Abstract
Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared with nontumor tissue. Thus, we examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002-2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: 1) HBV-related HCC and adjacent nontumor tissue, 2) HCV-related HCC and adjacent nontumor tissue, and 3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes, including HBx in the HBV-positive HCC cells. MiR-210-3p might, thus, be a new biomarker for the risk of HBV-related HCC.NEW & NOTEWORTHY Our present study demonstrated that miR-210-3p is the only microRNA with enhanced expression in HBV-related HCC, and the enhanced expression of miR-210-3p upregulates HBx expression. Therefore, miR-210-3p might be a pivotal biomarker of HBV-related hepatocarcinogenesis, and the inhibition of miR-210-3p could prevent inducing hepatocarcinogenesis related to HBV infection.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality [30] and the fifth most common cancer worldwide [15]
The miR-210-3p expression was significantly upregulated in the hepatitis B virus (HBV)-related HCC cancerous tissue samples compared with the HCV-related HCC cancerous tissue samples, the non-B, non-C (NBNC) hepatitis (NBNC)-related hepatocellular carcinoma (HCC) cancerous tissue samples, and the adjacent nontumor tissue samples corresponding to those two sets of samples (Fig. 2)
The results revealed that the hsa-miR-210-3p expression in the HBV-related HCC tissue samples was highly upregulated compared with the expression in the NBNC- and HCV-related HCC tissue samples (P Ͻ 0.021 and P Ͻ 0.0308, respectively) (Fig. 3)
Summary
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality [30] and the fifth most common cancer worldwide [15]. The clinical management of early-stage HCC has improved, the prognosis of HCC patients remains poor because of the high recurrence rate [46]. The HCC survival rate has improved over the past decade, the rate of recurrence after surgery remains high [21]. Cohort studies have indicated that longterm viral suppression is related to improvements in liver inflammation and fibrosis, resulting in a reduction in the risk of HCC [43]. Despite the availability of various nucleotide analogs for HBV patients, the rate of cure, defined as the confirmation of no detectable hepatitis B surface antigen or HBVDNA, remains low.
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