最近的证据表明，环状 RNA (circRNA) 在结直肠癌 (CRC) 的进展中发挥着重要作用；然而，它们在CRC中的作用和机制需要进一步探讨。本研究旨在揭示 circXPO1 在 CRC 进展中的生物学功能。CircXPO1 通过 Sanger 测序、RNase R 和放线菌素 D 治疗测定法进行鉴定。采用集落形成、划痕、transwell实验和小鼠异种移植模型来评估CRC细胞的体外和体内生长和转移。通过 FISH 和核质分离实验检测 circXPO1 的亚细胞表达。通过 MeRIP、RIP 和 RNA Pull-down 分析研究分子机制。通过RT-qPCR、Western blotting和免疫组化染色检测靶分子表达。circXPO1在CRC组织和细胞中表达上调，提示CRC患者预后不良。 circXPO1 缺陷会延迟 CRC 细胞的生长、EMT 和转移。机制实验表明，下调 ALKBH5 会增强 IGF2BP2 介导的 m6A 对 circXPO1 的修饰，从而增加 circXPO1 的表达。此外，circXPO1 与 FMRP 相互作用，降低了 WWC2 mRNA 的稳定性，从而导致 Hippo-YAP 通路激活。拯救实验表明，WWC2 过度表达消除了 circXPO1 介导的 CRC 细胞的恶性能力。 CRC细胞的体内生长和肝转移受到circXPO1耗竭或WWC2过表达的抑制。ALKBH5/IGF2BP2轴的m6A修饰的circXPO1通过与FMRP相互作用来不稳定WWC2，激活Hippo-YAP通路，从而促进CRC生长和转移。靶向 circXPO1 可能是 CRC 的潜在治疗策略。© 2024。作者。

Recent evidence has demonstrated the vital roles of circular RNAs (circRNAs) in the progression of colorectal cancer (CRC); however, their functions and mechanisms in CRC need to be further explored. This study aimed to uncover the biological function of circXPO1 in CRC progression.CircXPO1 was identified by Sanger sequencing, RNase R, and actinomycin D treatment assays. Colony formation, scratch, transwell assays, and mouse xenograft models were adopted to evaluate CRC cell growth and metastasis in vitro and in vivo. Subcellular expression of circXPO1 was detected by FISH and nuclear-cytoplasmic separation assays. Molecular mechanisms were investigated by MeRIP, RIP, and RNA pull-down assays. Target molecular expression was detected by RT-qPCR, Western blotting and immunohistochemical staining.circXPO1 was up-regulated in CRC tissues and cells, which indicated a poor prognosis of CRC patients. circXPO1 deficiency delayed the growth, EMT, and metastasis of CRC cells. Mechanistical experiments indicated that down-regulation of ALKBH5 enhanced IGF2BP2-mediated m6A modification of circXPO1 to increase circXPO1 expression. Furthermore, circXPO1 interacted with FMRP to reduce the mRNA stability of WWC2, which consequently resulted in Hippo-YAP pathway activation. Rescue experiments suggested that WWC2 overexpression abrogated circXPO1-mediated malignant capacities of CRC cells. The in vivo growth and liver metastasis of CRC cells were restrained by circXPO1 depletion or WWC2 overexpression.m6A-modified circXPO1 by ALKBH5/IGF2BP2 axis destabilized WWC2 via interaction with FMRP to activate Hippo-YAP pathway, thereby facilitating CRC growth and metastasis. Targeting circXPO1 might be a potential therapeutic strategy for CRC.© 2024. The Author(s).