Wang Cui-Hua, Yao Xin-Ming, Pan Chun-Xia, Zhan Hai-Feng, Zhou Hong-Feng
Oncology Department, Shanghai Putuo District Liqun Hospital, Shanghai, China.
Oncology Department, The Third People's Hospital of Dalian, Dalian, China.
Cancer Biol Ther. 2025 Dec;26(1):2522543. doi: 10.1080/15384047.2025.2522543. Epub 2025 Jun 23.
Targeted therapy-induced resistance is a significant factor contributing to treatment failure in patients with gastrointestinal stromal tumors (GIST). Despite the identification of the long non-coding RNA (lncRNA) OIP5-AS1 as a critical player in human malignancy development, its role in GIST-related drug resistance remains largely unexplored. This study revealed substantial up-regulation of both OIP5-AS1 and SOX9, alongside significant down-regulation of miR-145, within sunitinib-resistant GIST cells. OIP5-AS1 emerged as a competing endogenous RNA, exerting inhibition on miR-145 while concurrently promoting the expression of SOX9. Exosome-mediated transfer of OIP5-AS1 induced heightened proliferation and invasion of GIST cells, culminating in the induction of chemoresistance to sunitinib through the miR-145/SOX9 axis. The knockdown of OIP5-AS1-expressing exosomes resulted in reduced cell proliferation and invasion in chemo-resistant GIST cells. In summary, these findings collectively suggest that OIP5-AS1 fosters GIST cell proliferation and invasion by suppressing miR-145 and up-regulating SOX9, ultimately contributing to drug resistance and tumor progression in GIST.
靶向治疗诱导的耐药性是导致胃肠道间质瘤（GIST）患者治疗失败的一个重要因素。尽管长链非编码RNA（lncRNA）OIP5-AS1已被确定为人类恶性肿瘤发展中的关键因子，但其在GIST相关耐药性中的作用仍 largely未被探索。本研究揭示，在对舒尼替尼耐药的GIST细胞中，OIP5-AS1和SOX9均显著上调，同时miR-145显著下调。OIP5-AS1作为一种竞争性内源RNA，对miR-145起抑制作用，同时促进SOX9的表达。外泌体介导的OIP5-AS1转移诱导GIST细胞增殖和侵袭增强，最终通过miR-145/SOX9轴诱导对舒尼替尼的化疗耐药性。敲低表达OIP5-AS1的外泌体导致化疗耐药的GIST细胞增殖和侵袭减少。总之，这些发现共同表明，OIP5-AS1通过抑制miR-145和上调SOX9促进GIST细胞增殖和侵袭，最终导致GIST的耐药性和肿瘤进展。
