Association between indel polymorphism in the promoter region of lncRNA GAS5 and the risk of hepatocellular carcinoma.

The growth arrest special 5 (GAS5) is known to be involved in various cancers. However, its expression regulation remains unclear. Polymorphisms in the promoter region of GAS5 may affect its expression and be associated with cancer susceptibility. In this research, we first evaluated the association of a 5-base pair indel polymorphism (rs145204276) in the promoter region of GAS5 with hepatocelluar carcinoma (HCC) susceptibility in Chinese populations. Logistic regression analysis showed that the deletion allele of rs145204276 significantly increased the risk of HCC in two independent case control sets (1034 HCC and 1054 controls). Further genotype-phenotype association analysis revealed that the deletion allele was markedly correlated with higher expression of GAS5 in HCC tissues. The luciferase activity analysis in an in vitro reporter gene system suggested that the deletion allele improved an increased expression of GAS5 in three hepatoma cell lines. Intriguingly, overexpression of GAS5 displayed an anti-apoptosis effect in HCC cell lines, GAS5 knockdown could partially revert this anti-apoptosis effect, suggesting that GAS5 may act as a proto-oncogene in HCC, in contrast with its inhibitory role in other cancers. Further pyrosequencing revealed that the genotypes of rs145204276 were associated with methylation status of GAS5 promoter region. Taken together, our findings provided evidence that rs145204276 may contribute to hepatocarcinogenesis by affecting methylation status of the GAS5 promoter and subsequently its transcriptional activity thus serving as a potential therapy target for HCC.

[1]  C. Rupnarain,et al.  Colon cancer: genomics and apoptotic events , 2004, Biological chemistry.

[2]  M. Odeh,et al.  Relationship between tumor necrosis factor‐alpha and ammonia in patients with hepatic encephalopathy due to chronic liver failure , 2005, Annals of medicine.

[3]  M. Schuliga,et al.  Pro-inflammatory mediators increase levels of the noncoding RNA GAS5 in airway smooth muscle and epithelial cells. , 2015, Canadian journal of physiology and pharmacology.

[4]  M. Tong,et al.  Chronic hepatitis B and hepatocellular carcinoma. , 2010, Clinics in liver disease.

[5]  H. M. Reis,et al.  Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma , 2013, Nature Reviews Cancer.

[6]  Rajagopal N. Aravalli,et al.  Molecular mechanisms of hepatocellular carcinoma , 2008, Hepatology.

[7]  A. Hoffman,et al.  Aberrant allele-switch imprinting of a novel IGF1R intragenic antisense non-coding RNA in breast cancers. , 2015, European journal of cancer.

[8]  P. Conti,et al.  Cytokine patterns correlate with liver damage in patients with chronic hepatitis B and C. , 2006, Annals of clinical and laboratory science.

[9]  R. Kong,et al.  Long noncoding RNA GAS5 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer , 2014, Medical Oncology.

[10]  Long Yu,et al.  An insertion/deletion polymorphism within RERT-lncRNA modulates hepatocellular carcinoma risk. , 2012, Cancer research.

[11]  N. Matsubara,et al.  Allele-specific methylation analysis on upstream promoter region of H19 by methylation-specific PCR with confronting two-pair primers. , 2004, International Journal of Oncology.

[12]  E. Coccia,et al.  Regulation and expression of a growth arrest-specific gene (gas5) during growth, differentiation, and development. , 1992, Molecular and cellular biology.

[13]  Ming Sun,et al.  Decreased expression of long noncoding RNA GAS5 indicates a poor prognosis and promotes cell proliferation in gastric cancer , 2014, BMC Cancer.

[14]  Yuting Jiang,et al.  Association of HLA-G 3' UTR 14-bp insertion/deletion polymorphism with hepatocellular carcinoma susceptibility in a Chinese population. , 2011, DNA and cell biology.

[15]  R. Sethi,et al.  High serum level of matrix metalloproteinase 9 and promoter polymorphism - 1562 C:T as a new risk factor for metabolic syndrome. , 2014, DNA and cell biology.

[16]  Xing-Hua Li,et al.  Down-regulation of long non-coding RNA GAS5 is associated with the prognosis of hepatocellular carcinoma. , 2014, International journal of clinical and experimental pathology.

[17]  S. Spiegl-Kreinecker,et al.  Prognostic quality of activating TERT promoter mutations in glioblastoma: interaction with the rs2853669 polymorphism and patient age at diagnosis. , 2015, Neuro-oncology.

[18]  S. Gonzalo,et al.  Epigenetic alterations in aging. , 2010, Journal of applied physiology.

[19]  C. Peng,et al.  Downregulation of gas5 increases pancreatic cancer cell proliferation by regulating CDK6 , 2013, Cell and Tissue Research.

[20]  J. Herman,et al.  Alterations in DNA methylation: a fundamental aspect of neoplasia. , 1998, Advances in cancer research.

[21]  Jun-Tao Jiang,et al.  Downregulation of GAS5 Promotes Bladder Cancer Cell Proliferation, Partly by Regulating CDK6 , 2013, PloS one.

[22]  M. Mourtada-Maarabouni,et al.  Role of GAS5 noncoding RNA in mediating the effects of rapamycin and its analogues on mantle cell lymphoma cells. , 2014, Clinical lymphoma, myeloma & leukemia.

[23]  Gwyn T. Williams,et al.  Regulation of apoptosis by long non-coding RNA GAS5 in breast cancer cells: implications for chemotherapy , 2014, Breast Cancer Research and Treatment.

[24]  R. Spizzo,et al.  Long non-coding RNAs and cancer: a new frontier of translational research? , 2012, Oncogene.

[25]  M. Mourtada-Maarabouni,et al.  GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer , 2009, Oncogene.

[26]  Dario Strbenac,et al.  Regional activation of the cancer genome by long-range epigenetic remodeling. , 2013, Cancer cell.

[27]  Wei Zhao,et al.  Decreased expression of lncRNA GAS5 predicts a poor prognosis in cervical cancer. , 2014, International journal of clinical and experimental pathology.

[28]  Wei Gao,et al.  Long non-coding RNA GAS5 functions as a tumor suppressor in renal cell carcinoma. , 2013, Asian Pacific journal of cancer prevention : APJCP.

[29]  Jun Ding,et al.  An insertion/deletion polymorphism in the 3' untranslated region of beta-transducin repeat-containing protein (betaTrCP) is associated with susceptibility for hepatocellular carcinoma in Chinese. , 2010, Biochemical and biophysical research communications.

[30]  Ryan E. Mills,et al.  Small insertions and deletions (INDELs) in human genomes. , 2010, Human molecular genetics.

[31]  Chien-Jen Chen,et al.  Interaction of hepatitis B virus, chemical carcinogen, and genetic susceptibility: Multistage hepatocarcinogenesis with multifactorial etiology , 2002, Hepatology.

[32]  Lewis R. Roberts,et al.  Hepatocellular carcinoma: a global view , 2010, Nature Reviews Gastroenterology &Hepatology.

[33]  Yang Liu,et al.  An insertion/deletion polymorphism at miRNA-122-binding site in the interleukin-1alpha 3' untranslated region confers risk for hepatocellular carcinoma. , 2009, Carcinogenesis.

[34]  M. Mourtada-Maarabouni,et al.  Long non-coding RNA GAS5 regulates apoptosis in prostate cancer cell lines. , 2013, Biochimica et biophysica acta.

[35]  Stephen B Gruber,et al.  The Genetics of Colorectal Cancer , 2006, Annals of Internal Medicine.