Advertisement

Cytotechnology

, Volume 70, Issue 2, pp 513–521 | Cite as

microRNA-889 is downregulated by histone deacetylase inhibitors and confers resistance to natural killer cytotoxicity in hepatocellular carcinoma cells

  • Haitao Xie
  • Qiugui Zhang
  • Hui Zhou
  • Jun Zhou
  • Ji Zhang
  • Yan Jiang
  • Jinghong Wang
  • Xianglin Meng
  • Leping Zeng
  • Xiaoxin Jiang
Original Article

Abstract

Major histocompatibility complex class I chain-related gene B (MICB) is expressed on tumor cells and participates in natural killer (NK) cell-mediated antitumor immune response through engagement with the NKG2D receptor. This study was undertaken to identify novel microRNA (miRNA) regulators of MICB and clarify their functions in NK cell-mediated cytotoxicity to hepatocellular carcinoma (HCC) cells. Bioinformatic analysis and luciferase reporter assay were conducted to search for MICB-targeting miRNAs. Overexpression and knockdown experiments were performed to determine the roles of candidate miRNAs in the susceptibility of HCC cells to NK lysis. miR-889 was identified as a novel MICB-targeting miRNA and overexpression of miR-889 significantly inhibited the mRNA and protein expression of MICB in HepG2 and SMMC7721 HCC cells. miR-889 expression had a negative correlation with MICB mRNA levels in HCC specimens (r = −0.392, P = 0.0146). NK cell-mediated cytotoxicity was reduced in miR-889-overexpressing HCC cells, which was reversed by restoration of MICB expression. In contrast, knockdown of miR-889 led to more pronounced NK cell-mediated lysis in HCC cells. HCC cells exposed to the histone deacetylase (HDAC) inhibitor sodium valproate showed downregulation of miR-889. Enforced expression of miR-889 prevented the upregulation of MICB and enhancement of NK cell-mediated lysis by HDAC inhibitors. In conclusion, miR-889 upregulation attenuates the susceptibility of HCC cells to NK lysis and represents a potential target for improving NK cell-based antitumor therapies.

Keywords

Hepatocellular carcinoma Immune escape microRNA Natural killer cells Target gene 

Notes

Acknowledgements

This work was supported in part by the Hunan Province Natural Science Foundation of China (No. 14JJ2092).

