A novel soluble isoform of the human TGF-beta Type 2 receptor exerts strong antitumor activity in colorectal cancer-derived cell lines

ANA ROMO; GUO Y; TANIA MELINA RODRÍGUEZ; RICARDO A. DEWEY

virtual

Congreso; Reunión de Sociedades de Biociencias (SAIC, SAFIS, SAI) 2020; 2020

Sociedades de Biociencias

TGF-β signaling pathway is a key regulator of cancer progression, particularly in colorectal cancer, where 90% of microsatellite instable (MSI) tumors exhibit mutations in the TGF-β receptor type 2 (TGF- BR2) gene. Here, we show that lentiviral-mediated overexpression of TGFBR2-SE, a recently discovered soluble isoform of the human TGF-β type 2 receptor, fused to the human IgG1 Fc fragment (TG- FBR2-SE/Fc) reduces in vitro cell proliferation and migration while induces cell cycle arrest and apoptosis in the primary human col- orectal cancer-derived cell line HCT116. Moreover, TGFBR2-SE/ Fc impairs tumorigenicity of BALB/c nude athymic mice xenografts, increasing the survival rate of the animals. Tumors overexpressing TGFBR2-SE/Fc were considerable smaller or even unable to be established as only 3 out of 6 mice developed tumors in the TGF- BR2-SE/Fc group. Mechanistically, TGFBR2-SE/Fc downregulates TGF-β canonical pathway and leads to the activation of tumor sup- pressor genes such as p21, p57 and p53, as well as to the inacti- vation of cell cycle progression elements such as cyclin B1 and Id1. These findings suggest a strong antitumor activity of TGFBR2-SE/ Fc based on blocking TGF-β signaling pathway and Smad2/3- inde- pendent changes in gene expression supporting the further explora- tion and development of TGFBR2-SE/Fc as a new biopharmaceuti- cal for the treatment of solid tumors.