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.
Highlights
There is a growing body of evidence showing that the formation and seeding of circulating tumour cells are highly dependent on a subpopulation of tumour cells with self-renewal potential and ability to differentiate into diverse tumour populations, this subpopulation of cells is called the cancer stem cells (CSCs) that can repopulate a tumour or seed a metastasis [1]
We demonstrate the importance of Transglutaminase 2 (TG2) in CSC development in human Colorectal cancer (CRCs) cell lines HCT116 and SW620
The CD44 cell surface protein marker for CSCs shows a significant increase in expression in the SW620 and HCT116 spheroid cells (SW620-S and HCT116-S, respectively) compared to their parental monolayer cells SW620-M and HCT116-M (Figure 1B)
Summary
There is a growing body of evidence showing that the formation and seeding of circulating tumour cells are highly dependent on a subpopulation of tumour cells with self-renewal potential and ability to differentiate into diverse tumour populations, this subpopulation of cells is called the cancer stem cells (CSCs) that can repopulate a tumour or seed a metastasis [1]. Cancer researchers have become aware of the existence of colorectal CSCs, which possess self-renewing capabilities and essentially have the potential to acquire the many mutations that result in a cancerous cell [2]. These CSCs form the hierarchy of tumours and possess metastatic and drug-resistant phenotypes [3]. Various studies are providing evidence that EMT process is important in the development and acquisition of a CSC phenotype in various epithelial cancers [6, 7]
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