Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Frontier Medical Center, Tianfu Jincheng Laboratory, 610212, Chengdu, China.
Nat Commun. 2023 Oct 28;14(1):6876. doi: 10.1038/s41467-023-42571-1.
Metastasis is the leading cause of cancer-related death, where TGFβ-induced epithelial-mesenchymal transition (EMT) process confers on cancer cells increased metastatic potential. However, the involvement of circRNAs in this process is still obscure. Here, we identify a TGFβ-induced circRNA called circITGB6 as an indispensable factor during the TGFβ-mediated EMT process. circITGB6 is significantly upregulated in metastatic cancer samples and its higher abundance is closely correlated to worse prognosis of colorectal cancer (CRC) patients. Through gain- and loss-of-function assays, circITGB6 is found to potently promote EMT process and tumor metastasis in various models in vitro and in vivo. Mechanistically, circITGB6 enhances the mRNA stability of PDPN, an EMT-promoting gene, by directly interacting with IGF2BP3. Notably, interfering circITGB6 with PEI-coated specific siRNA effectively represses liver metastasis. Therefore, our study reveals the function of a TGFβ-regulated circRNA in tumor metastasis and suggests that targeting circITGB6 is a promising strategy for cancer therapy.
转移是癌症相关死亡的主要原因，其中 TGFβ 诱导的上皮-间充质转化（EMT）过程赋予癌细胞更高的转移潜能。然而，circRNAs 在这个过程中的参与仍然不清楚。在这里，我们鉴定出一种 TGFβ 诱导的 circRNA，称为 circITGB6，它是 TGFβ 介导的 EMT 过程中不可缺少的因素。circITGB6 在转移性癌症样本中显著上调，其丰度的增加与结直肠癌（CRC）患者的预后不良密切相关。通过功能获得和功能丧失实验，发现 circITGB6 在体外和体内的各种模型中强力促进 EMT 过程和肿瘤转移。在机制上，circITGB6 通过直接与 IGF2BP3 相互作用增强 EMT 促进基因 PDPN 的 mRNA 稳定性。值得注意的是，用 PEI 包裹的特异性 siRNA 干扰 circITGB6 可有效抑制肝转移。因此，我们的研究揭示了 TGFβ 调节的 circRNA 在肿瘤转移中的功能，并表明靶向 circITGB6 是癌症治疗的一种有前途的策略。
