Increased RAB31 Expression in Cancer-Associated Fibroblasts Promotes Colon Cancer Progression Through HGF-MET Signaling

Abstract

RAB family proteins participate in the dynamic regulation of cellular membrane compartments and are dysregulated in a variety of tumor types, which may alter the biological properties of cancer cells such as proliferation, migration, and invasion. In our previous study, we found that Ras-related protein Rab-31 (RAB31) expression was increased in late-stage colorectal cancer (CRC). The role of RAB31 has never been investigated in CRC. In this study, we found that expression of RAB31 in the tumor stroma but not cancer cells of colon cancer predicted poor survival. RAB31 can be detected in primary cancer-associated fibroblasts (CAFs) and paired normal fibroblasts. Conditioned medium (CM) from RAB31 overexpressing CAFs significantly promoted migration of colon cancer cell lines in vitro and in vivo. This process may be mediated by paracrine action of hepatocyte growth factor (HGF), which was increased in the CM of RAB31-overexpressing CAFs. Blockade of HGF/MET signaling by drug inhibition, knockdown of mesenchymal to epithelial transition factor (MET) in RKO, or antibody neutralization of HGF abolished migration of RKO cells mediated by RAB31 expression in CAFs. We propose that in colon cancer, increased RAB31 expression in CAFs may contribute to tumor progression by regulating the secretion of HGF in the tumor stroma.

CCL20 induces colorectal cancer neoplastic epithelial cell proliferation, migration, and further CCL20 production through autocrine HGF-c-Met and MSP-MSPR signaling pathways

“…To our knowledge, the findings that CCL20 induces secretion of HGF and phosphorylation of c-Met and that this pathway mediates the effects of CCL20 in eliciting migration and further secretion of CCL20 by colorectal cancer cells have not previously been reported in the literature. Our finding that signaling through the HGF/c-Met pathway induces migration of colorectal cancer cells is substantiated by several studies including those using the HT-29 and HCT116 cell lines [ 27 – 29 ]. In fact, the HGF/c-Met pathway has been implicated in the metastatic process of colorectal cancer [ 30 – 32 ].…”

The Versatile Roles of Cancer-Associated Fibroblasts in Colorectal Cancer and Therapeutic Implications

“…Typically, the hepatocyte growth factor (HGF) can activate cancer cell invasion and metastasis. Consistently, it was reported that the migration of CRC cells could be promoted by the Ras-related protein Rab-31 (RAB31) through regulating HGF secretion in the tumor stroma (Yang et al, 2020). Human CRC-derived CAFs also enhance the adhesion of CRC cells to ECs by secretion of HGF (Zhang et al, 2019a).…”

Rab31 promotes the invasion and metastasis of cervical cancer cells by inhibiting MAPK6 degradation

“…Hepatocyte growth factor (HGF), which is secreted predominantly by cancer-associated fibroblasts and present in the tumor microenvironment, promotes the survival and migration of cancer cells [26]. Rab31 was reported to promote the migration of colon cancer cell lines by paracrine HGF, and HGF inhibition abolished the migration of cancer cells mediated by Rab31 expression [27].…”