The Role Of Single Nucleotide Polymorphism Of DICER Gene And Its Expression In The Occurrence And Development Of Hepatocellular Carcinoma

PurposeHepatocellular carcinoma(HCC) is the second most common cancer and one of the leading causes of cancer-related deaths in China. An estimated 340,000 new cases of HCC were diagnosed in China, accounting for 55% of newly diagnosed cases in the world, and it had been as one of the most important health threats. Moreover, the prognosis for HCC patients is ultimately poor despite appropriate therapy, such as surgical resection, chemotherapy, and liver transplantation. HCC is a complex disease caused by multiple genetic and environmental factors. Previous epidemiological studies have identified several risk factors in the pathogenesis of HCC, including exposure to aflatoxins, alcohol abuse, decreased intake of antioxidant micronutrients,and hepatitis B virus infection. Recently, numerous reports have shown that genomics and epigenetics play important roles in the susceptibility, progression and prognosis of HCC.Micro RNA(miRNA), functions as gene regulators, plays crucial roles in pathogenesis and prognosis of hepatocellular carcinoma(HCC). Genetic variants in miRNA processing genes may affect miRNAs expression and contribute to HCC risk and survival. We hypothesized that single nucleotide polymorphisms(SNPs) in miRNA processing genes may be associated with HCC susceptibility and prognosis and the alteral expression of Dicer in HCC may influence the occurrence and development of HCC.MethodWe first genotyped the selected three SNPs of miRNA processing genes(RAN rs3803012 A>G, HIWI rs10773771 T>C, and DICER rs1057035 T>C) in 312 HCC patients and 320 cancer-free controls using the Taq Man assay, and evaluated the associations of the three SNPs with HCC risk. Then, we also investigated the effect of the three SNPs on the overall survival of 312 HCC patients.We detected the Dicer expressions in 11 HCC tissues, 11 normal liver tissues, 2liver cells and 4 HCC cells using western blot. We transfected HCC cell line MHCC97 H cells with recombinant plasmid pc DNA3.1-DICER, and detected the expression change of Dicer in MHCC97 H cells by western blot, evaluated the proliferation, apoptosis and invasion of MHCC97 H cells using MTT, flow cytometry,and Transwell respectively.ResultsThere was no significant associations between the three SNPs(RAN rs3803012A>G, HIWI rs10773771 T>C, and DICER rs1057035 T>C) and HCC risk. However,HCC patients carrying DICER rs1057035 CT+CC genotypes had significantly longer median survival time(log-rank P = 0.018) and decreased death risk(adjusted HR =0.68, 95%CI: 0.49-0.95, P = 0.022) than patients with rs1057035 TT genotypes.These effects were more obvious in patients with age less than 60, smoking, stage B,in female patients, and in patients underwent chemotherapy or intervention(HR =0.48, 0.60, 0.69, 0.46, and 0.67, all P< 0.05).The expression level of Dicer both in HCC tissues and HCC cell lines were lower than that in normal liver tissues and live cells. Furthermore, overexpression of Dicer in MHCC97 H cell decreased the proliferation and invasion abilities of MHCC97 H cells, but promoted the MCC97 H cells apoptosis.ConclusionThis study provides evidence that DICER rs1057035 T>C polymorphism may be a prognostic biomarker for HCC patients. In addition, this study indicates that Dicer may be a new target of molecular therapy for HCC patients.