Transglutaminase 2 maintains a colorectal cancer stem phenotype by regulating epithelial-mesenchymal transition

Oluseyi Ayinde, Zhuo Wang, Giulia Pinton, Laura Moro, Martin Griffin

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
Pages (from-to) 4556-4569
Number of pages14
JournalOncotarget
Volume10
Issue number44
DOIs
Publication statusPublished - 16 Jul 2019

Bibliographical note

Ayinde et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License
3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and
source are credited.

Funding: EC Marie Curie ITN TRANSPATH (289964).

Keywords

  • Cancer stem cells
  • Colorectal cancer
  • Epithelial-mesenchymal transition
  • Transglutaminase 2
  • β-catenin

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