p53 Deficiency in Colon Cancer Cells Promotes Tumor Progression Through the Modulation of Meflin in Fibroblasts

Abstract

Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play an important role in tumor progression. Colon cancer cells deficient in p53 activate fibroblasts and enhance fibroblast-mediated tumor growth. Meflin is a CAF marker capable of inhibiting tumor growth. In this study, we investigated the role of Meflin in fibroblasts using human cell lines (colon cancer HCT116 and fibroblasts CCD-18Co) and clinical specimens. TP53-suppressed HCT116 (HCT116^{sh p53}) cells cocultured with CCD-18Co cells showed significantly faster proliferation than HCT116^{sh control} cells. In xenograft experiments, the volume of tumors induced by coinoculation with HCT116^{sh p53} and CCD-18Co cells was significantly larger than that induced by HCT116^{sh control} cells co-inoculated with CCD-18Co cells. HCT116^{sh p53} cells increased the levels of CAF-like phenotypic markers in CCD-18Co cells. Moreover, Meflin expression was significantly reduced in CCD-18Co cells cocultured with HCT116^{sh p53} cells compared to that in CCD-18Co cells cocultured with HCT116^{sh control} cells. si-RNA-mediated inhibition of Meflin activated CCD-18Co cells into tumor-promoting CAF-like cells, which significantly promoted xenograft tumor growth. Overexpression of Meflin in CCD-18Co cells using lentivirus suppressed fibroblast-mediated growth of HCT116^{sh p53} tumor xenografts. The expression of Meflin in CCD-18Co cells was suppressed by TGF-β and enhanced by vitamin D. These results indicate that colon cancer cells deficient in p53 suppress Meflin expression in fibroblasts, which affects tumor growth by altering the properties of tumor growth-promoting CAFs. Our results suggest that targeting Meflin in fibroblasts may be a novel therapeutic strategy for colorectal cancer.