A Novel Protein Encoded by Exosomal CircATG4B Induces Oxaliplatin Resistance in Colorectal Cancer by Promoting Autophagy.
A Novel Protein Encoded by Exosomal CircATG4B Induces Oxaliplatin Resistance in Colorectal Cancer by Promoting Autophagy.
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外泌体 CircATG4B 编码的新型蛋白质通过促进自噬诱导结直肠癌奥沙利铂耐药
DOI：
10.1002/advs.202204513
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发表时间：
2022-12
期刊：
影响因子：
15.1
通讯作者：
Li, Yong
中科院分区：
文献类型：
--
作者：
Pan, Zihao;Zheng, Jun;Zhang, Jiebin;Lin, Jiatong;Lai, Jianguo;Lyu, Zejian;Feng, Huolun;Wang, Junjiang;Wu, Deqing;Li, Yong
奥沙利铂常用于手术切除后结直肠癌（CRC）的化疗方案。然而，获得性耐药严重影响了结直肠癌患者的疗效，其机制尚不清楚。在此，鉴定了一种环状RNA，circATG 4 B，其在CRC的奥沙利铂耐药性中起重要作用。发现circATG 4 B表达在奥沙利铂耐药CRC细胞分泌的外泌体中增加。此外，结果表明，circATG 4 B通过促进自噬诱导奥沙利铂耐药性。进一步的体内和体外研究表明，circATG 4 B的作用归因于其编码新蛋白circATG 4 B-222 aa的潜力。接下来，发现circATG 4 B-222 aa作为诱饵与TMED 10竞争性相互作用并阻止TMED 10与ATG 4 B结合，这导致自噬增加，随后诱导化学抗性。因此，这项研究揭示了外泌体circATG 4 B参与了CRC细胞的化疗敏感性降低，为CRC中奥沙利铂耐药性的潜在治疗靶点提供了新的理论基础。
Oxaliplatin is commonly used in chemotherapeutic regimens for colorectal cancer (CRC) after surgical resection. However, acquired chemoresistance seriously affects the curative effect in CRC patients, and the mechanism is still unclear. Here, a circular RNA, circATG4B is identified, which plays an important role in oxaliplatin resistance in CRC. circATG4B expression is found to be increased in exosomes secreted by oxaliplatin‐resistant CRC cells. In addition, the results suggest that circATG4B induces oxaliplatin resistance by promoting autophagy. Further in vivo and in vitro studies indicate that the effect of circATG4B is attributed to its potential to encode a novel protein, circATG4B‐222aa. Next, circATG4B‐222aa is found to function as a decoy to competitively interact with TMED10 and prevent TMED10 from binding to ATG4B, which leads to increased autophagy followed by induction of chemoresistance. Therefore, this study reveals that exosomal circATG4B participates in the decreased chemosensitivity of CRC cells, providing a new rationale for a potential therapeutic target for oxaliplatin resistance in CRC.
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