Meng Qing, Xiang Haoyi, Wang Yijing, Hu Kepeng, Luo Xin, Wang Jiawei, Chen Engeng, Zhang Wei, Chen Jiaxin, Chen Xiaoyu, Wang Huogang, Ju Zhenyu, Song Zhangfa
Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
Key Laboratory of Biological Treatment of Zhejiang Province, Hangzhou, 310016, China.
Biol Direct. 2024 Dec 20;19(1):130. doi: 10.1186/s13062-024-00571-1.
Exosomes have emerged as significant biomarkers for multiple diseases, including cancers. Circular RNAs (circRNAs), abundant in exosomes, are involved in regulating cancer development. However, the regulatory function and the underlying molecular mechanism of hsa_circ_0006906 (circSCP2) in colorectal cancer (CRC) metastasis remain unclear. A competing endogenous RNA microarray was used to analyze circRNA expression in serum exosomes in patients with CRC at early and late stages. circSCP2 expression was evaluated using qRT-PCR. The biological functions of circSCP2 in CRC were assessed through in vitro and in vivo experiments. The molecular mechanism of circSCP2 was explored using western blotting, RNA pulldown, RNA immunoprecipitation, luciferase assays, and relative rescue experiments. circSCP2 expression was significantly elevated in CRC tissues, with higher levels in serum exosomes correlating with advanced TNM stages. circSCP2 knockdown inhibited CRC cell proliferation, migration, invasion, and metastasis in vitro and in vivo. Mechanistically, circSCP2 sponged miR-92a-1-5p to increase insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) expression. Additionally, circSCP2 directly bound to and stabilized polypyrimidine tract binding protein 1 (PTBP1) by inhibiting protein ubiquitination, resulting in IGF2BP1 mRNA stabilization and enhanced CRC migration and invasion. Our findings demonstrate that circSCP2 regulates the miR-92a-1-5p/IGF2BP1 pathway, promotes PTBP1/IGF2BP1 interaction, and accelerates CRC progression. Exosomal circSCP2 is a promising circulating biomarker for CRC prognosis and needs further therapeutic investigation.
外泌体已成为包括癌症在内的多种疾病的重要生物标志物。环状RNA（circRNA）在外泌体中含量丰富，参与调节癌症发展。然而，hsa_circ_0006906（circSCP2）在结直肠癌（CRC）转移中的调控功能及潜在分子机制仍不清楚。采用竞争性内源性RNA微阵列分析早期和晚期CRC患者血清外泌体中的circRNA表达。使用qRT-PCR评估circSCP2表达。通过体外和体内实验评估circSCP2在CRC中的生物学功能。利用蛋白质印迹、RNA下拉、RNA免疫沉淀、荧光素酶测定和相关拯救实验探索circSCP2的分子机制。circSCP2在CRC组织中表达显著升高，血清外泌体中较高水平与晚期TNM分期相关。circSCP2敲低在体外和体内均抑制CRC细胞增殖、迁移、侵袭和转移。机制上，circSCP2通过海绵化miR-92a-1-5p增加胰岛素样生长因子2 mRNA结合蛋白1（IGF2BP1）表达。此外，circSCP2通过抑制蛋白质泛素化直接结合并稳定多嘧啶序列结合蛋白1（PTBP1），导致IGF2BP1 mRNA稳定并增强CRC迁移和侵袭。我们的研究结果表明，circSCP2调节miR-92a-1-5p/IGF2BP1通路，促进PTBP1/IGF2BP1相互作用，并加速CRC进展。外泌体circSCP2是一种有前景的用于CRC预后的循环生物标志物，需要进一步的治疗研究。
