Abstract
Purpose
To investigate the expression of SRHC and the role of SRHC in the pathogenesis of hepatocellular carcinoma (HCC).
Methods
We analyzed HCC samples and matched non-tumor liver tissues (controls) collected from 81 patients who underwent hepatectomy in Shanghai, China. The expression levels of SRHC were determined by quantitative reverse-transcription polymerase chain reaction. Statistical analyses were used to associate the levels of SRHC with tumor features and patient outcomes.
Results
We found that a lower SRHC expression level was significantly more frequent in tissues with a high serum a-fetoprotein level (positive, >20 µg/L, P = 0.004) and a low degree of differentiated tumors (poorly differentiated, P = 0.017). Furthermore, we found that the promoter region of SRHC contains a CpG-rich island and that SRHC is down-regulated in tumors by DNA methylation.
Conclusion
Here, we identified a new long noncoding RNA designated as SRHC that is capable of inhibiting cancer proliferation and is down-regulated in tumors at least partly by DNA methylation.
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References
Block TM, Mehta AS, Fimmel CJ, Jordan R (2003) Molecular viral oncology of hepatocellular carcinoma. Oncogene 22(33):5093–5107. doi:10.1038/sj.onc.1206557
Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, Wang XW (2006) Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 10(2):99–111. doi:10.1016/j.ccr.2006.06.016
Chen CJ, Chen DS (2002) Interaction of hepatitis B virus, chemical carcinogen, and genetic susceptibility: multistage hepatocarcinogenesis with multifactorial etiology. Hepatology 36(5):1046–1049. doi:10.1053/jhep.2002.37084
Du Y, Kong G, You X, Zhang S, Zhang T, Gao Y, Zhang X (2012) Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. J Biol Chem 287(31):26302–26311. doi:10.1074/jbc.M112.342113
Eissmann M, Gutschner T, Hammerle M, Gunther S, Caudron-Herger M, Gross M, Diederichs S (2012) Loss of the abundant nuclear non-coding RNA MALAT1 is compatible with life and development. RNA Biol 9(8):1076–1087. doi:10.4161/rna.21089
El-Serag HB (2012) Surveillance for hepatocellular carcinoma: long way to achieve effectiveness. Dig Dis Sci 57(12):3050–3051. doi:10.1007/s10620-012-2413-z
Gonzalez FJ (2008) Regulation of hepatocyte nuclear factor 4 alpha-mediated transcription. Drug Metab Pharmacokinet 23(1):2–7
Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ (2001) Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21(4):1393–1403. doi:10.1128/MCB.21.4.1393-1403.2001
Huang JF, Guo YJ, Zhao CX, Yuan SX, Wang Y, Tang GN, Sun SH (2013) Hepatitis B virus X protein (HBx)-related long noncoding RNA (lncRNA) down-regulated expression by HBx (Dreh) inhibits hepatocellular carcinoma metastasis by targeting the intermediate filament protein vimentin. Hepatology 57(5):1882–1892. doi:10.1002/hep.26195
Inoue Y, Peters LL, Yim SH, Inoue J, Gonzalez FJ (2006a) Role of hepatocyte nuclear factor 4alpha in control of blood coagulation factor gene expression. J Mol Med (Berl) 84(4):334–344. doi:10.1007/s00109-005-0013-5
Inoue Y, Yu AM, Yim SH, Ma X, Krausz KW, Inoue J, Gonzalez FJ (2006b) Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4alpha. J Lipid Res 47(1):215–227. doi:10.1194/jlr.M500430-JLR200
Lagisetti C, Palacios G, Goronga T, Freeman B, Caufield W, Webb TR (2013) Optimization of antitumor modulators of pre-mRNA splicing. J Med Chem 56(24):10033–10044. doi:10.1021/jm401370h
Lan SH, Wu SY, Zuchini R, Lin XZ, Su IJ, Tsai TF, Liu HS (2014) Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224. Hepatology 59(2):505–517. doi:10.1002/hep.26659
Lazarevich NL, Cheremnova OA, Varga EV, Ovchinnikov DA, Kudrjavtseva EI, Morozova OV, Duncan SA (2004) Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors. Hepatology 39(4):1038–1047. doi:10.1002/hep.20155
Liu Y, Zhang JB, Qin Y, Wang W, Wei L, Teng Y, Xie Y (2013) PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1alpha expression and protein stability. Hepatology 58(2):692–705. doi:10.1002/hep.26398
