Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, 518055, Shenzhen, China.
Integrative Cancer Center&Cancer Clinical Research Center, Sichuan Cancer Hospital & Institute Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610000, P. R. China.
J Exp Clin Cancer Res. 2020 Dec 7;39(1):274. doi: 10.1186/s13046-020-01768-8.
The identification of novel targets for recovering sorafenib resistance is pivotal for Hepatocellular carcinoma (HCC) patients. Mitophagy is the programmed degradation of mitochondria, and is likely involved in drug resistance of cancer cells. Here, we identified hyperactivated mitophagy is essential for sorafenib resistance, and the mitophagy core regulator gene ATAD3A (ATPase family AAA domain containing 3A) was down regulated in hypoxia induced resistant HCC cells. Blocking mitophagy may restore the sorafenib sensitivity of these cells and provide a new treatment strategy for HCC patients.
Hypoxia induced sorafenib resistant cancer cells were established by culturing under 1% O with increasing drug treatment. RNA sequencing was conducted in transfecting LM3 cells with sh-ATAD3A lentivirus. Subsequent mechanistic studies were performed in HCC cell lines by manipulating ATAD3A expression isogenically where we evaluated drug sensitivity, molecular signaling events. In vivo study, we investigated the combined treatment effect of sorafenib and miR-210-5P antagomir.
We found a hyperactivated mitophagy regulating by ATAD3A-PINK1/PARKIN axis in hypoxia induced sorafenib resistant HCC cells. Gain- and loss- of ATAD3A were related to hypoxia-induced mitophagy and sorafenib resistance. In addition, ATAD3A is a functional target of miR-210-5p and its oncogenic functions are likely mediated by increased miR-210-5P expression. miR-210-5P was upregulated under hypoxia and participated in regulating sorafenib resistance. In vivo xenograft assay showed that miR-210-5P antagomir combined with sorafenib abrogated the tumorigenic effect of ATAD3A down-regulation in mice.
Loss of ATAD3A hyperactivates mitophagy which is a core event in hypoxia induced sorafenib resistance in HCC cells. Targeting miR-210-5P-ATAD3A axis is a novel therapeutic target for sorafenib-resistant HCC.
鉴定恢复索拉非尼耐药的新靶点对肝细胞癌（HCC）患者至关重要。线粒体自噬是线粒体的程序性降解，可能与癌细胞的耐药性有关。在这里，我们发现过度激活的线粒体自噬对于索拉非尼耐药是必不可少的，并且在缺氧诱导的耐药 HCC 细胞中，线粒体自噬核心调节基因 ATAD3A（ATPase 家族 AAA 结构域包含 3A）下调。阻断线粒体自噬可能恢复这些细胞对索拉非尼的敏感性，并为 HCC 患者提供新的治疗策略。
通过在 1%O 下培养并增加药物处理来建立缺氧诱导的索拉非尼耐药癌细胞。用 sh-ATAD3A 慢病毒转染 LM3 细胞进行 RNA 测序。随后在 HCC 细胞系中通过操纵 ATAD3A 表达同基因来进行机制研究，我们评估了药物敏感性、分子信号事件。在体内研究中，我们研究了索拉非尼和 miR-210-5P 反义寡核苷酸联合治疗的效果。
我们发现 ATAD3A-PINK1/PARKIN 轴在缺氧诱导的索拉非尼耐药 HCC 细胞中调节过度激活的线粒体自噬。ATAD3A 的获得和缺失与缺氧诱导的线粒体自噬和索拉非尼耐药有关。此外，ATAD3A 是 miR-210-5p 的功能性靶标，其致癌功能可能是通过增加 miR-210-5p 的表达来介导的。miR-210-5p 在缺氧下上调，并参与调节索拉非尼耐药性。体内异种移植实验表明，miR-210-5P 反义寡核苷酸联合索拉非尼可消除 ATAD3A 下调在小鼠中对肿瘤形成的影响。
ATAD3A 的缺失会过度激活线粒体自噬，这是 HCC 细胞中缺氧诱导的索拉非尼耐药的核心事件。靶向 miR-210-5P-ATAD3A 轴是索拉非尼耐药 HCC 的一种新的治疗靶点。
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