Wang Jingzhi, Ling Rui, Zhou Yuepeng, Gao Xingyu, Yang Yun, Mao Chaoming, Chen Deyu
Institute of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China.
Department of Nuclear Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China.
Oncol Lett. 2020 Sep;20(3):2855-2869. doi: 10.3892/ol.2020.11853. Epub 2020 Jul 10.
Sterol regulatory element-binding protein 1 (SREBP1) is dysregulated in a variety of types of human cancer. However, the functional roles of SREBP1 in esophageal squamous cell carcinoma (ESCC) remain poorly understood. The present study investigated the function of SREBP1 in cell proliferation and motility. Microarray datasets in Oncomine, reverse transcription-quantitative PCR and western blot analysis revealed that SREBP1 was overexpressed in ESCC tumors when compared with normal tissues. In addition, SREBP1 overexpression was significantly associated with tumor differentiation, lymphatic metastasis and Ki67 expression. Results suggested that silencing SREBP1 inhibited the proliferation, migration and invasion of ESCC cells, whereas overexpression of SREBP1 had opposite effects on proliferation and metastasis. In addition, loss of SREBP1 significantly increased E-cadherin and decreased N-cadherin, Vimentin, Snail, matrix metalloproteinase 9 and vascular endothelial growth factor C expression levels, which were restored via SREBP1-overexpression. Mechanistically, loss of SREBP1 suppressed T-cell factor 1/lymphoid enhancer factor 1 (TCF1/LEF1) activity and downregulated TCF1/LEF1 target proteins, including CD44 and cyclin D1. Moreover, knockdown of SREBP1 downregulated the expression levels of stearoyl-CoA desaturase 1 (SCD1), phosphorylated glycogen synthase kinase-3β and nuclear β-catenin. Furthermore, the inhibitors of SREBP1 and/or SCD1 and small interfering RNA-SCD1 efficiently inhibited the activation of the Wnt/β-catenin pathway driven by constitutively active SREBP1. Finally, results indicated that SREBP1-knockdown suppressed the proliferation and metastasis of ESCC. Taken together, these findings demonstrated that SREBP1 exerts oncogenic effects in ESCC by promoting proliferation and inducing epithelial-mesenchymal transition via the SCD1-induced activation of the Wnt/β-catenin signaling pathway.
固醇调节元件结合蛋白1（SREBP1）在多种人类癌症中表达失调。然而，SREBP1在食管鳞状细胞癌（ESCC）中的功能作用仍知之甚少。本研究调查了SREBP1在细胞增殖和运动中的功能。Oncomine中的微阵列数据集、逆转录定量PCR和蛋白质印迹分析显示，与正常组织相比，SREBP1在ESCC肿瘤中过表达。此外，SREBP1过表达与肿瘤分化、淋巴转移和Ki67表达显著相关。结果表明，沉默SREBP1可抑制ESCC细胞的增殖、迁移和侵袭，而SREBP1的过表达对增殖和转移有相反的影响。此外，SREBP1的缺失显著增加E-钙黏蛋白并降低N-钙黏蛋白、波形蛋白、Snail、基质金属蛋白酶9和血管内皮生长因子C的表达水平，这些通过SREBP1过表达得以恢复。机制上，SREBP1的缺失抑制了T细胞因子1/淋巴样增强因子1（TCF1/LEF1）的活性，并下调了TCF1/LEF1靶蛋白，包括CD44和细胞周期蛋白D1。此外，敲低SREBP1下调了硬脂酰辅酶A去饱和酶1（SCD1）、磷酸化糖原合酶激酶-3β和核β-连环蛋白的表达水平。此外，SREBP1和/或SCD1的抑制剂以及小干扰RNA-SCD1有效抑制了由组成型活性SREBP1驱动的Wnt/β-连环蛋白信号通路的激活。最后，结果表明敲低SREBP1可抑制ESCC的增殖和转移。综上所述，这些发现表明SREBP1通过SCD1诱导的Wnt/β-连环蛋白信号通路激活促进增殖并诱导上皮-间质转化，从而在ESCC中发挥致癌作用。
