Transcription factor SOX2 up-regulates stomach-specific pepsinogen A gene expression

Tani, Yasuyo; Akiyama, Yoshimitsu; Fukamachi, Hiroshi; Yanagihara, Kazuyoshi; Yuasa, Yasuhito

doi:10.1007/s00432-006-0165-x

Cited by 29 publications

(25 citation statements)

References 30 publications

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“…Our present results may therefore be similar to the normal cell differentiation process in the stomach. Furthermore, SOX2 has been found to upregulate the expression levels of gastric differentiation markers, MUC5AC and pepsinogen A (Li et al, 2004;Tani et al, 2007). These data, combined with the findings for antiproliferation effects of SOX2 in gastric epithelial cell lines, suggest that SOX2 may control the gastric epithelial cells differentiating into mature cells and its disruption may cause continual dividing, eventually leading to gastric cancer.…”

Section: Roles Of Sox2 In Gastric Carcinogenesismentioning

confidence: 83%

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

Otsubo

Akiyama

Yanagihara³

et al. 2008

Br J Cancer

197

173

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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.

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Section: Roles Of Sox2 In Gastric Carcinogenesismentioning

confidence: 83%

“…Ten human gastric cancer cell lines (MKN7, MKN45, MKN74, NUGC3, NUGC4, GCIY, TGBC11TKB, KATOIII, HSC58 and HSC59) were obtained as described previously (Tani et al, 2007). Rat gastric epithelial cell line OUMS37 was obtained from Dr Masayoshi Namba (Okayama University Medical School, Japan) (Pu et al, 1999).…”

Section: Cell Lines and Tissue Samplesmentioning

confidence: 99%

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

Otsubo

Akiyama

Yanagihara³

et al. 2008

Br J Cancer

197

173

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“…32 SOX2 contributes to the development of foregut-derived organs, such as the esophagus and stomach, 33,34 and controls the expression of pepsinogen A and Muc5ac. 35,36 The expression of SOX2 is downregulated during the progression from incomplete to complete intestinal metaplasia. 37 In addition, it was suggested that SOX2 can function as a tumor suppressor by regulating the cell cycle and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation

et al. 2016

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Intestinal metaplasia in gastric mucosa is considered a preneoplastic lesion that progresses to gastric cancer. However, the molecular networks underlying this lesion formation are largely unknown. NKX6.3 is known to be an important regulator in gastric mucosal epithelial differentiation. In this study, we characterized the effects of NKX6.3 that may contribute to gastric intestinal metaplasia. NKX6.3 expression was significantly reduced in gastric mucosae with intestinal metaplasia. The mRNA expression levels of both NKX6.3 and CDX2 predicted the intestinal metaplasia risk, with an area under the receiver operating characteristic curve value of 0.9414 and 0.9971, respectively. Notably, the NKX6.3 expression level was positively and inversely correlated with SOX2 and CDX2, respectively. In stable AGS NKX6.3 and MKN1 NKX6.3 cells, NKX6.3 regulated the expression of CDX2 and SOX2 by directly binding to the promoter regions of both genes. Nuclear NKX6.3 expression was detected only in gastric epithelial cells without intestinal metaplasia. Furthermore, NKX6.3-induced TWSG1 bound to BMP4 and inhibited BMP4-binding activity to BMPR-II. These data suggest that NKX6.3 might function as a master regulator of gastric differentiation by affecting SOX2 and CDX2 expression and the NKX6. Gastric cancer is still one of the malignancies with high incidence and mortality rates worldwide. 1 The stages of the precancerous cascade for gastric adenocarcinoma are a series of histologically recognizable changes in the gastric mucosa that follow a specific sequence: non-atrophic gastritis, multifocal atrophic gastritis, intestinal metaplasia, and dysplasia. 2-4 Of these, intestinal metaplasia is the replacement of gastric epithelium by epithelium displaying an intestinal phenotype with the appearance of goblet, Paneth, and absorptive cells. It is well known that Helicobacter pylori infection, high salt intake, smoking, and alcohol consumption are risk factors for gastric intestinal metaplasia. [5][6][7][8] Interestingly, altered expression of Muc5ac with the aberrant expression of Muc2 and caudal-related homologue 2 (CDX2) was detected in intestinal metaplasia of the stomach, which is characterized by the appearance of goblet cells and is considered to be a preneoplastic stage of gastric carcinogenesis. [9][10][11][12] Patients with gastric intestinal metaplasia showed a six-fold increased risk of gastric cancer than did those without gastric intestinal metaplasia. 13 Although much is known about the morphology and physiology of gastric intestinal metaplasia, the regulatory mechanisms that govern their intestinal differentiation still remain unclear.It was recently reported that NKX6.3, a third member of the NKX6 subfamily of NKX genes, is a novel transcription factor required for gastric epithelial differentiation. 14 In mouse embryos, NKX6.3 expression is restricted to endoderm-derived cells in the gastric antrum, pylorus, and proximal duodenum. 15 As a stratified squamous epithelium extends from the esophagus to the fundus of the m...

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“…[8][9][10] Recently, increasing evidence suggests that factors involved in cell pluripotency and self-renewal, key characteristics of stem cells, are implicated in cancer biology. [11][12][13][14][15][16][17][18][19][20][21][22][23] Specifically, the existence of human ovarian cancer-initiating cells with stemness properties and enhanced resistance to cisplatin and paclitaxel has been reported. 17 Indeed, since the isolation of human embryonic stem cells (ESCs), 24 significant interests have been generated in science and medicine because of their therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

Sox2 Gene Amplification Significantly Impacts Overall Survival in Serous Epithelial Ovarian Cancer

et al. 2015

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Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer. Recently, the existence of ovarian cancer stem cells has been reported. Sox2, Nanog and Oct4 are key markers of ''stemness''. The objective of this study was to determine whether Sox2, Nanog, and Oct4 are associated with EOC and poor outcome. The expression of these markers was assessed by immunofluorescence staining and real-time RT-PCR in human EOC cell lines MDAH-2774 and SKOV-3, while the cancer genome atlas (TCGA) dataset was analyzed for associations with survival. Sox2, Nanog and Oct4 (POU5F1) were all detected by immunofluorescence staining and these results were confirmed by real-time RT-PCR. The TCGA dataset revealed a 26%, 9%, and 6% amplification of Sox2, Nanog and POU5F1, respectively. Additionally, K-M survival analyses showed a significant median overall survival difference (41 versus 48.3 months, P ¼ .01) for Sox2 amplification, but not for Nanog (44.1 versus 36.2 months, P > .05) and POU5F1 (43.5 versus 45.0 months, P > .05). Our results suggest that Sox2 gene amplification significantly influences overall survival.

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Transcription factor SOX2 up-regulates stomach-specific pepsinogen A gene expression

Abstract: These data suggest that SOX2 plays an important role in regulation of pepsinogen A, and ectopic expression of SOX2 may be associated with abnormal differentiation of colorectal cancer cells.

Cited by 29 publications

References 30 publications

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

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

Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation

Sox2 Gene Amplification Significantly Impacts Overall Survival in Serous Epithelial Ovarian Cancer

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