Nagano T, Fraser P (2011) No-nonsense functions for long noncoding RNAs. Cell 145(2):178–181. doi:10.1016/j.cell.2011.03.014
Ning BF, Ding J, Yin C, Zhong W, Wu K, Zeng X, Xie WF (2010) Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma. Cancer Res 70(19):7640–7651. doi:10.1158/0008-5472.CAN-10-0824
Orom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G, Shiekhattar R (2010) Long noncoding RNAs with enhancer-like function in human cells. Cell 143(1):46–58. doi:10.1016/j.cell.2010.09.001
Prensner JR, Chinnaiyan AM (2011) The emergence of lncRNAs in cancer biology. Cancer Discov 1(5):391–407. doi:10.1158/2159-8290.CD-11-0209
Prensner JR, Iyer MK, Sahu A, Asangani IA, Cao Q, Patel L, Chinnaiyan AM (2013) The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet 45(11):1392–1398. doi:10.1038/ng.2771
Qureshi IA, Mattick JS, Mehler MF (2010) Long non-coding RNAs in nervous system function and disease. Brain Res 1338:20–35. doi:10.1016/j.brainres.2010.03.110
Sladek FM (1993) Orphan receptor HNF-4 and liver-specific gene expression. Receptor 3(3):223–232
Sladek FM, Zhong WM, Lai E, Darnell JE Jr (1990) Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev 4(12B):2353–2365
Tan YJ (2011) Hepatitis B virus infection and the risk of hepatocellular carcinoma. World J Gastroenterol 17(44):4853–4857. doi:10.3748/wjg.v17.i44.4853
Tripathi V, Shen Z, Chakraborty A, Giri S, Freier SM, Wu X, Prasanth KV (2013) Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet 9(3):e1003368. doi:10.1371/journal.pgen.1003368
van Malenstein H, Verslype C, Windmolders P, van Eijsden R, Nevens F, van Pelt J (2012) Characterization of a cell culture model for clinically aggressive hepatocellular carcinoma induced by chronic hypoxia. Cancer Lett 315(2):178–188. doi:10.1016/j.canlet.2011.09.039
Walesky C, Edwards G, Borude P, Gunewardena S, O’Neil M, Yoo B, Apte U (2013) Hepatocyte nuclear factor 4 alpha deletion promotes diethylnitrosamine-induced hepatocellular carcinoma in rodents. Hepatology 57(6):2480–2490. doi:10.1002/hep.26251
Whittaker S, Marais R, Zhu AX (2010) The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 29(36):4989–5005. doi:10.1038/onc.2010.236
Wilusz JE, Sunwoo H, Spector DL (2009) Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 23(13):1494–1504. doi:10.1101/gad.1800909
Xu L, Hui L, Wang S, Gong J, Jin Y, Wang Y, Hu G (2001) Expression profiling suggested a regulatory role of liver-enriched transcription factors in human hepatocellular carcinoma. Cancer Res 61(7):3176–3181
Xu Y, Hu B, Choi AJ, Gopalan B, Lee BH, Kalady MF, Ting AH (2012) Unique DNA methylome profiles in CpG island methylator phenotype colon cancers. Genome Res 22(2):283–291. doi:10.1101/gr.122788.111
Yang F, Huo XS, Yuan SX, Zhang L, Zhou WP, Wang F, Sun SH (2013) Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis. Mol Cell 49(6):1083–1096. doi:10.1016/j.molcel.2013.01.010
Zhang L, Yang F, Yuan JH, Yuan SX, Zhou WP, Huo XS, Sun SH (2013) Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma. Carcinogenesis 34(3):577–586. doi:10.1093/carcin/bgs381
Zhu Z, Gao X, He Y, Zhao H, Yu Q, Jiang D, Gao Y (2012) An insertion/deletion polymorphism within RERT-lncRNA modulates hepatocellular carcinoma risk. Cancer Res 72(23):6163–6172. doi:10.1158/0008-5472.CAN-12-0010
Acknowledgments
The authors acknowledge Shuai Li for his detailed bioinformatics analysis of SRHC.
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We declare that we have no conflict of interest.
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Hao Zheng and Sen Yang have contributed equally to this study.
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Zheng, H., Yang, S., Yang, Y. et al. Epigenetically silenced long noncoding-SRHC promotes proliferation of hepatocellular carcinoma. J Cancer Res Clin Oncol 141, 1195–1203 (2015). https://doi.org/10.1007/s00432-014-1871-4
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DOI: https://doi.org/10.1007/s00432-014-1871-4