MicroRNA Gene Polymorphisms and Environmental Factors Increase Patient Susceptibility to Hepatocellular Carcinoma

Background Micro RNAs (miRNAs) are small RNA fragments that naturally exist in the human body. Through various physiological mechanisms, miRNAs can generate different functions for regulating RNA protein levels and balancing abnormalities. Abnormal miRNA expression has been reported to be highly related to several diseases and cancers. Single-nucleotide polymorphisms (SNPs) in miRNAs have been reported to increase patient susceptibility and affect patient prognosis and survival. We adopted a case-control research design to verify the relationship between miRNAs and hepatocellular carcinoma. Methodology/Principal Findings A total of 525 subjects, including 377 controls and 188 hepatocellular carcinoma patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real-time PCR were used to analyze miRNA146a (rs2910164), miRNA149 (rs2292832), miRNA196 (rs11614913), and miRNA499 (rs3746444) genetic polymorphisms between the control group and the case group. The results indicate that people who carry the rs3746444 CT or CC genotypes may have a significantly increased susceptibility to hepatocellular carcinoma (adjusted odds ratio [AOR] = 2.84, 95% confidence interval [CI] = 1.88–4.30). In addition, when combined with environmental risk factors, such as smoking and alcohol consumption, interaction effects were observed between gene polymorphisms and environmental factors (odds ratio [OR] = 4.69, 95% CI = 2.52–8.70; AOR = 3.38, 95% CI = 1.68–6.80). Conclusions These results suggest that a significant association exists between miRNA499 SNPs and hepatocellular carcinoma. Gene-environment interactions of miRNA499 polymorphisms, smoking, and alcohol consumption might alter hepatocellular carcinoma susceptibility.

[1]  A. Shiras,et al.  MiR-145 functions as a tumor-suppressive RNA by targeting Sox9 and adducin 3 in human glioma cells. , 2013, Neuro-oncology.

[2]  Q. Yao,et al.  MicroRNA-196: critical roles and clinical applications in development and cancer , 2011, Journal of cellular and molecular medicine.

[3]  A. Hofman,et al.  Serum liver enzymes are associated with all‐cause mortality in an elderly population , 2014, Liver international : official journal of the International Association for the Study of the Liver.

[4]  Zhiyong Zhang,et al.  MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4. , 2011, Carcinogenesis.

[5]  Zhiyong Zhang,et al.  microRNA-499-5 p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO 4 and PDCD 4 , 2011 .

[6]  G. Cao,et al.  Distribution and Hepatocellular Carcinoma–Related Viral Properties of Hepatitis B Virus Genotypes in Mainland China: A Community-Based Study , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[7]  J. Rowley,et al.  Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. , 2009, Blood.

[8]  G. Sun,et al.  Association of microRNA-499 rs3746444 Polymorphism with Cancer Risk: Evidence from 7188 Cases and 8548 Controls , 2012, PloS one.

[9]  R. Stam,et al.  Expression of miR-196b is not exclusively MLL-driven but is especially linked to activation of HOXA genes in pediatric acute lymphoblastic leukemia , 2010, Haematologica.

[10]  Ping Chen,et al.  miR-499 rs3746444 polymorphism is associated with cancer development among Asians and related to breast cancer susceptibility , 2012, Molecular Biology Reports.

[11]  K. Sliwa,et al.  MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. , 2013, The Journal of clinical investigation.

[12]  R. Weber,et al.  A functional variant at the miR-184 binding site in TNFAIP2 and risk of squamous cell carcinoma of the head and neck. , 2011, Carcinogenesis.

[13]  I. Adcock,et al.  Airway smooth muscle hyperproliferation is regulated by microRNA-221 in severe asthma. , 2013, American journal of respiratory cell and molecular biology.

[14]  Ding‐Shinn Chen,et al.  Increased risk of cirrhosis and its decompensation in chronic hepatitis B patients with newly diagnosed diabetes: a nationwide cohort study. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  Ding‐Shinn Chen,et al.  Increased risk of cirrhosis and its decompensation in chronic hepatitis C patients with new‐onset diabetes: A nationwide cohort study , 2014, Hepatology.

[16]  Marcus Schuchmann,et al.  Trends in Epidemiology, Treatment, and Survival of Hepatocellular Carcinoma Patients Between 1998 and 2009: An Analysis of 1066 Cases of a German HCC Registry , 2014, Journal of clinical gastroenterology.

[17]  O. Ichii,et al.  Altered expression of microRNA miR-146a correlates with the development of chronic renal inflammation. , 2012, Kidney international.

[18]  M. Qiu,et al.  Lack of Association between Hsa-miR-149 rs2292832 Polymorphism and Cancer Risk: A Meta-Analysis of 12 Studies , 2013, PloS one.

[19]  Lin Xu,et al.  Hsa-miR-499 rs3746444 Polymorphism Contributes to Cancer Risk: A Meta-Analysis of 12 Studies , 2012, PloS one.

[20]  D. Bishop,et al.  The role of microRNA-binding site polymorphisms in DNA repair genes as risk factors for bladder cancer and breast cancer and their impact on radiotherapy outcomes , 2011, Carcinogenesis.

[21]  O. Kim,et al.  Association of the miR-146a, miR-149, miR-196a2, and miR-499 Polymorphisms With Ischemic Stroke and Silent Brain Infarction Risk , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[22]  M. Rozman,et al.  Impact of MiRSNPs on Survival and Progression in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation , 2012, Clinical Cancer Research.

