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miR-139-5p inhibits aerobic glycolysis, cell proliferation, migration, and invasion in hepatocellular carcinoma via a reciprocal regulatory interaction with ETS1

Oncogene volume 37, pages 1624–1636 (2018)Cite this article

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Abstract

Cancer cells have metabolic features that allow them to preferentially metabolize glucose through aerobic glycolysis, providing them with a progression advantage. However, microRNA (miRNA) regulation of aerobic glycolysis in cancer cells has not been extensively investigated. We addressed this in the present study by examining the regulation of miR-139-5p on aerobic glycolysis of hepatocellular carcinoma (HCC) using clinical specimens, HCC cells, and a mouse xenograft model. We found that overexpressing miR-139-5p restrained aerobic glycolysis, suppressing proliferation, migration, and invasion in HCC cells. miR-139-5p regulated hexokinase 1 (HK1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression by directly targeting the transcription factor ETS1, which bound to the promoters of the HK1 and PFKFB3 genes. miR-139-5p-induced aerobic glycolysis, proliferation, migration, and invasion were reversed by ETS1 overexpression, while ETS1 silencing induced the expression of miR-139-5p via a post-transcriptional regulation mode involving Drosha. miR-139-5p expression was reduced in HCC compared to para-carcinoma tissue, which was confirmed in The Cancer Genome Atlas and GSE54751 HCC cohorts. Notably, the lower expression of mir-139 was correlated with worse prognosis. These outcomes indicate that reciprocal regulatory interactions between miR-139-5p and ETS1 modulate aerobic glycolysis, proliferation, and metastasis in HCC cells, suggesting new targets for HCC treatment.

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References

  1. Endig J, Buitrago-Molina LE, Marhenke S, Reisinger F, Saborowski A, Schutt J, et al. Dual role of the adaptive immune system in liver injury and hepatocellular carcinoma development. Cancer Cell. 2016;30:308–23.

    Article  CAS  Google Scholar 

  2. Tsoulfas G, Kawai T, Elias N, Ko SC, Agorastou P, Cosimi AB, et al. Long-term experience with liver transplantation for hepatocellular carcinoma. J Gastroenterol. 2011;46:249–56.

    Article  Google Scholar 

  3. Zeng S, Zhang Y, Ma J, Deng G, Qu Y, Guo C, et al. BMP4 promotes metastasis of hepatocellular carcinoma by an induction of epithelial–mesenchymal transition via upregulating ID2. Cancer Lett. 2017;390:67–76.

    Article  CAS  Google Scholar 

  4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  Google Scholar 

  5. Warburg O, On the origin of cancer cells. Sci (New York, NY). 1956;123:309–14.

    Article  CAS  Google Scholar 

  6. Nie H, Li J, Yang XM, Cao QZ, Feng MX, Xue F, et al. Mineralocorticoid receptor suppresses cancer progression and the Warburg effect by modulating the miR-338-3p-PKLR axis in hepatocellular carcinoma. Hepatol (Baltim, Md). 2015;62:1145–59.

    Article  CAS  Google Scholar 

  7. Vander Heiden MG, Cantley LC, Thompson CB, Understanding the Warburg effect: the metabolic requirements of cell proliferation. Sci (New York, NY). 2009;324:1029–33.

    Article  Google Scholar 

  8. Hu J, Sun T, Wang H, Chen Z, Wang S, Yuan L, et al. MiR-215 is induced post-transcriptionally via HIF-Drosha complex and mediates glioma-initiating cell adaptation to hypoxia by targeting KDM1B. Cancer Cell. 2016;29:49–60.

    Article  CAS  Google Scholar 

  9. Nucera S, Giustacchini A, Boccalatte F, Calabria A, Fanciullo C, Plati T, et al. miRNA-126 orchestrates an oncogenic program in B cell precursor acute lymphoblastic leukemia. Cancer Cell. 2016;29:905–21.

    Article  CAS  Google Scholar 

  10. Rayner KJ, Suarez Y, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Sci (New York, NY). 2010;328:1570–3.

    Article  CAS  Google Scholar 

  11. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762–5.

    Article  CAS  Google Scholar 

  12. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–22.

