Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan.
Life Science Research Center, Kagawa University, Kagawa, Japan.
Am J Physiol Gastrointest Liver Physiol. 2020 Mar 1;318(3):G401-G409. doi: 10.1152/ajpgi.00269.2019. Epub 2020 Jan 6.
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: ) HBV-related HCC and adjacent nontumor tissue, ) HCV-related HCC and adjacent nontumor tissue, and ) 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. 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.
乙型肝炎病毒（HBV）相关的肝癌发生不一定与肝纤维化阶段有关，偶尔也会在早期纤维化阶段出现。微小 RNA（miRNA）本质上是 18 到 22 个核苷酸长的内源性非编码 RNA。miRNA 表达异常是各种人类癌症的共同特征。与非肿瘤组织相比，肝癌组织中存在特定 miRNA 的异常表达。因此，我们将靶向 miRNA 作为一种与 HBV 相关肝癌发生风险相关的潜在新生物标志物进行研究，以预防与癌症相关的死亡。我们从 2002 年至 2013 年在我院接受肝切除术的 29 名患者的 HCC 组织样本中获得了总 RNA，并通过 miRNA 阵列、实时 RT-PCR 以及三种比较进行了分析：）HBV 相关 HCC 和相邻非肿瘤组织，）HCV 相关 HCC 和相邻非肿瘤组织，）非 HBV、非 HCV 相关 HCC 和相邻非肿瘤组织。我们还通过使用 HBV 阳性 HCC 细胞系对针对 HBV 相关 HCC 的 miRNA 进行了功能分析。仅在 HBV 相关 HCC 组织样本中，miR-210-3p 的表达显著增加。在 HBV 阳性 HCC 细胞中，miR-210-3p 的表达上调，其靶基因的水平降低。miR-210-3p 的抑制增强了 HBV 阳性 HCC 细胞中其靶基因的表达。此外，miR-210-3p 在 HBV 感染的 Huh7/NTCP 细胞中调节 HBx 的表达。在 HBV 相关 HCC 中特异性检测到 miR-210-3p 的增强表达，并调节包括 HBV 阳性 HCC 细胞中的 HBx 在内的各种靶基因。miR-210-3p 因此可能是 HBV 相关 HCC 风险的新生物标志物。本研究表明，miR-210-3p 是唯一在 HBV 相关 HCC 中表达增强的 microRNA，miR-210-3p 的增强表达上调 HBx 表达。因此，miR-210-3p 可能是 HBV 相关肝癌发生的关键生物标志物，抑制 miR-210-3p 可能预防与 HBV 感染相关的肝癌发生。
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