Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China; Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
Cancer Lett. 2022 Nov 1;548:215864. doi: 10.1016/j.canlet.2022.215864. Epub 2022 Aug 15.
Gemcitabine (GEM) resistance is one of the major causes of treatment failure in pancreatic ductal adenocarcinoma (PDAC) in clinic. Here, through CRISPR/Cas9 activation library screen, we found that MTA3 mediates the GEM resistance of PDAC and thus might be a potential therapeutic target for combination chemotherapy. The CRISPR library screening showed that MTA3 is the most enriched gene in the surviving GEM-treated cells, and bioinformatic and histology analysis implied its high correlation with GEM resistance. MTA3 promoted GEM resistance of PDAC cells in in vitro and in vivo experiments. Mechanistically, as a component of the Mi-2/nucleosome remodeling and deacetylase transcriptional repression complex, MTA3 transcriptionally represses CRIP2, a transcriptional repressor of NF-κB/p65, activating NF-κB signaling and consequently leading to GEM resistance. Furthermore, the treatment of GEM increases MTA3 expression in PDAC cells via activating STAT3 signaling, thereby inducing the acquired chemoresistance of PDAC to GEM. In patients derived xenografts (PDX) mouse model, Colchicine suppresses the expression of MTA3 and increases the sensitivity of tumor cells to GEM. Based on these findings, MTA3 plays a key role in GEM resistance in pancreatic cancer and is a promising therapeutic target for reversing GEM chemotherapy resistance.
吉西他滨（GEM）耐药性是临床胰腺导管腺癌（PDAC）治疗失败的主要原因之一。在这里，我们通过 CRISPR/Cas9 激活文库筛选发现，MTA3 介导 PDAC 的 GEM 耐药性，因此可能是联合化疗的潜在治疗靶点。CRISPR 文库筛选显示，MTA3 是 GEM 处理存活细胞中最丰富的基因，生物信息学和组织学分析表明其与 GEM 耐药性高度相关。MTA3 在体外和体内实验中促进了 PDAC 细胞的 GEM 耐药性。在机制上，作为 Mi-2/核小体重塑和去乙酰化酶转录抑制复合物的一个组成部分，MTA3 转录抑制 CRIP2，NF-κB/p65 的转录抑制剂，激活 NF-κB 信号通路，从而导致 GEM 耐药性。此外，GEM 处理通过激活 STAT3 信号通路增加 PDAC 细胞中 MTA3 的表达，从而诱导 PDAC 对 GEM 的获得性化疗耐药性。在患者来源的异种移植（PDX）小鼠模型中，秋水仙碱抑制 MTA3 的表达并增加肿瘤细胞对 GEM 的敏感性。基于这些发现，MTA3 在胰腺癌的 GEM 耐药性中起关键作用，是逆转 GEM 化疗耐药性的有前途的治疗靶点。