References

  1. Amin PJ, Shankar BS (2015) Sulforaphane induces ROS mediated induction of NKG2D ligands in human cancer cell lines and enhances susceptibility to NK cell mediated lysis. Life Sci 126:19–27CrossRefGoogle Scholar
  2. Armeanu S, Bitzer M, Lauer UM, Venturelli S, Pathil A, Krusch M, Kaiser S, Jobst J, Smirnow I, Wagner A, Steinle A, Salih HR (2005) Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res 65:6321–6329CrossRefGoogle Scholar
  3. Codo P, Weller M, Meister G, Szabo E, Steinle A, Wolter M, Reifenberger G, Roth P (2014) MicroRNA-mediated down-regulation of NKG2D ligands contributes to glioma immune escape. Oncotarget 5:7651–7662CrossRefGoogle Scholar
  4. Fang L, Gong J, Wang Y, Liu R, Li Z, Wang Z, Zhang Y, Zhang C, Song C, Yang A, Ting JP, Jin B, Chen L (2014) MICA/B expression is inhibited by unfolded protein response and associated with poor prognosis in human hepatocellular carcinoma. J Exp Clin Cancer Res 33:76CrossRefGoogle Scholar
  5. Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T (1996) Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci USA. 93:12445–12450CrossRefGoogle Scholar
  6. Gu S, Jin L, Zhang F, Sarnow P, Kay MA (2009) Biological basis for restriction of microRNA targets to the 3′ untranslated region in mammalian mRNAs. Nat Struct Mol Biol 16:144–150CrossRefGoogle Scholar
  7. Lanier LL (2015) NKG2D Receptor and Its Ligands in Host Defense. Cancer Immunol Res 3:575–582CrossRefGoogle Scholar
  8. Min D, Lv XB, Wang X, Zhang B, Meng W, Yu F, Hu H (2013) Downregulation of miR-302c and miR-520c by 1,25(OH)2D3 treatment enhances the susceptibility of tumour cells to natural killer cell-mediated cytotoxicity. Br J Cancer 109:723–730CrossRefGoogle Scholar
  9. Molina-Pinelo S, Carnero A, Rivera F, Estevez-Garcia P, Bozada JM, Limon ML, Benavent M, Gomez J, Pastor MD, Chaves M, Suarez R, Paz-Ares L, de la Portilla F, Carranza-Carranza A, Sevilla I, Vicioso L, Garcia-Carbonero R (2014) MiR-107 and miR-99a-3p predict chemotherapy response in patients with advanced colorectal cancer. BMC Cancer 14:656CrossRefGoogle Scholar
  10. Pahl J, Cerwenka A (2017) Tricking the balance: NK cells in anti-cancer immunity. Immunobiology 222:11–20Google Scholar
  11. Paydas S, Acikalin A, Ergin M, Celik H, Yavuz B, Tanriverdi K (2016) Micro-RNA (miRNA) profile in Hodgkin lymphoma: association between clinical and pathological variables. Med Oncol 33:34CrossRefGoogle Scholar
  12. Ren J, Nie Y, Lv M, Shen S, Tang R, Xu Y, Hou Y, Zhao S, Wang T (2015) Estrogen upregulates MICA/B expression in human non-small cell lung cancer through the regulation of ADAM17. Cell Mol Immunol 12:768–776CrossRefGoogle Scholar
  13. Ribeiro CH, Kramm K, Gálvez-Jirón F, Pola V, Bustamante M, Contreras HR, Sabag A, Garrido-Tapia M, Hernández CJ, Zúñiga R, Collazo N, Sotelo PH, Morales C, Mercado L, Catalán D, Aguillón JC, Molina MC (2016) Clinical significance of tumor expression of major histocompatibility complex class I-related chains A and B (MICA/B) in gastric cancer patients. Oncol Rep 35:1309–1317CrossRefGoogle Scholar
  14. Schilling D, Tetzlaff F, Konrad S, Li W, Multhoff G (2015) A hypoxia-induced decrease of either MICA/B or Hsp70 on the membrane of tumor cells mediates immune escape from NK cells. Cell Stress Chaperones 20:139–147CrossRefGoogle Scholar
  15. Schmiedel D, Tai J, Yamin R, Berhani O, Bauman Y, Mandelboim O (2016) The RNA binding protein IMP3 facilitates tumor immune escape by downregulating the stress-induced ligands ULPB2 and MICB. Elife 5:e13426Google Scholar
  16. Svoronos AA, Engelman DM, Slack FJ (2016) OncomiR or tumor suppressor? The duplicity of microRNAs in cancer. Cancer Res 76:3666–3670CrossRefGoogle Scholar
  17. Tong HV, le Song H, Hoan NX, Cuong BK, Sy BT, Son HA, Quyet D, Binh VQ, Kremsner PG, Bock CT, Velavan TP, Toan NL (2015) Soluble MICB protein levels and platelet counts during hepatitis B virus infection and response to hepatocellular carcinoma treatment. BMC Infect Dis 15:25CrossRefGoogle Scholar
  18. Tsukerman P, Stern-Ginossar N, Gur C, Glasner A, Nachmani D, Bauman Y, Yamin R, Vitenshtein A, Stanietsky N, Bar-Mag T, Lankry D, Mandelboim O (2012) MiR-10b downregulates the stress-induced cell surface molecule MICB, a critical ligand for cancer cell recognition by natural killer cells. Cancer Res 72:5463–5472CrossRefGoogle Scholar
  19. Wang B, Wang Q, Wang Z, Jiang J, Yu SC, Ping YF, Yang J, Xu SL, Ye XZ, Xu C, Yang L, Qian C, Wang JM, Cui YH, Zhang X, Bian XW (2014) Metastatic consequences of immune escape from NK cell cytotoxicity by human breast cancer stem cells. Cancer Res 74:5746–5757CrossRefGoogle Scholar
  20. Wu J, Zhang XJ, Shi KQ, Chen YP, Ren YF, Song YJ, Li G, Xue YF, Fang YX, Deng ZJ, Xu X, Gao J, Tang KF (2014) Hepatitis B surface antigen inhibits MICA and MICB expression via induction of cellular miRNAs in hepatocellular carcinoma cells. Carcinogenesis 35:155–163CrossRefGoogle Scholar
  21. Xie J, Liu M, Li Y, Nie Y, Mi Q, Zhao S (2014) Ovarian tumor-associated microRNA-20a decreases natural killer cell cytotoxicity by downregulating MICA/B expression. Cell Mol Immunol 11:495–502CrossRefGoogle Scholar
  22. Xu Y, He J, Wang Y, Zhu X, Pan Q, Xie Q, Sun F (2015) miR-889 promotes proliferation of esophageal squamous cell carcinomas through DAB2IP. FEBS Lett 589:1127–1135CrossRefGoogle Scholar
  23. Yang H, Lan P, Hou Z, Guan Y, Zhang J, Xu W, Tian Z, Zhang C (2015) Histone deacetylase inhibitor SAHA epigenetically regulates miR-17-92 cluster and MCM7 to upregulate MICA expression in hepatoma. Br J Cancer 112:112–121CrossRefGoogle Scholar
  24. Zhang C, Wang Y, Zhou Z, Zhang J, Tian Z (2009) Sodium butyrate upregulates expression of NKG2D ligand MICA/B in HeLa and HepG2 cell lines and increases their susceptibility to NK lysis. Cancer Immunol Immunother 58:1275–1285CrossRefGoogle Scholar
  25. Zingoni A, Cecere F, Vulpis E, Fionda C, Molfetta R, Soriani A, Petrucci MT, Ricciardi MR, Fuerst D, Amendola MG, Mytilineos J, Cerboni C, Paolini R, Cippitelli M, Santoni A (2015) Genotoxic stress induces senescence-associated ADAM10-dependent release of NKG2D MIC ligands in multiple myeloma cells. J Immunol 195:736–748CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  • Haitao Xie
    • 1
  • Qiugui Zhang
    • 1
  • Hui Zhou
    • 2
  • Jun Zhou
    • 3
  • Ji Zhang
    • 4
  • Yan Jiang
    • 1
  • Jinghong Wang
    • 1
  • Xianglin Meng
    • 1
  • Leping Zeng
    • 5
  • Xiaoxin Jiang
    • 1
  1. 1.Department of Clinical LaboratoryThe First Affiliated Hospital, University of South ChinaHengyangChina
  2. 2.Tumor Hospital Xiangya School of Medicine of Central South UniversityChangshaChina
  3. 3.Department of RehabilitationThe First Affiliated Hospital, University of South ChinaHengyangChina
  4. 4.Laboratory of Rheumatology and ImmunologyThe First Affiliated Hospital, University of South ChinaHengyangChina
  5. 5.Department of Anatomy and Neurobiology, Biology Postdoctoral Workstation, Basic School of MedicineCentral South UniversityChangshaChina

Personalised recommendations