Genome-scale CRISPRa screening identifies MTX1 as a contributor for sorafenib resistance in hepatocellular carcinoma by augmenting autophagy.
Genome-scale CRISPRa screening identifies MTX1 as a contributor for sorafenib resistance in hepatocellular carcinoma by augmenting autophagy.
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基因组规模的 CRISPRa 筛选发现 MTX1 通过增强自噬而导致肝细胞癌索拉非尼耐药
DOI：
10.7150/ijbs.62393
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发表时间：
2021
影响因子：
9.2
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Li L;Yu S;Hu Q;Hai Y;Li Y
索拉非尼是治疗晚期肝细胞癌（HCC）的标准一线药物，但由于HCC细胞的原发性或继发性耐药，其治疗效果并不令人满意。在本研究中，我们通过基因组规模的CRISPR激活（CRISPRa）筛选将Metaxin 1（MTX 1）确定为HCC中索拉非尼耐药的新调节因子。我们发现MTX 1在HCC组织中频繁上调，并且MTX 1的过表达促进了HCC细胞在体外和体内的增殖。同样，MTX 1过表达增加索拉非尼处理后的细胞生长速率并减少细胞凋亡。在皮下移植瘤模型中也观察到MTX 1诱导的耐药。临床上，MTX 1的高表达与接受索拉非尼治疗的HCC患者的不良结局密切相关。机制上，MTX 1过表达可通过与自噬负调控因子CDGSH铁硫结构域1（CISD 1）相互作用并抑制其表达而促进肝癌细胞自噬。综上所述，我们的研究结果表明，MTX 1在HCC中上调，并通过CISD 1介导的自噬的可能机制导致索拉非尼耐药。
Sorafenib is the standard first-line drug for the treatment of advanced hepatocellular carcinoma (HCC), however, its therapeutic efficacy is not satisfactory due to primary or secondary resistance of HCC cells. In the present study, we identified Metaxin 1 (MTX1) as a new regulator of sorafenib resistance in HCC through genome-scale CRISPR activation (CRISPRa) screening. We found that MTX1 was frequently upregulated in HCC tissues and overexpression of MTX1 promoted HCC cell proliferation in vitro and in vivo. As well, MTX1 overexpression increased cell growth rate and decreased cell apoptosis upon sorafenib treatment. Consistently, the resistance induced by MTX1 was also observed in subcutaneous xenograft tumor model. Clinically, high expression of MTX1 was closely related with poor outcomes in HCC patients who received sorafenib treatment. Mechanistically, overexpression of MTX1 could promote HCC cell autophagy via interacting with and inhibiting CDGSH iron sulfur domain 1 (CISD1), an autophagy negative regulator. Taken together, our findings suggest that MTX1 is upregulated in HCC and contributes to sorafenib resistance via a possible mechanism involving CISD1 mediated autophagy.
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