Zhou Yulai, Gao Yan, Peng Yinghui, Cai Changjing, Han Ying, Chen Yihong, Deng Gongping, Ouyang Yanhong, Shen Hong, Zeng Shan, Du Yangfeng, Xiao Zemin
Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Cell Death Discov. 2025 Apr 23;11(1):192. doi: 10.1038/s41420-025-02478-w.
Colorectal cancer (CRC) is the third most common cancer and remains a significant challenge due to high rates of drug resistance and limited therapeutic options. Circular RNAs (circRNAs) are increasingly recognized for their roles in CRC initiation, progression, and drug resistance. However, no circRNA-based therapies have yet entered clinical development, underscoring the need for comprehensive detection and mechanistic studies of circRNAs in CRC. Here, we identified and characterized a circular RNA, circ_0001766 (hsa_circ_0001766), through microarray analysis of CRC tissues. Our results showed that circ_0001766 is downregulated in CRC tissues and closely associated with patient survival and metastasis. Functional experiments demonstrated that circ_0001766 inhibits CRC cell proliferation, migration and invasion both in-vitro and in-vivo. Mechanistically, hypoxia downregulates Quaking (QKI), an RNA-binding protein essential for the biogenesis of circ_0001766 by binding to introns 1 and 3 of PDIA4 pre-mRNA. Reduced QKI expression under hypoxic conditions leads to decreased circ_0001766 levels in CRC. Circ_0001766 acts as a competitive endogenous RNA, sponging miR-1203 to prevent the degradation of PPP1R3C mRNA. Loss of circ_0001766 results in decreased PPP1R3C expression, leading to the activation of mTOR signaling and increased phosphorylation of Myc, which promotes CRC progression and rapamycin resistance. Our study reveals that overexpression of circ_0001766 or PPP1R3C in CRC cells inhibits the mTOR and Myc pathway, thereby resensitizing cells to rapamycin. The combination of circ_0001766 or PPP1R3C with rapamycin markedly inhibits CRC cell proliferation and induces apoptosis by reducing rapamycin-induced Myc phosphorylation. In summary, our study elucidates a critical circ_0001766/miR-1203/PPP1R3C axis that modulates CRC progression and rapamycin resistance. Our findings highlight circ_0001766 as a promising therapeutic target in CRC, providing a new avenue for enhancing the efficacy of existing treatments and overcoming drug resistance.
结直肠癌（CRC）是第三大常见癌症，由于耐药率高和治疗选择有限，仍然是一个重大挑战。环状RNA（circRNAs）在CRC的发生、发展和耐药性中的作用越来越受到认可。然而，尚未有基于circRNA的疗法进入临床开发阶段，这凸显了对CRC中circRNAs进行全面检测和机制研究的必要性。在此，我们通过对CRC组织进行微阵列分析，鉴定并表征了一种环状RNA，即circ_0001766（hsa_circ_0001766）。我们的结果表明，circ_0001766在CRC组织中表达下调，且与患者的生存和转移密切相关。功能实验表明，circ_0001766在体外和体内均能抑制CRC细胞的增殖、迁移和侵袭。机制上，缺氧下调了震颤蛋白（QKI），QKI是一种RNA结合蛋白，通过与PDIA4前体mRNA的内含子1和3结合，对circ_0001766的生物合成至关重要。缺氧条件下QKI表达降低导致CRC中circ_0001766水平下降。circ_0001766作为一种竞争性内源性RNA，吸附miR-1203以防止PPP1R3C mRNA降解。circ_0001766缺失导致PPP1R3C表达降低，从而导致mTOR信号激活以及Myc磷酸化增加，促进CRC进展和对雷帕霉素的耐药性。我们的研究表明，CRC细胞中circ_0001766或PPP1R3C的过表达可抑制mTOR和Myc通路，从而使细胞对雷帕霉素重新敏感。circ_0001766或PPP1R3C与雷帕霉素联合使用可通过减少雷帕霉素诱导的Myc磷酸化，显著抑制CRC细胞增殖并诱导细胞凋亡。总之，我们的研究阐明了一个关键的circ_0001766/miR-1203/PPP1R3C轴，该轴调节CRC进展和雷帕霉素耐药性。我们的发现突出了circ_0001766作为CRC中一个有前景的治疗靶点，为提高现有治疗效果和克服耐药性提供了一条新途径。
