MicroRNA-423-5p Promotes Autophagy in Cancer Cells and Is Increased in Serum From Hepatocarcinoma Patients Treated With Sorafenib
MicroRNA-423-5p Promotes Autophagy in Cancer Cells and Is Increased in Serum From Hepatocarcinoma Patients Treated With Sorafenib
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DOI：
10.1038/mtna.2015.8
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发表时间：
2015-03-01
影响因子：
8.8
通讯作者：
Caraglia, Michele
中科院分区：
文献类型：
--
作者：
Stiuso, Paola;Potenza, Nicoletta;Caraglia, Michele
肝细胞癌（HCC）是全球第三大癌症相关死亡原因。索拉非尼是唯一被批准用于晚期HCC患者的药物，但活性有限。microRNA（miRs）已经涉及包括HCC在内的几种肿瘤，表明它们作为HCC治疗的良好工具的用途或靶向。本研究的目的是确定通过miR使HCC细胞对索拉非尼敏感的新方法。通过瞬时转染miR和抗miR分子，验证miR-423 - 5p是HCC细胞系中自噬的正调控因子。通过实时聚合酶链反应（PCR）评估了从39名肝癌患者接受索拉非尼治疗前后收集的血清中miR-423 - 5 p的表达水平。用索拉非尼和miR-423 - 5p共处理HCC细胞，并评价对细胞周期、凋亡和自噬的影响。通过索拉非尼治疗，分泌型miR-423 - 5p在体外和体内均上调，并且其增加与对治疗的响应相关，因为在其中发现分泌型miR-423 - 5p增加的患者中，75%在从治疗开始6个月后处于部分缓解或稳定的疾病。用miR-423 - 5p转染的HCC细胞显示细胞周期S期的细胞百分比增加，通过在荧光激活细胞分选仪（FACS）和透射电子显微镜下评估的自噬细胞的类似增加。我们的研究结果表明，miR423 - 5p可以作为一个有用的工具来预测肝癌患者对索拉非尼的反应，并参与肝癌细胞的自噬调控。
Hepatocellular carcinoma (HCC) is the third cause of cancer-related deaths worldwide. Sorafenib is the only approved drug for patients with advanced HCC but has shown limited activity. microRNAs (miRs) have been involved in several neoplasms including HCC suggesting their use or targeting as good tools for HCC treatment. The purpose of this study was to identify novel approaches to sensitize HCC cells to sorafenib through miRs. miR-423-5p was validated as positive regulator of autophagy in HCC cell lines by transient transfection of miR and anti-miR molecules. miR-423-5p expression level was evaluated by real-time polymerase chain reaction (PCR) in sera collected from 39 HCC patients before and after treatment with sorafenib. HCC cells were cotreated with sorafenib and miR-423-5p and the effects on cell cycle, apoptosis, and autophagy were evaluated. Secretory miR-423-5p was upregulated both in vitro and in vivo by sorafenib treatment and its increase was correlated with response to therapy since 75% of patients in which an increase of secretory miR423-5p was found were in partial remission or stable disease after 6 moths from the beginning of therapy. HCC cells transfected with miR-423-5p showed an increase of cell percentage in S-phase of cell cycle paralleled by a similar increase of autophagic cells evaluated at both fluorescence activated cell sorter (FACS) and transmission electron microscopy. Our results suggest the miR423-5p can be used as a useful tool to predict response to sorafenib in HCC patients and is involved in autophagy regulation in HCC cells.