    Article  CAS  Google Scholar 

  13. Pichiorri F, Suh SS, Rocci A, De Luca L, Taccioli C, Santhanam R, et al. Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer Cell. 2016;30:349–51.

    Article  CAS  Google Scholar 

  14. Liu L, Wang Y, Bai R, Yang K, Tian Z. MiR-186 inhibited aerobic glycolysis in gastric cancer via HIF-1alpha regulation. Oncogenesis. 2017;6:e318.

    Article  CAS  Google Scholar 

  15. Guo W, Qiu Z, Wang Z, Wang Q, Tan N, Chen T, et al. MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer. Hepatol (Baltim, Md). 2015;62:1132–44.

    Article  CAS  Google Scholar 

  16. Ma X, Li C, Sun L, Huang D, Li T, He X, et al. Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1. Nat Commun. 2014;5:5212.

    Article  Google Scholar 

  17. Li L, Kang L, Zhao W, Feng Y, Liu W, Wang T, et al. miR-30a-5p suppresses breast tumor growth and metastasis through inhibition of LDHA-mediated Warburg effect. Cancer Lett. 2017;400:89–98.

    Article  CAS  Google Scholar 

  18. Shen K, Mao R, Ma L, Li Y, Qiu Y, Cui D, et al. Post-transcriptional regulation of the tumor suppressor miR-139-5p and a network of miR-139-5p-mediated mRNA interactions in colorectal cancer. FEBS J. 2014;281:3609–24.

    Article  CAS  Google Scholar 

  19. Rupaimoole R, Wu SY, Pradeep S, Ivan C, Pecot CV, Gharpure KM, et al. Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression. Nat Commun. 2014;5:5202.

    Article  Google Scholar 

  20. Chabre O, Libe R, Assie G, Barreau O, Bertherat J, Bertagna X, et al. Serum miR-483-5p and miR-195 are predictive of recurrence risk in adrenocortical cancer patients. Endocr Relat Cancer. 2013;20:579–94.

    Article  CAS  Google Scholar 

  21. Wong CC, Wong CM, Tung EK, Au SL, Lee JM, Poon RT, et al. The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. Gastroenterology. 2011;140:322–31.

    Article  CAS  Google Scholar 

  22. Xu K, Shen K, Liang X, Li Y, Nagao N, Li J, et al. MiR-139-5p reverses CD44 + /CD133 + -associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells. Oncotarget. 2016;7:75118–29.

    PubMed  PubMed Central  Google Scholar 

  23. Li Q, Liang X, Wang Y, Meng X, Xu Y, Cai S, et al. miR-139-5p inhibits the epithelial–mesenchymal transition and enhances the chemotherapeutic sensitivity of colorectal cancer cells by downregulating BCL2. Sci Rep. 2016;6:27157.

    Article  CAS  Google Scholar 

  24. Guo J, Miao Y, Xiao B, Huan R, Jiang Z, Meng D, et al. Differential expression of microRNA species in human gastric cancer versus non-tumorous tissues. J Gastroenterol Hepatol. 2009;24:652–7.

    Article  CAS  Google Scholar 

  25. Haakensen VD, Nygaard V, Greger L, Aure MR, Fromm B, Bukholm IR, et al. Subtype-specific micro-RNA expression signatures in breast cancer progression. Int J Cancer. 2016;139:1117–28.

    Article  CAS  Google Scholar 

  26. Corbetta S, Vaira V, Guarnieri V, Scillitani A, Eller-Vainicher C, Ferrero S, et al. Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue. Endocr Relat Cancer. 2010;17:135–46.

    Article  CAS  Google Scholar 

  27. Hiroki E, Akahira J, Suzuki F, Nagase S, Ito K, Suzuki T, et al. Changes in microRNA expression levels correlate with clinicopathological features and prognoses in endometrial serous adenocarcinomas. Cancer Sci. 2010;101:241–9.

    Article  CAS  Google Scholar 

  28. Emmrich S, Engeland F, El-Khatib M, Henke K, Obulkasim A, Schoning J, et al. miR-139-5p controls translation in myeloid leukemia through EIF4G2. Oncogene. 2016;35:1822–31.

