Department of Gastrointestinal Surgery, Wuhan University, Renmin Hospital, No. 99 Zhang Zhidong Road, Wuhan, 430060, Hubei Province, PR China.
Department of Gastrointestinal Surgery, Wuhan University, Renmin Hospital, No. 99 Zhang Zhidong Road, Wuhan, 430060, Hubei Province, PR China.
Biochem Biophys Res Commun. 2019 Jun 30;514(3):933-939. doi: 10.1016/j.bbrc.2019.05.076. Epub 2019 May 11.
Cancer-associated fibroblasts comprise the major stromal cell populations in gastric cancer, which is a significant contributor to cancer-related death worldwide. As a member of the serine protease family, HTRA1 is reportedly involved in malignant transformation of various tumor types. In the present study, we observed that HTRA1 is positively correlated with α-SMA expression in gastric cancer tissues, which was also confirmed by correlation analysis and Gene Set Enrichment Analysis (GSEA) using the GEO database. Upregulation of HTRA1 in gastric cancer cell lines induces expression of α-SMA in normal fibroblasts. To explore how HTRA1 activates normal fibroblasts, an ELISA assay was performed. Secretion of bFGF/FGF2 from gastric cancer cells was significantly increased in response to HTRA1 overexpression. However, upreguation of α-SMA in normal fibroblasts induced by HTRA1 was restored by inhibiting the expression of bFGF. Furthermore, HTRA1 promotes bFGF/FGF2 expression through activation of NF-κB signaling in gastric cancer cells. Inhibition of the NF-κB signaling pathway partially restored baseline expression levels of α-SMA induced by HTRA1. In conclusion, HTRA1 promotes transdifferentiation of normal fibroblasts to cancer-associated fibroblasts by increasing bFGF/FGF2 expression, which is dependent upon activation of NF-κB signaling in gastric cancer.
癌相关成纤维细胞构成了胃癌中主要的基质细胞群体，这是全球癌症相关死亡的一个重要因素。作为丝氨酸蛋白酶家族的一员，据报道 HTRA1 参与了多种肿瘤类型的恶性转化。在本研究中，我们观察到 HTRA1 与胃癌组织中 α-SMA 的表达呈正相关，这一点也通过 GEO 数据库中的相关性分析和基因集富集分析（GSEA）得到了证实。胃癌细胞系中 HTRA1 的上调诱导正常成纤维细胞中 α-SMA 的表达。为了探索 HTRA1 如何激活正常成纤维细胞，我们进行了 ELISA 检测。结果显示，HTRA1 过表达可显著增加胃癌细胞分泌 bFGF/FGF2。然而，通过抑制 bFGF 的表达，可恢复 HTRA1 诱导的正常成纤维细胞中 α-SMA 的上调。此外，HTRA1 通过激活胃癌细胞中的 NF-κB 信号通路促进 bFGF/FGF2 的表达。抑制 NF-κB 信号通路可部分恢复 HTRA1 诱导的 α-SMA 的基础表达水平。总之，HTRA1 通过增加 bFGF/FGF2 的表达促进正常成纤维细胞向癌相关成纤维细胞的转分化，这依赖于胃癌中 NF-κB 信号通路的激活。
