CX43 down-regulation promotes cell aggressiveness and 5-fluorouracil-resistance by attenuating cell stiffness in colorectal carcinoma.
CX43 down-regulation promotes cell aggressiveness and 5-fluorouracil-resistance by attenuating cell stiffness in colorectal carcinoma.
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DOI：
10.1080/15384047.2023.2221879
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发表时间：
2023-12-31
影响因子：
3.6
通讯作者：
Wang, Shuang
中科院分区：
文献类型：
--
作者：
Han, Yue;Wang, Haowei;Chen, Hui;Tan, Tianyuan;Wang, Yiqing;Yang, Hongjun;Ding, Yanqing;Wang, Shuang
化疗是晚期结直肠癌（CRC）最常用的治疗方法之一。然而，化疗后的耐药是CRC临床治疗的一个重大挑战。因此，迫切需要了解耐药机制和开发新的策略来提高敏感性，以改善CRC的结果。连接蛋白参与相邻细胞间缝隙连接的形成，促进细胞间缝隙连接通讯（GJIC），促进离子和小分子的转运。虽然GJIC功能障碍导致的耐药性是由连接蛋白的异常表达相对较好的理解，负责化疗耐药的连接蛋白介导的机械刚度的潜在机制在CRC中很大程度上是未知的。在这里，我们证明，连接蛋白43（CX43）表达下调，在大肠癌和CX43表达的损失与大肠癌患者的转移和预后不良呈正相关。CX43过表达抑制CRC进展，并通过增强GJIC在体外和体内增加对5-氟尿嘧啶（5-FU）的敏感性。此外，我们还强调了CRC中CX43的下调通过降低细胞刚度来增加细胞的干细胞性，从而促进耐药性。我们的研究结果进一步表明，这两种效应，即细胞的机械刚度的变化和由CX43失调介导的GJIC，与结直肠癌的耐药性密切相关，这表明CX43是结直肠癌中抗肿瘤生长和耐药性的靶点。
Chemotherapy is one of the most commonly treatments of advanced colorectal cancer (CRC). However, the drug resistant following chemotherapeutic treatment is a significant challenge in the clinical management of CRC. Therefore, understanding the resistance mechanisms and developing new strategies for enhancing the sensitivity are urgently needed to improve CRC outcome. Connexins contribute to the formation of gap junctions among neighboring cells and then advance gap junctional intercellular communication (GJIC) for transportation of ions and small molecules. Although the drug resistance resulted from GJIC dysfunctional by aberrant expression of connexins is relatively well understood, the underlying mechanisms of mechanical stiffness mediated by connexin responsible for chemoresistance are largely unknown in CRC. Here, we demonstrated that connexin 43 (CX43) expression was downregulated in CRC and that loss of CX43 expression was positively correlated with metastasis and poor prognosis of CRC patients. The CX43 overexpressing suppressed CRC progression and increased the sensitivity to 5-fluorouracil (5-FU) via enhanced GJIC in vitro and in vivo. Moreover, we also highlight that the downregulation of CX43 in CRC increases the stemness of cells via reducing the cell stiffness, thus promoting the drug resistance. Our results further suggest that both effects, that is changes in the mechanical stiffness of the cell and GJIC mediated by CX43 deregulated, are closely related to drug resistance in CRC, which indicating CX43 as a target against cancer growth and chemoresistance in CRC.
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影响因子：
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作者：
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