Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2 E2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan.
Biochem Biophys Res Commun. 2011 Nov 4;414(4):675-80. doi: 10.1016/j.bbrc.2011.09.124. Epub 2011 Oct 1.
Interferon-based (IFN-based) therapy is effective in the treatment of advanced hepatocellular carcinoma (HCC). However, the issue of resistance to this therapy remains to be solved. The aim of this study was to identify microRNAs (miRNAs) that govern the sensitivity to IFN-α in HCC cells.
miRNA microarray analysis using IFN-α-resistant clones of PLC/PRF/5 (PLC-Rs) and their parental cells (PLC-P) was conducted. Changes in the anti-cancer effects of IFN-α were studied after gain-of-function and loss-of-function of the candidate miRNA.
miR-146a expression was significantly higher in PLC-Rs than in PLC-P. miR-146a decreased the sensitivity to IFN-α through the suppression of apoptosis. Further experiments showed that miR-146a-related resistance to IFN-α was mediated through SMAD4.
The results indicated that miR-146a regulated the sensitivity of HCC cells to the cytotoxic effects of IFN-α through SMAD4, suggesting that this miRNA could be suitable for prediction of the clinical response and potential therapeutic target in HCC patients on IFN-based therapy.
基于干扰素（IFN）的治疗在治疗晚期肝细胞癌（HCC）方面是有效的。然而，这种治疗的耐药性问题仍有待解决。本研究旨在确定调节 HCC 细胞对 IFN-α敏感性的 microRNAs（miRNAs）。
使用 IFN-α耐药的 PLC/PRF/5（PLC-Rs）克隆及其亲本细胞（PLC-P）进行 miRNA 微阵列分析。在获得候选 miRNA 的功能和丧失功能后，研究了 IFN-α抗癌作用的变化。
与 PLC-P 相比，PLC-Rs 中的 miR-146a 表达明显更高。miR-146a 通过抑制细胞凋亡降低了对 IFN-α的敏感性。进一步的实验表明，miR-146a 相关的 IFN-α耐药性是通过 SMAD4 介导的。
结果表明，miR-146a 通过 SMAD4 调节 HCC 细胞对 IFN-α细胞毒性作用的敏感性，提示该 miRNA 可用于预测接受 IFN 为基础治疗的 HCC 患者的临床反应和潜在治疗靶点。
