Wang Da, Xiong Fei, Wu Guanhua, Liu Wenzheng, Wang Bing, Chen Yongjun
Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang avenue 1095, Wuhan, Hubei, China.
Department of General Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
Cancer Cell Int. 2021 Dec 7;21(1):656. doi: 10.1186/s12935-021-02374-0.
Accumulating evidence has demonstrated the close relation of SOX1 with tumorigenesis and tumor progression. Upregulation of SOX1 was recently shown to suppress growth of human cancers. However, the expression and role of SOX1 in cholangiocarcinoma (CCA) is not well characterized.
Expression levels of SOX1 in CCA tissues and normal bile duct tissues were examined using public GEO database. Western blot and immunohistochemistry were used to confirm the expression levels. Cell proliferation assay (CCK-8) and colony formation assay were performed to assess proliferation of CCA cells. A mouse model of subcutaneous transplantable tumors was used to evaluated proliferation of CCA in vivo. The putative regulating factor of SOX1 were determined using Targetscan and dual-luciferase reporter assay.
SOX1 was downregulated in CCA tissues. Overexpression of SOX1 significantly inhibited cell proliferation in vitro and suppressed tumor growth in vivo. miR-155-5p directly targeted the 3'-untranslated region (3'UTR) of SOX1 and inhibited expression of SOX1, resulting in the activation of RAF, MEK and ERK phosphorylation, and thus CCA proliferation. However, restoration of SOX1 expression in miR-155-5p overexpressing cell lines decreased the phosphorylation level of RAF, MEK and ERK, as well as the proliferation of CCA cells.
MiR-155-5p decreased the expression of SOX1 by binding to its 3'UTR, which activated the RAF/MEK/ERK signaling pathway and promoted CCA progression.
越来越多的证据表明SOX1与肿瘤发生和肿瘤进展密切相关。最近有研究显示SOX1的上调可抑制人类癌症的生长。然而，SOX1在胆管癌（CCA）中的表达及作用尚未得到充分表征。
利用公共基因表达综合数据库（GEO数据库）检测CCA组织和正常胆管组织中SOX1的表达水平。采用蛋白质免疫印迹法和免疫组织化学法确认表达水平。进行细胞增殖试验（CCK-8法）和集落形成试验以评估CCA细胞的增殖情况。使用皮下可移植肿瘤小鼠模型评估CCA在体内的增殖情况。利用Targetscan软件和双荧光素酶报告基因检测法确定SOX1的假定调节因子。
SOX1在CCA组织中表达下调。SOX1的过表达显著抑制体外细胞增殖并抑制体内肿瘤生长。miR-155-5p直接靶向SOX1的3'-非翻译区（3'UTR）并抑制SOX1的表达，导致RAF、MEK和ERK磷酸化激活，从而促进CCA增殖。然而，在过表达miR-155-5p的细胞系中恢复SOX1表达可降低RAF、MEK和ERK的磷酸化水平以及CCA细胞的增殖。
miR-155-5p通过与SOX1的3'UTR结合降低其表达，激活RAF/MEK/ERK信号通路并促进CCA进展。
