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Myc target gene, long intergenic noncoding RNA, Linc00176 in hepatocellular carcinoma regulates cell cycle and cell survival by titrating tumor suppressor microRNAs

Oncogene volume 37, pages 75–85 (2018)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is a frequent form of cancer with a poor prognosis and with limited possibilities for medical intervention. Recent evidence has accumulated that long noncoding RNAs (lncRNAs) are important regulators of disease processes including cancer. Chromatin remodeling in cancer cells may result in an unusual expression of lncRNAs and indeed it has been shown that more than 7000 unannotated lncRNAs are expressed in HCCs. We identified a novel long intergenic noncoding RNA, Linc00176, that plays a role in proliferation and survival of HCC. Linc00176 regulates expression of more than 200 genes by the sponge function for tumor suppressor miRNAs, miR-9 and miR-185. Linc00176 is expressed at a high level only in HCC, and is activated by Myc, Max and AP-4 transcription regulators. Myc also upregulates miR-9 and miR-185. In Linc00176-depleted HCC, these miRNAs were released from Linc00176 and downregulated their target mRNAs. Thus, depletion of Linc00176 disrupted the cell cycle and induced necroptosis in HCC via released tumor suppressor miRNAs. These data indicate that atypically expressed lncRNAs may be useful targets for cancer therapy.

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Accession codes

Accessions

Gene Expression Omnibus

Abbreviations

LincRNA:

long intergenic noncoding RNA

HCC:

hepatocellular carcinoma

THOC5 :

suppressors of the transcriptional defects of hpr1 delta by overexpression

GST:

glutathione S transferase

DAPI:

4′,6-diamidin-2-phenylindole

TUNEL:

terminal deoxynucleotidyl transferase dUTP nick end labeling.

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.

    Article  Google Scholar 

  2. Whittaker S, Marais R, Zhu AX . The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 2010; 29: 4989–5005.

    Article  CAS  Google Scholar 

  3. Ferrin G, Aguilar-Melero P, Rodriguez-Peralvarez M, Montero-Alvarez JL, de la Mata M . Biomarkers for hepatocellular carcinoma: diagnostic and therapeutic utility. Hepat Med 2015; 7: 1–10.

    PubMed  PubMed Central  Google Scholar 

  4. Schulze K, Imbeaud S, Letouze E, Alexandrov LB, Calderaro J, Rebouissou S et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015; 47: 505–511.

    Article  CAS  PubMed Central  Google Scholar 

  5. Consortium EP Consortium EP Birney E Consortium EP Stamatoyannopoulos JA Consortium EP Dutta A Consortium EP Guigo R Consortium EP Gingeras TR et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007; 447: 799–816.

    Article  Google Scholar 

  6. Evans JR, Feng FY, Chinnaiyan AM . The bright side of dark matter: lncRNAs in cancer. J Clin Invest 2016; 126: 2775–2782.

    Article  PubMed Central  Google Scholar 

  7. Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y et al. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet 2015; 47: 199–208.

    Article  CAS  PubMed Central  Google Scholar 

  8. Yang Y, Chen L, Gu J, Zhang H, Yuan J, Lian Q et al. Recurrently deregulated lncRNAs in hepatocellular carcinoma. Nat Commun 2017; 8: 14421.

    Article  CAS  PubMed Central  Google Scholar 

  9. Chen LL . Linking long noncoding RNA localization and function. Trends Biochem Sci 2016; 41: 761–772.

    Article  CAS  Google Scholar 

  10. Saran S, Tran DD, Ewald F, Koch A, Hoffmann A, Koch M et al. Depletion of three combined THOC5 mRNA export protein target genes synergistically induces human hepatocellular carcinoma cell death. Oncogene 2015; 35: 3872–3879.

    Article  Google Scholar 

  11. Padgett RA . New connections between splicing and human disease. Trends Genet 2012; 28: 147–154.

    Article  CAS  PubMed Central  Google Scholar 

  12. Martin G, Gruber AR, Keller W, Zavolan M . Genome-wide analysis of pre-mRNA 3' end processing reveals a decisive role of human cleavage factor I in the regulation of 3' UTR length. Cell Rep 2012; 1: 753–763.

