A NOVEL SOLUBLE ISOFORM OF THE HUMAN TGF-beta; TYPE 2 RECEPTOR EXERTS STRONG ANTITUMOR ACTIVITY IN COLORECTAL CANCER-DERIVED CELL LINES

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

Mar del Plata

Congreso; LXIII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2020

Sociedad Argentina de Investigación Clínica

TGF-β signaling pathway is a key regulator of cancer progression, particularly incolorectal cancer, where 90% of microsatellite instable (MSI) tumors exhibitmutations in the TGF-β receptor type 2 (TGFBR2) gene. Here, we show thatlentiviral-mediated overexpression of TGFBR2-SE, a recently discovered solubleisoform of the human TGF-β type 2 receptor, fused to the human IgG1 Fc fragment(TGFBR2-SE/Fc) reduces in vitro cell proliferation and migration while induces cellcycle arrest and apoptosis in the primary human colorectal cancer-derived cell lineHCT116. Moreover, TGFBR2-SE/Fc impairs tumorigenicity of BALB/c nudeathymic mice xenografts, increasing the survival rate of the animals. Tumorsoverexpressing TGFBR2-SE/Fc were considerable smaller or even unable to beestablished as only 3 out of 6 mice developed tumors in the TGFBR2-SE/Fc group.Mechanistically, TGFBR2-SE/Fc downregulates TGF-β canonical pathway andleads to the activation of tumor suppressor genes such as p21, p57 and p53, aswell as to the inactivation of cell cycle progression elements such as cyclin B1 andId1. These findings suggest a strong antitumor activity of TGFBR2-SE/Fc based onblocking TGF-β signaling pathway and Smad2/3-independent changes in geneexpression supporting the further exploration and development of TGFBR2-SE/Fcas a new biopharmaceutical for the treatment of solid tumors.