    Article  CAS  Google Scholar 

  29. Huang Y, Chen HC, Chiang CW, Yeh CT, Chen SJ, Chou CK. Identification of a two-layer regulatory network of proliferation-related microRNAs in hepatoma cells. Nucleic Acids Res. 2012;40:10478–93.

    Article  CAS  Google Scholar 

  30. Au SL, Wong CC, Lee JM, Fan DN, Tsang FH, Ng IO, et al. Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatol (Baltim, Md). 2012;56:622–31.

    Article  CAS  Google Scholar 

  31. Findlay VJ, LaRue AC, Turner DP, Watson PM, Watson DK. Understanding the role of ETS-mediated gene regulation in complex biological processes. Adv Cancer Res. 2013;119:1–61.

    Article  CAS  Google Scholar 

  32. He G, Tolic A, Bashkin JK. Heterogeneous dynamics in DNA site discrimination by the structurally homologous DNA-binding domains of ETS-family transcription factors. Nucleic Acids Res. 2015;43:4322–31.

    Article  CAS  Google Scholar 

  33. Wang C, Kam RK, Shi W, Xia Y, Chen X, Cao Y, et al. The proto-oncogene transcription factor Ets1 regulates neural crest development through histone deacetylase 1 to mediate output of bone morphogenetic protein signaling. J Biol Chem. 2015;290:21925–38.

    Article  CAS  Google Scholar 

  34. Dong Z. Acetylation of Ets-1 is the key to chromatin remodeling for miR-192 expression. Sci Signal. 2013;6:pe21.

    Article  Google Scholar 

  35. Zhao J, Lu B, Xu H, Tong X, Wu G, Zhang X, et al. Thirty-kilodalton Tat-interacting protein suppresses tumor metastasis by inhibition of osteopontin transcription in human hepatocellular carcinoma. Hepatol (Baltim, Md). 2008;48:265–75.

    Article  CAS  Google Scholar 

  36. Adam M, Schmidt D, Wardelmann E, Wernert N, Albers P. Angiogenetic protooncogene ets-1 induced neovascularization is involved in the metastatic process of testicular germ cell tumors. Eur Urol. 2003;44:329–36.

    Article  CAS  Google Scholar 

  37. Zhang Y, Yan LX, Wu QN, Du ZM, Chen J, Liao DZ, et al. miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer. Cancer Res. 2011;71:3552–62.

    Article  CAS  Google Scholar 

  38. Dittmer J. The role of the transcription factor Ets1 in carcinoma. Semin Cancer Biol. 2015;35:20–38.

    Article  CAS  Google Scholar 

  39. Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 2009;11:228–34.

    Article  CAS  Google Scholar 

  40. Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 2014;15:509–24.

    Article  CAS  Google Scholar 

  41. Bao W, Fu HJ, Xie QS, Wang L, Zhang R, Guo ZY, et al. HER2 interacts with CD44 to up-regulate CXCR4 via epigenetic silencing of microRNA-139 in gastric cancer cells. Gastroenterology. 2011;141:2076. e2076.

    Article  CAS  Google Scholar 

  42. Shen J, LeFave C, Sirosh I, Siegel AB, Tycko B, Santella RM. Integrative epigenomic and genomic filtering for methylation markers in hepatocellular carcinomas. BMC Med Genom. 2015;8:28.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by Nation’s Nature Science Foundation of China (Grant nos. 81472711, 91540111, 81672756, 81401180, and 81372283) and the Guangdong Province Nature Science Foundation (Grant no. 2014A030311013).

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Authors and Affiliations

  1. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Shengni Hua, Ling Lei, Ling Deng, Chengdong Liu, Dongyan Zhang, Chuanhui Cao & Dehua Wu

  2. Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Xie Weng, Xuejing Zou & Li Liu

  3. Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Xiaolong Qi

  4. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Shuang Wang

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Hua, S., Lei, L., Deng, L. et al. miR-139-5p inhibits aerobic glycolysis, cell proliferation, migration, and invasion in hepatocellular carcinoma via a reciprocal regulatory interaction with ETS1. Oncogene 37, 1624–1636 (2018). https://doi.org/10.1038/s41388-017-0057-3

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