Study On The Function Of APOBEC3B Gene In Hepatitis B - Related

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and occurs predominantly in patients with underlying hepatocyte damage and cirrhotic liver in which chronic inflammation and fibrosis subsequently occurred. The prevalence of HCC in China is due to the the epidemic of hepatitis B virus (HBV) infection among Chinese population.The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3B or APOBEC3B (A3B), a cytidine deaminase, is a member of APOBEC3 family which provides both innate and adaptive immune responses via deaminating DNA of pathogenes thus far to exert host defense against endogenous retroelements and exogenous viruses. A handful of recent studies have revealed that A3B is playing a role as a source of mutations in a variety of carcinogenesis including breast, cervical and bladder cancers and etc. For example, A3B was found upregulated and hyperactivated in the majority of breast cancer cell lines, and its upregulation in tumors are correlated with elevated C-to-T mutations and overall base substitutions. More strikingly, the transgenic mice or rabbit expressing APOBEC1 in their livers induced tumor formation and cell transformation, suggesting the association existed between the cytidine deaminase superfamily and cancer development. However, so far, few studies if any have evaluated the influence of A3B to that of HCC oncogenesis. Moreover, a recent study revealed that A3B overexpression in HCCs was significantly associated with more aggressive tumor behavior including the presence of tumor microsatellite formation, venous invasion, direct invasion into the adjacent liver tissue and more advanced tumor stages, with the mechanism still unclarified.This study is aimed to reveal the roles of A3B in Hepatitis B-related hepatocellular carcinoma (HBV-HCC). We retrospectively enrolled 205 HBV-HCC patients who had undergone hepatectomy at a single center from 2005 to 2015. Clinicopathologic variables in terms of recurrence-free survival (RFS) and overall survival (OS) were recorded. APOBEC3B expression levels were determined by immunohistochemistry in tumor tissues and adjacent liver tissues. McNemar test and Mann-Whitney U test were applied to compare the expression discrepancy, logistic regression and chi-square test were utilized to test the significant assocation between clinicopathologic variables and A3B expression levels. In addition, Kaplan-Meier method was used to compare survival curves, and Cox regression models were fitted to analyze the effect of prognostic factors on RFS.With respect to our analysis, we found that A3B expression was significantly higher in HBV-HCC samples compared to the corresponding non-tumorous liver (p= 0.004). Clinical-pathological analysis revealed that A3B overexpression in HCCs was significantly associated with expansion of tumor size (p= 0.038) and progress to advanced tumor stages (p= 0.010). However, A3B overexpression in HCCs was not associated with the overall survival (p= 0.788) or recurrence-free survival (p= 0.341).Furthermore, we also examined the A3B expression in specific HCC cell lines and found that the A3B mRNA levels were higher in the HCC cell lines than in the control. In that regard, we thereby studied the function of APOBEC3B on the growth and migration of HCC cells, the in-vitro assays allowed us to detect HCC cell growth and migration after overexpression of APOBEC3B. By this assay, we observed that by inducing the overexpression of APOBEC3B, the growth and migration of HCC cell lines were enhanced remarkably.In conclusion, we have demonstrated that A3B expression was elevated in the primary HCC cells and this higher level expression was associated with more aggressive tumor behavior. A3B overexpression in HCC cell lines enhanced the growth and migration of tumor cell and may therefore enhance the metastasis of HCC cells.