TSG-6 Promotes Cancer Cell Aggressiveness in a CD44-Dependent Manner and Reprograms Normal Fibroblasts to Create a Pro-metastatic Microenvironment in Colorectal Cancer

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2022 Mar 14

PMID 35280699

Authors

Binbin Liu

Tengfei Liu

Yiting Liu

Xingzhi Feng

Xuefei Jiang

Jiahui Long

Shubiao Ye

Daici Chen

Jianping Wang

Zihuan Yang

Affiliations

Soon will be listed here.

Abstract

Tumor necrosis factor α stimulated gene 6 (TSG-6), a 30-KD secretory protein, plays an essential role in modulating inflammatory responses and extracellular matrix remodeling. However, little is known regarding the role of TSG-6 in human cancers. Here, we investigated the mechanism of action and the role of TSG-6 in colorectal cancer (CRC) metastasis. We found that TSG-6 was highly expressed in tumor tissues and was associated with poor prognosis and metastasis in CRC. Mechanistically, TSG-6 overexpression in CRC cells resulted in ERK activation and epithelial-mesenchymal transition by means of stabilizing CD44 and facilitating the CD44-EGFR complex formation on the cell membrane. Consequently, this resulted in the promotion of tumor migration and invasion both and . Notably, our data showed that CRC cells secreted TSG-6 could trigger a paracrine activation of JAK2-STAT3 signaling and reprogram normal fibroblasts into cancer-associated fibroblasts, which exhibited upregulation of pro-metastatic cytokines (CCL5 and MMP3) and higher movement ability. In animal models, the co-injection of cancer cells and TSG6-reprogrammed fibroblasts led to a significant increase in tumor metastasis. Our findings indicated that TSG-6 overexpression in CRC cells could promote cancer metastasis in both an autocrine and paracrine manner. Therefore, targeting TSG-6 might be a potential therapeutic strategy for the treatment of metastatic CRC.

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