    Article  CAS  Google Scholar 

  13. Luscher B, Vervoorts J . Regulation of gene transcription by the oncoprotein MYC. Gene 2012; 494: 145–160.

    Article  Google Scholar 

  14. Jung P, Hermeking H . The c-MYC-AP4-p21 cascade. Cell Cycle 2009; 8: 982–989.

    Article  CAS  Google Scholar 

  15. Bossone SA, Asselin C, Patel AJ, Marcu KB . MAZ, a zinc finger protein, binds to c-MYC and C2 gene sequences regulating transcriptional initiation and termination. Proc Natl Acad Sci USA 1992; 89: 7452–7456.

    Article  CAS  Google Scholar 

  16. Deng H, Jiang Q, Yang Y, Zhang S, Ma Y, Xie G et al. Intravenous liposomal delivery of the short hairpin RNAs against Plk1 controls the growth of established human hepatocellular carcinoma. Cancer Biol Ther 2011; 11: 401–409.

    Article  CAS  Google Scholar 

  17. Remijsen Q, Goossens V, Grootjans S, Van den Haute C, Vanlangenakker N, Dondelinger Y et al. Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis. Cell Death Dis 2014; 5: e1004.

    Article  CAS  PubMed Central  Google Scholar 

  18. Steitz JA, Vasudevan S . miRNPs: versatile regulators of gene expression in vertebrate cells. Biochem Soc Trans 2009; 37 (Pt 5): 931–935.

    Article  CAS  Google Scholar 

  19. Betel D, Koppal A, Agius P, Sander C, Leslie C . Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome Biol 2010; 11: R90.

    Article  PubMed Central  Google Scholar 

  20. Zhang J, Cheng J, Zeng Z, Wang Y, Li X, Xie Q et al. Comprehensive profiling of novel microRNA-9 targets and a tumor suppressor role of microRNA-9 via targeting IGF2BP1 in hepatocellular carcinoma. Oncotarget 2015; 6: 42040–42052.

    PubMed  PubMed Central  Google Scholar 

  21. Wu WL, Wang WY, Yao WQ, Li GD . Suppressive effects of microRNA-16 on the proliferation, invasion and metastasis of hepatocellular carcinoma cells. Int J Mol Med 2015; 36: 1713–1719.

    Article  Google Scholar 

  22. Zhu XC, Dong QZ, Zhang XF, Deng B, Jia HL, Ye QH et al. microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma. Int J Mol Med 2012; 30: 1321–1326.

    Article  CAS  Google Scholar 

  23. Kim HS, Lee KS, Bae HJ, Eun JW, Shen Q, Park SJ et al. MicroRNA-31 functions as a tumor suppressor by regulating cell cycle and epithelial-mesenchymal transition regulatory proteins in liver cancer. Oncotarget 2015; 6: 8089–8102.

    PubMed  PubMed Central  Google Scholar 

  24. Dang YW, Zeng J, He RQ, Rong MH, Luo DZ, Chen G . Effects of miR-152 on cell growth inhibition, motility suppression and apoptosis induction in hepatocellular carcinoma cells. Asian Pac J Cancer Prev 2014; 15: 4969–4976.

    Article  Google Scholar 

  25. Qadir XV, Han C, Lu D, Zhang J, Wu T . miR-185 inhibits hepatocellular carcinoma growth by targeting the DNMT1/PTEN/Akt pathway. Am J Pathol 2014; 184: 2355–2364.

    Article  CAS  PubMed Central  Google Scholar 

  26. Yoon JH, Srikantan S, Gorospe M . MS2-TRAP (MS2-tagged RNA affinity purification): tagging RNA to identify associated miRNAs. Methods 2012; 58: 81–87.

    Article  CAS  PubMed Central  Google Scholar 

  27. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 2012; 22: 1775–1789.

