MiR-106b inhibitors sensitize TRAIL-induced apoptosis in hepatocellular carcinoma through increase of death receptor 4.
MiR-106b inhibitors sensitize TRAIL-induced apoptosis in hepatocellular carcinoma through increase of death receptor 4.
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DOI：
10.18632/oncotarget.16707
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发表时间：
2017-06-27
期刊：
影响因子：
--
通讯作者：
Pan C
中科院分区：
文献类型：
--
作者：
Xu C;Shi L;Chen W;Fang P;Li J;Jin L;Pan Z;Pan C
肿瘤坏死因子相关凋亡诱导配体（TNF-related apoptosis-inducing ligand，TRAIL）是肿瘤坏死因子超家族成员之一，可诱导肿瘤细胞凋亡。然而，多种类型的肿瘤，包括肝细胞癌，显示对TRAIL的耐受性。已有研究表明，肿瘤细胞通过改变microRNA（miRNA）的表达谱来获得对药物的耐受能力。然而，这种miRNA对TRAIL敏感性的改变是否在肝细胞癌中观察到仍需要探索。在这项研究中，我们观察到miR-106 b在HCC患者的肿瘤组织和细胞系中的过表达。此外，我们发现miR-106 b的过表达与TRAIL对HCC的敏感性相关。miR-106 b反义寡核苷酸沉默miR-106 b可增强TRAIL诱导的肝癌细胞凋亡，降低肝癌细胞对TRAIL的获得性耐药。在机制上，抗miR-106 b处理后，促凋亡蛋白Bax和Bid以及抗凋亡蛋白Bcl-2、Mcl-1和Bcl-xl的表达没有明显变化。本研究采用生物信息学、流式细胞术、细胞和分子生物学等方法证明miR-106 b直接靶向死亡受体4（DR 4）3′-UTR（3′-Untranslated Regions，3′-非翻译区）。miR-106 b抑制剂诱导DR 4表达增加，从而增强肝癌中TRAIL介导的凋亡。总之，这些结果表明miR-106 b抑制剂在HCC治疗中的应用。miR-106 b抑制剂与TRAIL联合应用有望成为肝癌治疗的新方法。
TNF-related apoptosis-inducing ligand (TRAIL), which is a member of the TNF superfamily, can induce tumor cell apoptosis. However, multiple types of tumor, including hepatocellular carcinoma, show tolerance to TRAIL. Previous studies have demonstrated that tumor cells usually change their expression profile of microRNA (miRNA) to obtain the ability of tolerance to drugs. However, whether such change of miRNA on TRAIL sensitivity is seen in hepatocellular carcinoma still needs to be explored. In this study, we observed overexpression of miR-106b in both HCC patients’ tumor tissues and cell lines. Furthermore, we found that overexpression of miR-106b is associated with the sensitivity of TRAIL to HCC. Silencing of miR-106b with antisense oligonucleotide (anti-miR-106b) is proved to enhance the TRAIL-induced apoptosis and reduce the acquired drug resistance to TRAIL in HCC. Mechanically, we didn't observe the obvious change of pro-apoptotic proteins (Bax and Bid) and anti-apoptotic proteins (Bcl-2, Mcl-1 and Bcl-xl) after treatment of anti-miR-106b. However, we used the methods of bioinformatics, flow cytometry, cellular and molecular methods to prove that miR-106b directly targeted to death receptor 4 (DR4) 3′-UTR (3′-Untranslated Regions). MiR-106b inhibitors induced increase of DR4 expression and therefore enhancing TRAIL-mediated apoptosis in HCC. In summary, these results suggest the application of miR-106b inhibitors in HCC treatment. Combination with miR-106b inhibitors and TRAIL may be a novel clinical treatment method on HCC treatment in the future.
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