SOX9 in prostate cancer is upregulated by cancer-associated fibroblasts to promote tumor progression through HGF/c-Met-FRA1 signaling

Abstract

Background Previous studies have demonstrated that transcription factor SOX9 which was reactivated in prostate cancer (Pca) and promoted tumor growth was a poor prognostic biomarker for Pca. Nevertheless, the regulatory mechanism underlying SOX9 upregulation in Pca still remains unclear. Several cytokines widely distributed in the tumor microenvironment (TME) 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 TME, may play a role in regulating SOX9 expression. Methods Herein, an in vitro model of paracrine interaction between primary CAFs and Pca cells (both AR-positive and AR-negative 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 (TCGA) data. Results Conditional medium from Pca CAFs (CAF-CM) upregulated the expression of SOX9, which was also proved to be essential for CAF-induced tumor progression. Further analysis showed that it was hepatocyte growth factor (HGF) secreted by CAFs that was responsible for the SOX9 elevation in Pca cells via activating c-Met signaling. Mechanistically, HGF/c-Met signaling specifically activated MEK1/2-ERK1/2 pathway which then induced phosphorylated status and protein upregulation of FRA1. Furthermore, ChIP assay demonstrated that FRA1 transcriptionally upregulated SOX9 expression by binding to the TPA-responsive element (TRE) sequence in the promoter of SOX9 gene. We also found that HGF/c-Met-ERK1/2-FRA1-SOX9 axis was relatively conserved in human and mouse species by validating in mouse Pca cells (RM-1). Conclusions Our results revealed a novel insight into the molecular mechanism that SOX9 expression in Pca cells is promoted by CAFs, through the HGF/cMet-ERK1/2-FRA1 axis. Besides, 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.

NNT-AS1 in CAFs-derived exosomes promotes progression and glucose metabolism through miR-889-3p/HIF-1α in pancreatic adenocarcinoma

“…Changes in the microenvironment can activate and maintain HIF, which, in turn, stimulates the transcription of related genes involved in metabolic reprogramming and PDAC generation, invasion, metastasis, and angiogenesis 2 , 3 . Meanwhile, cancer-associated fibroblasts (CAFs), a kind of activated fibroblast, are present in practically all solid tumors, especially in pancreatic, breast, and prostate cancers 4 – 6 . CAFs play a critical role in the formation and progression of a variety of cancers since they are one of the most important components of the tumor microenvironment (TME).…”

Diagnostic and Prognostic Significances of SOX9 in Thymic Epithelial Tumor

“…SOX9, a member of the family of SOX (SRY-related highmobility group box) genes, exerts regulatory functions in multiple organs development, cell-fate decision, and differentiation (8). Accumulating studies have demonstrated that SOX9 is also involved in the development of multiple cancers, including gastrointestinal, breast, brain, urological, and lung cancers and others (9)(10)(11)(12)(13). Collectively, SOX9 plays critical roles in tumor development and progression, including tumor initiation, tumor microenvironment regulation, metastasis, and drug resistance (14,15).…”