Abstract
This study aims to investigate the expression status of miRNA-216b in familial hepatocellular carcinoma (HCC) and the correlation between miRNA-216b expression and pathogenesis, as well as the progression of HCC. The expression profile of miRNAs in plasma of peripheral blood between HCC patients with HCC family history and healthy volunteers without HCC family history was determined by microarray. Using real-time quantitative PCR to detect the expression in paired tissues from 150 patients with HCC, miR-216b was selected as its expression value in HCC patients was significantly lower compared with healthy volunteers. Next, miR-216b expression and the clinicopathological features of HCC were evaluated. The effect of miR-216b expression on tumor cells was investigated by regulating miR-216b expression in SMMC-7721 and HepG2 in vitro and in vivo. Finally, we explored mRNA targets of miR-216b. In 150 HCC, 37 (75%) tumors showed reduced miR-216b expression comparing with their adjacent liver tissues. The decreased expression of miR-216b was significantly correlated with tumor volume (P=0.044), HBV infection (P=0.026), HBV DNA quantitative (P=0.001) and vascular invasion (P=0.032). The 5-year disease-free survival and overall rates after liver resection in low expression and high expression groups of miR-216b are 62% and 54%, 25% and 20%, respectively. MiR-216b overexpression inhibited cell proliferation, migration and invasion, and miR-216b inhibition did the opposite. The expression of hepatitis B virus x protein (HBx) has tight correlation with downregulation of miR-216b. Furthermore, miR-216b downregulated the expression of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and exerted its tumor-suppressor function through inhibition of protein kinase B and extracellular signal-regulated kinase signaling downstream of IGF2. MiR-216b inhibits cell proliferation, migration and invasion of HCC by regulating IGF2BP2 and it is regulated by HBx.
Highlights
Are diagnosed at an advanced stage that renders surgical therapy ineffective
Our study differs from this strategy, in that we examined miRNA expression in the plasma of patients with Hepatocellular carcinoma (HCC) who had a family history of hepatitis B virus (HBV)-associated HCC and healthy volunteers and identified miRNAs with significantly altered expression levels
Of the identified miRNAs, we focused on miR-216b because its expression showed the highest difference between the two groups and because it was previously identified as a tumor suppressor in other cancers
Summary
Are diagnosed at an advanced stage that renders surgical therapy ineffective. Prognosis of HCC is poor even among patients who undergo liver resection, with 5-year cumulative tumor recurrence rate being 77–100%.3 Chronic hepatitis B virus (HBV) infection accounts for approximately 50% of the total cases of adult HCC and almost all cases of childhood HCC.[4]. Studies have suggested that altered miRNA expression is associated with cancer.[11,12] MiRNAs may act as oncogenes or tumor suppressors; their functions vary depending on the organs and tumors in which they are expressed.[13] MiRNA expression miR-216b suppress HCC F Liu et al in the plasma or tumor cells of patients with HCC and healthy controls is commonly measured to screen novel miRNAs associated with the pathogenesis and progression of HCC. Our study differs from this strategy, in that we examined miRNA expression in the plasma of patients with HCC who had a family history of HBV-associated HCC and healthy volunteers and identified miRNAs with significantly altered expression levels. We validated these miRNAs by measuring their expression in tumors tissues and adjacent liver tissues. We determined the molecular functions of these miRNAs and identified their underlying mechanisms by using HCC cell lines, nude mice and patients with HCC
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