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

Tang Yang,Zheng Shu,Wei Jingsun,Xiao Qian,Huang Zhiheng,Liu Yue,Ding Kefeng,Ge Xiaoxu,Wang Zhanhuai

doi:10.3389/fonc.2020.01747

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.

Highlights

Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide with over 1 million cases diagnosed every year [1]
We demonstrate that increased RAB31 expression in cancer-associated fibroblasts (CAFs), a major component of stromal cells, may promote colon cancer progression by increasing hepatocyte growth factor (HGF) secretion which subsequently activates HGF/Met signaling in CRC cells
While studies have investigated the role of RAB31 in the cancer cells of hepatic cancer, breast cancer, pancreatic cancer, gastric cancer, and glioblastoma [10,11,12, 34, 35], we described the functional role of RAB31 in colon cancer-derived CAFs because its expression in the tumor stroma but not cancer cells predicted poor survival

Summary

Introduction

Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide with over 1 million cases diagnosed every year [1]. RAB31 has been reported to mediate the transport of the cation-dependent mannose-6-phosphate (CDMPR) from the trans-Golgi network (TGN) to endosomes [7]. Accumulating evidence has shown that altered RAB protein expression is associated with cancer progression [9]. RAB31 has been reported to be associated with the malignant behavior of breast cancer, hepatocellular carcinoma, and gastric cancer [10,11,12]. Increased RAB31 expression is significantly associated with distant metastasis-free survival and overall survival rate in breast cancer [13]. Breast cancer cell lines with RAB31 overexpression in vitro switch from an invasive to a more proliferative phenotype [10], suggesting a pro-tumorigenic role for this protein in the respective cancer types

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