    Article  CAS  PubMed Central  Google Scholar 

  28. Higashi T, Hayashi H, Ishimoto T, Takeyama H, Kaida T, Arima K et al. miR-9-3p plays a tumour-suppressor role by targeting TAZ (WWTR1) in hepatocellular carcinoma cells. Br J Cancer 2015; 113: 252–258.

    Article  CAS  PubMed Central  Google Scholar 

  29. Cai L, Cai X . Up-regulation of miR-9 expression predicate advanced clinicopathological features and poor prognosis in patients with hepatocellular carcinoma. Diagn Pathol 2014; 9: 1000.

    Article  PubMed Central  Google Scholar 

  30. Drakaki A, Hatziapostolou M, Polytarchou C, Vorvis C, Poultsides GA, Souglakos J et al. Functional microRNA high throughput screening reveals miR-9 as a central regulator of liver oncogenesis by affecting the PPARA-CDH1 pathway. BMC Cancer 2015; 15: 542.

    Article  PubMed Central  Google Scholar 

  31. Sun J, Fang K, Shen H, Qian Y . MicroRNA-9 is a ponderable index for the prognosis of human hepatocellular carcinoma. Int J Clin Exp Med 2015; 8: 17748–17756.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhu S, Li W, Liu J, Chen CH, Liao Q, Xu P et al. Genome-scale deletion screening of human long non-coding RNAs using a paired-guide RNA CRISPR-Cas9 library. Nat Biotechnol 2016; 34: 1279–1286.

    Article  CAS  PubMed Central  Google Scholar 

  33. Levens D . How the c-myc promoter works and why it sometimes does not. J Natl Cancer Inst Monogr 2008; 39: 41–43.

    Article  CAS  Google Scholar 

  34. Liu SJ, Horlbeck MA, Cho SW, Birk HS, Malatesta M, He D et al. CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells. Science 2017; 355: pii.aah7111.

    Article  Google Scholar 

  35. Tran DD, Koch A, Allister A, Saran S, Ewald F, Koch M et al. Treatment with MAPKAP2 (MK2) inhibitor and DNA methylation inhibitor, 5-aza dC, synergistically triggers apoptosis in hepatocellular carcinoma (HCC) via tristetraprolin (TTP). Cell Signal 2016; 28: 1872–1880.

    Article  CAS  Google Scholar 

  36. Guria A, Tran DD, Ramachandran S, Koch A, El Bounkari O, Dutta P et al. Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts. RNA 2011; 17: 1048–1056.

    Article  CAS  PubMed Central  Google Scholar 

  37. Tamura T, Mancini A, Joos H, Koch A, Hakim C, Dumanski J et al. FMIP, a novel Fms-interacting protein, affects granulocyte/macrophage differentiation. Oncogene 1999; 18: 6488–6495.

    Article  CAS  Google Scholar 

  38. Yang JS, Nam HJ, Seo M, Han SK, Choi Y, Nam HG et al. OASIS: online application for the survival analysis of lifespan assays performed in aging research. PLoS ONE 2011; 6: e23525.

    Article  CAS  PubMed Central  Google Scholar 

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Acknowledgements

We thank C Bruce Boschek for critically reading the manuscript. This work is a part of thesis of CK. This research was supported by Deutsche Krebshilfe (111153), DFG Ta-111/13-3, Niedersächsische Krebsgesellschaft to AK and DDHT, PhD program Molecular Medicine and Structure Medicine in HBRS and Leistungsorientierte Mittelvergabe with Frauenfaktor from MHH.

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  1. D D H Tran and C Kessler: These two authors contributed equally to this work.

Authors and Affiliations

  1. Institut fuer Biochemie, OE4310, Medizinische Hochschule Hannover, Hannover, Germany

    D D H Tran, C Kessler, S E Niehus, M Mahnkopf, A Koch & T Tamura

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  1. D D H Tran
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Correspondence to T Tamura.

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Tran, D., Kessler, C., Niehus, S. et al. Myc target gene, long intergenic noncoding RNA, Linc00176 in hepatocellular carcinoma regulates cell cycle and cell survival by titrating tumor suppressor microRNAs. Oncogene 37, 75–85 (2018). https://doi.org/10.1038/onc.2017.312

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