SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis

Abstract

SOX transcription factors are essential for embryonic development and play critical roles in cell fate determination, differentiation and proliferation. We previously reported that the SOX2 protein is expressed in normal gastric mucosae but downregulated in some human gastric carcinomas. To clarify the roles of SOX2 in gastric carcinogenesis, we carried out functional characterisation of SOX2 in gastric epithelial cell lines. Exogenous expression of SOX2 suppressed cell proliferation in gastric epithelial cell lines. Flow cytometry analysis revealed that SOX2-overexpressing cells exhibited cell-cycle arrest and apoptosis. We found that SOX2-mediated cell-cycle arrest was associated with decreased levels of cyclin D1 and phosphorylated Rb, and an increased p27Kip1 level. These cells exhibited further characteristics of apoptosis, such as DNA laddering and caspase-3 activation. SOX2 hypermethylation signals were observed in some cultured and primary gastric cancers with no or weak SOX2 expression. Among the 52 patients with advanced gastric cancers, those with cancers showing SOX2 methylation had a significantly shorter survival time than those without this methylation (P ¼ 0.0062). Hence, SOX2 plays important roles in growth inhibition through cell-cycle arrest and apoptosis in gastric epithelial cells, and the loss of SOX2 expression may be related to gastric carcinogenesis and poor prognosis.

Establishment and initial characterization of SOX2-overexpressing NT2/D1 cell clones

“…On the other hand, SOX2 overexpression inhibited cell proliferation through cell-cycle (G1) arrest and apoptosis in gastric epithelial cell lines (Otsubo et al, 2008). In this study, the G3 cell clone exhibits increased ability to proliferate.…”

“…Previous studies demonstrated that SOX2 up-regulation could promote (Lang et al, 2011;Tompkins et al, 2011) or inhibit cell proliferation (Otsubo et al, 2008). Accordingly, we tested whether SOX2 overexpression has an influence on cell proliferation of NT2/D1 cells.…”

“…By performing an MTT cell proliferation assay, we detected that the growth rate of the G3 cell clone is approximately 1.3-fold higher when compared to parental cells ( Figure 7A). Since it was previously reported that the altered expression of SOX2 can influence cell cycle transition (Boyer et al, 2005;Chen et al, 2008;Otsubo et al, 2008), we performed flow cytometry analysis by PI nuclei staining ( Figure 7B). This analysis revealed that the relative distribution of cells in cell cycle phases was not altered in F5 and G3 cell clones when compared to parental NT2/D1 cells.…”

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors

“…Effect of C3B3 on b-catenin and pluripotency-associated transcription factors Because Wnt/b-catenin signaling molecules are implicated in the maintenance of pluripotency-associated transcription factors, 24,25 we further evaluated mRNA expression of Sox2, [33][34][35] Oct3/4, 36,37 Nanog, 38,39 Klf-4 and Bmi-1. 40 Notably, Nanog and b-catenin were more highly expressed in SP fraction than in MP fraction of RPMI 8226 cells (Figure 6a).…”

The overexpression of SOX2 affects the migration of human teratocarcinoma cell line NT2/D1

“…Moreover, a number of literature data indicate that altered expression of this transcription factor is associated with oncogenic (Bass et al 2009, Gangemi et al 2009, Bae et al 2010, Leung et al 2010, Lu et al 2010, Basu-Roy et al 2012, Girouard et al 2012, Rudin et al 2012, Herreros-Villanueva et al 2013, Pham et al 2013, Tang et al 2013 or tumor suppressor (Otsubo et al 2008, Wu et al 2013) roles in human cancers. It has also been postulated that SOX2 may be involved in the maintenance of cancer stem cells (CSCs) (Liang et al 2013).…”