Transgelin is an actin-binding protein that promotes cancer progression via activation of cancer-associated fibroblasts and has been identified as a prognostic marker. However, its distribution and functional role in colon cancer remain unclear. In this study, we aimed to elucidate the mechanistic role of transgelin in colon cancer progression by focusing on its functional impact in cancer-associated fibroblasts. Tissue microarrays from 359 human colon cancer tissues were investigated to elucidate the clinical importance of transgelin expression in cancer stroma. We focused on transgelin in fibroblasts and investigated its functional role in stromal activation using in vitro knockdown experiments and in vivo co-transplantation models. Primary cultures of human colon fibroblasts were evaluated for their biological function. Our data showed that transgelin expression is predominant in activated cancer-associated fibroblasts in colon cancer tissues. Stimulation by cancer-cell-conditioned medium (CM) significantly upregulated transgelin, ACTA2, COL1A1, and TNC expression in colonic fibroblasts. Additionally, transgelin knockdown (KD) in fibroblasts did not influence the upregulation except for transgelin itself. Transgelin KD in fibroblasts did not result in drastic alterations in gene expression profiles. Transgelin KD suppressed collagen gel contractility. Furthermore, co-transplantation experiments of cancer cells and colonic fibroblasts into immunodeficient mice revealed that transgelin KD inhibited tumor growth in fibroblasts. In conclusion, stromal transgelin expression in colon cancer strongly correlated with distant metastasis and served as a prognostic factor for colon cancer. Mechanistically, transgelin in cancer-associated fibroblasts promotes tumor growth by regulating stromal contractility, suggesting transgelin as a potential therapeutic target.
Okamoto et al. (Wed,) studied this question.