinoma of tongue through microRNA profiling. Int J Cancer 123(2):251–257Google Scholar
  77. Yamamoto Y, Yoshioka Y, Minoura K, Takahashi RU, Takeshita F, Taya T, Horii R, Fukuoka Y, Kato T, Kosaka N, Ochiya T (2011) An integrative genomic analysis revealed the relevance of microRNA and gene expression for drug-resistance in human breast cancer cells. Mol Cancer 3(10):135CrossRefGoogle Scholar
  78. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu CG, Croce CM, Harris CC (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9(3):189–198PubMedCrossRefGoogle Scholar
  79. Yang SM, Huang C, Li XF, Yu MZ, He Y, Li J (2013) miR-21 confers cisplatin resistance in gastric cancer cells by regulating PTEN. Toxicology 5(306):162–168CrossRefGoogle Scholar
  80. Yuya-Aydemir Y, Simkin A, Gascon E, Gao FB (2011) MicroRNA-9: functional evolution of a conserved small regulatory RNA. RNA Biol 8:557–564CrossRefGoogle Scholar
  81. Zhuang G, Wu X, Jiang Z, Kasman I, Yao J, Guan Y, Oeh J, Modrusan Z, Bais C, Sampath D (2013) Ferrara N Tumor secreted mir9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J 31:3513–3523CrossRefGoogle Scholar
  82. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer diabetes, and ageing. Nat Rev Mol Cell Biol 12:21–35PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Pathology and Anatomical SciencesUniversity of Missouri School of MedicineColumbiaUSA
  2. 2.Department of Chemistry and BiochemistryHarper Cancer Research InstituteSouth BendUSA

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