[23]  Shuang Huang,et al.  Ratio of miR-196s to HOXC8 messenger RNA correlates with breast cancer cell migration and metastasis. , 2010, Cancer research.

[24]  Yifeng Zhou,et al.  A sequence polymorphism in miR-608 predicts recurrence after radiotherapy for nasopharyngeal carcinoma. , 2013, Cancer research.

[25]  T. Ørntoft,et al.  Non‐CpG island promoter hypomethylation and miR‐149 regulate the expression of SRPX2 in colorectal cancer , 2013, International journal of cancer.

[26]  Mu-Kuan Chen,et al.  Impacts of MicroRNA Gene Polymorphisms on the Susceptibility of Environmental Factors Leading to Carcinogenesis in Oral Cancer , 2012, PloS one.

[27]  Liping Zhang,et al.  Association of the microRNA-499 variants with susceptibility to hepatocellular carcinoma in a Chinese population , 2012, Molecular Biology Reports.

[28]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[29]  Yanlei Ma,et al.  SP1 mediates the link between methylation of the tumour suppressor miR‐149 and outcome in colorectal cancer , 2013, The Journal of pathology.

[30]  G. Cao,et al.  Associations of pri-miR-34b/c and pre-miR-196a2 Polymorphisms and Their Multiplicative Interactions with Hepatitis B Virus Mutations with Hepatocellular Carcinoma Risk , 2013, PloS one.

[31]  P. Linsley,et al.  miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice , 2011, The Journal of experimental medicine.

[32]  Yang Wang,et al.  Hsa-miR-499 polymorphism (rs3746444) and cancer risk: a meta-analysis of 17 case-control studies. , 2012, Gene.

[33]  D. Baltimore,et al.  miR-146a controls the resolution of T cell responses in mice , 2012, The Journal of experimental medicine.

[34]  Brigitte Schlegelberger,et al.  Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells. , 2012, Gastroenterology.

[35]  R. Postier,et al.  DCLK1 Regulates Pluripotency and Angiogenic Factors via microRNA-Dependent Mechanisms in Pancreatic Cancer , 2013, PloS one.

[36]  Pei Wang,et al.  The Association between Genetic Polymorphism and the Processing Efficiency of miR-149 Affects the Prognosis of Patients with Head and Neck Squamous Cell Carcinoma , 2012, PloS one.

[37]  L. Holmberg,et al.  Integrated genomic analysis of triple-negative breast cancers reveals novel microRNAs associated with clinical and molecular phenotypes and sheds light on the pathways they control , 2013, BMC Genomics.

[38]  G. Cao,et al.  Genotypes, mutations, and viral load of hepatitis B virus and the risk of hepatocellular carcinoma , 2011, Hepatitis monthly.

[39]  Shu-Chun Lin,et al.  miR‐134 induces oncogenicity and metastasis in head and neck carcinoma through targeting WWOX gene , 2014, International journal of cancer.

[40]  Z. Meng,et al.  Effect and Safety of Interferon for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis , 2013, PloS one.

[41]  K. Selmaj,et al.  MicroRNA-146a Negatively Regulates the Immunoregulatory Activity of Bone Marrow Stem Cells by Targeting Prostaglandin E2 Synthase-2 , 2013, The Journal of Immunology.

[42]  Pre-mir-27a rs895819 polymorphism and cancer risk: a meta-analysis , 2013, Molecular Biology Reports.

[43]  Zu-hong Lu,et al.  The association between hsa-miR-499 T>C polymorphism and cancer risk: a meta-analysis. , 2012, Gene.

[44]  Y. Niu,et al.  MiR-130b Is a Prognostic Marker and Inhibits Cell Proliferation and Invasion in Pancreatic Cancer through Targeting STAT3 , 2013, PloS one.

[45]  Min-tze Wu,et al.  n-Butylidenephthalide induced apoptosis in the A549 human lung adenocarcinoma cell line by coupled down-regulation of AP-2α and telomerase activity , 2009, Acta Pharmacologica Sinica.

[46]  G. Kennedy,et al.  MicroRNA-21 as a potential colon and rectal cancer biomarker. , 2013, World journal of gastroenterology.

[47]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[48]  T. Bonetti,et al.  Evaluation of single nucleotide polymorphisms in microRNAs (hsa-miR-196a2 rs11614913 C/T) from Brazilian women with breast cancer , 2012, BMC Medical Genetics.

[49]  H. Harn,et al.  Synergistic anti‐tumor activity of isochaihulactone and paclitaxel on human lung cancer cells , 2012, Journal of cellular physiology.

[50]  L. Zhao,et al.  Integrative Analysis in Oral Squamous Cell Carcinoma Reveals DNA Copy Number–Associated miRNAs Dysregulating Target Genes , 2012, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[51]  L. Ait-Ali,et al.  Germline hereditary, somatic mutations and microRNAs targeting-SNPs in congenital heart defects. , 2013, Journal of molecular and cellular cardiology.

[52]  J. Wilmott,et al.  MicroRNA-149*, a p53-responsive microRNA, functions as an oncogenic regulator in human melanoma , 2011, Proceedings of the National Academy of Sciences.

[53]  Meng-jie Feng,et al.  MicroRNA-181a, -146a and -146b in spleen CD4+ T lymphocytes play proinflammatory roles in a murine model of asthma. , 2012, International immunopharmacology.