Transglutaminase 2 maintains a colorectal cancer stem phenotype by regulating epithelial-mesenchymal transition
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Oluseyi Ayinde1, Zhuo Wang1, Giulia Pinton2, Laura Moro2 and Martin Griffin1
1 Department of Biology and Biomedical Science, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom
2 Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale, Novara 28100, Italy
Keywords: transglutaminase 2; colorectal cancer; epithelial-mesenchymal transition; cancer Stem Cells; β-catenin
Received: May 03, 2019 Accepted: June 14, 2019 Published: July 16, 2019
Transglutaminase 2 (TG2), a multifunctional protein, is reported in regulating the cancer stem cell (CSC) phenotype in various cancers. Our previous work suggested the link between TG2 and Epithelial-Mesenchymal Transition (EMT) in colorectal cancer (CRC). Here we demonstrate the importance of TG2 in CSC development in human CRC cell lines HCT116 and SW620. CRC spheroid cells showed increased CSC characteristics over their monolayer cells with increased expression of CD44 and over expression of Oct3/4, Sox2 and Nanog. They also showed increased EMT and invasiveness, and enhanced expression of TG2. TG2 inhibition by its selective inhibitor 1-155 reduced both spheroid formation and invasive potential of the spheroid cells. β-catenin, a mediator of stem cell maintenance, was overexpressed in the spheroid cells and could be attenuated by TG2 inhibition. Spheroid cells possessed increased angiogenesis stimulating ability via overexpression of Vascular Endothelial Growth Factor (VEGF). Increased VEGF was present in the culture media from spheroid cells when compared to monolayer cultures which could be reduced by selective inhibition by 1-155. Stemness and malignancy in the colorectal spheroid cells was associated with increased TG2, EMT, β-catenin and VEGF. Here we demonstrate that inhibiting TG2 reduces both stemness and angiogenic stimulating activity in CRC.
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