Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
George Whipple Lab for Cancer Research, Departments of Urology, Pathology, Radiation Oncology and The Wilmot Cancer Center Institute, University of Rochester Medical Center, Rochester, New York 14642, USA.
Oncogene. 2020 Mar;39(12):2493-2508. doi: 10.1038/s41388-019-1150-6. Epub 2020 Jan 29.
Early studies indicated that estrogen receptor α (ERα) might impact the progression of hepatocellular carcinoma (HCC). However, the detailed mechanisms, especially its linkage to the gelsolin (GSN)-mediated cell invasion, remain unclear. Here we found that ERα could decrease HCC cell invasion via suppressing the circular RNA-SMG1.72 (circRNA-SMG1.72) expression via transcriptional regulation through directly binding to the 5' promoter region of its host gene SMG1, We showed that ERα-suppressed circ-SMG1.72 could sponge and inhibit the expression of the microRNA (miRNA, miR), miR-141-3p, which could then result in increasing the GSN messenger RNA translation via reduced miR binding to its 3' untranslated region (3'UTR). The preclinical study using an in vivo mouse model with orthotopic xenografts of HCC cells confirmed the in vitro data, and the human HCC clinical sample survey and tissue staining also confirmed the linkage of ERα/miR-141-3p/GSN signaling to the HCC progression. Together, our findings suggest that ERα can suppress HCC cell invasion via altering the ERα/circRNA-SMG1.72/miR-141-3p/GSN signaling, and targeting this newly identified signaling with small molecules may help in the development of novel therapies to better suppress the HCC progression.
早期研究表明，雌激素受体 α（ERα）可能影响肝细胞癌（HCC）的进展。然而，其详细机制，尤其是与桩蛋白（GSN）介导的细胞侵袭的联系，仍不清楚。在这里，我们发现 ERα 可以通过直接结合其宿主基因 SMG1 的 5'启动子区域，通过转录调控来降低 HCC 细胞的侵袭，通过抑制环状 RNA-SMG1.72（circRNA-SMG1.72）的表达。我们表明，ERα 抑制的 circ-SMG1.72 可以通过海绵作用抑制 microRNA（miRNA，miR），miR-141-3p 的表达，从而通过减少 miR 与其 3'非翻译区（3'UTR）的结合来增加 GSN 信使 RNA 的翻译。使用 HCC 细胞原位异种移植的体内小鼠模型进行的临床前研究证实了体外数据，并且对人类 HCC 临床样本的调查和组织染色也证实了 ERα/miR-141-3p/GSN 信号与 HCC 进展之间的联系。总之，我们的研究结果表明，ERα 可以通过改变 ERα/circRNA-SMG1.72/miR-141-3p/GSN 信号来抑制 HCC 细胞的侵袭，并且用小分子靶向这个新鉴定的信号可能有助于开发新的治疗方法，以更好地抑制 HCC 的进展。
