SOX9 in prostate cancer is upregulated by cancer‐associated fibroblasts to promote tumor progression through HGF/c‐Met‐FRA1 signaling. (2nd April 2021)

• Record Type: Journal Article
• Authors: Qin, Haixiang; Yang, Yang; Jiang, Bo; Pan, Chun; Chen, Wei; Diao, Wenli; Ding, Meng; Cao, Wenmin; Zhang, Zhenxing; Chen, Mengxia; Gao, Jie; Zhao, Xiaozhi; Qiu, Xuefeng; Guo, Hongqian
• Is Part Of: FEBS journal. Volume 288:Number 18(2021)
• Page Start: 5406
• Page End: 5429
• Publication Date: 2021-04-02
• Subjects: cancer‐associated fibroblasts -- FRA1 -- hepatocyte growth factor -- prostate cancer -- SOX9; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.15816
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Transcription factor SOX9 was a biomarker for prostate cancer (Pca) with poor prognosis. Nevertheless, the regulatory mechanism underlying SOX9 upregulation still remains unclear. Several cytokines have been reported to be involved in the regulation of SOX9, suggesting that cancer‐associated fibroblasts (CAFs), one of the main sources of secreted factors in the tumor microenvironment (TME), may play a role in regulating SOX9 expression. Herein, an in vitro model of paracrine interaction between primary CAFs and Pca cells was applied to investigate the molecular mechanism of SOX9 upregulation during Pca progression. The regulatory axis was validated by in vivo experiments and The Cancer Genome Atlas data. Conditional medium of CAFs (CAF‐CM) upregulated the expression of SOX9, which was mutually proved to be essential for CAF‐induced tumor progression. Further analysis showed that hepatocyte growth factor (HGF) secreted by CAFs was responsible for SOX9 elevation in Pca cells, via the activation of c‐Met signaling. Mechanistically, HGF/c‐Met signaling specifically activated MEK1/2‐ERK1/2 pathway, which induced phosphorylation and upregulation of FRA1, which then transcriptionally upregulated SOX9 by binding to the promoter of SOX9 gene. Moreover, we identified that HGF/c‐Met‐ERK1/2‐FRA1‐SOX9 axis was relatively conserved between human and mouse species by validating in mouse Pca cells. Our results reveal a novel insight into the molecular mechanism that SOX9 in Pca cells is promoted by CAFs through HGF/c‐Met‐ERK1/2‐FRA1 axis. Furthermore, SOX9 may serve as an alternative marker for the activated HGF/c‐Met signaling to enroll the optimal Pca patients for HGF/c‐Met inhibition treatment, since it is much more stable and easier to detect. Abstract : Transcription factor SOX9 plays an important role in the initiation and progression of prostate cancer (Pca). SOX9 in Pca cells could be promoted by HGF, which is secreted by cancer‐associated fibroblasts (CAFs) through HGF/c‐Met‐ERK1/2‐FRA1 signaling, and is also proved to be essential for CAF‐induced tumor progression. SOX9 may serve as an alternative marker for the activated HGF/c‐Met signaling to enroll the optimal Pca patients for HGF/c‐Met inhibition treatment.