Histopathologic evaluation of stepwise progression of pancreatic carcinoma with immunohistochemical analysis of gastric epithelial transcription factor SOX2: comparison of expression patterns between invasive components and cancerous or nonneoplastic intraductal components

雄市, 眞田; 和弘, 吉田

doi:10.2958/suizo.21.456

Cited by 31 publications

(36 citation statements)

References 4 publications

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“…However, SOX2 expression was not correlated with MUC5AC in PanIN and in PDA (Sanada et al, 2006), suggesting that unknown mechanism(s) might be involved in MUC5AC expression during pancreatic carcinogenesis. In this study, we provide the first evidence identifying a gel-forming mucin, MUC5AC, as a direct transcriptional target of GLI1 in PDA cells.…”

Section: Discussionmentioning

confidence: 92%

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin

2010

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The Kru¨ppel-like zinc-finger protein GLI1 functions as a downstream transcription factor of Hedgehog signaling and plays a pivotal role in the cellular proliferation of many types of tumors, including pancreatic ductal adenocarcinoma (PDA). PDA develops from dysplastic lesions called pancreatic intraepithelial neoplasia (PanIN) through a multistep carcinogenesis process that changes its cellular characteristics, including a mucin expression profile. Increased expression of a gel-forming mucin, MUC5AC, was previously revealed as a major biomarker for the poor prognosis of PDA patients, but the molecular mechanisms responsible for its expression and correlation with poor prognosis are not fully understood. Here we show that MUC5AC is a direct transcriptional target of GLI1 in PDA cells. Overexpression of GLI1 enhanced MUC5AC expression, and a double knockdown of GLI1 and GLI2 suppressed endogenous MUC5AC expression in PDA cells. Luciferase reporter assays revealed that GLI1 and GLI2 can activate the MUC5AC promoter through its conserved CACCC-box-like cis-regulatory elements. We also found that GLI1-upregulated MUC5AC was expressed in the intercellular junction between cultured PDA cells and interfered with the membrane localization of E-cadherin, leading to decreased E-cadherin-dependent cell-cell adhesion and promoting the migration and invasion of PDA cells. Consistently, GLI1 induced the nuclear accumulation and target gene expression of b-catenin in a MUC5AC-dependent manner. Finally, immunohistochemical analysis revealed that GLI1 expression statistically correlated with MUC5AC expression and also with altered subcellular localization of E-cadherin and b-catenin in PanIN lesions and PDA. This evidence revealed a new aspect of GLI1 function in modulating E-cadherin/ b-catenin-regulated cancer cell properties through the expression of a gel-forming mucin.

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Section: Discussionmentioning

confidence: 92%

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin

2010

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“…[29][30][31][32][33][34][35][36][37][38][39][40][41]60 Its role in carcinogenesis is poorly understood, although deregulation of homeobox gene expression has been implicated in the determining phenotypic expression of gastric, ampullar and pancreatic neoplastic cells and in the biology of cancers arising in these anatomical sites. [61][62][63][64][65][66][67] Furthermore, expression analysis studies have shown that SOX2 is one of the genes differentially expressed between embryonal carcinomas and seminomas. Previous studies 39 have suggested that neoplastic cells of seminomas have phenotypic characteristics similar to those of undifferentiated germ cells, whereas embryonal carcinoma cells resemble pluripotent embryonic stem cells, which have the ability to differentiate.…”

Section: Discussionmentioning

confidence: 99%

Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer

et al. 2007

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Tumours arising in BRCA1 mutation carriers and sporadic basal-like breast carcinomas have similar phenotypic, immunohistochemical and clinical characteristics. SOX2 is an embryonic transcription factor located at chromosome 3q, a region frequently gained in sporadic basal-like and BRCA1 germline mutated tumours. The aim of the study was to establish whether sox2 expression was related to basal-like sporadic breast tumours. Two hundred and twenty-six sporadic node-negative invasive breast carcinomas were immunohistochemically analysed for oestrogen receptor (ER), progesterone receptor (PR), CK5/6, EGFR, vimentin, HER2, ki67, p53 and sox2 using tissue microarrays. Tumours were considered to have basal-like phenotype if they were ER/HER2-negative and CK5/6 and/or EGFR-positive. Thirty cases of this series (13.7%) displayed a basal-like phenotype. Sox2 expression was observed in 16.7% of cases and was significantly more frequently expressed in basal-like breast carcinomas (43.3% in basal-like, 10.6% in luminal and 13.3% in HER2 þ tumours, Po0.001). Moreover, Sox2 showed a statistically significant inverse association with ER and PR (P ¼ 0.001 and 0.017, respectively) and direct association with CK5/6, EGFR and vimentin (P ¼ 0.022, 0.005 and o0.001, respectively). Sox2 is preferentially expressed in tumours with basal-like phenotype and may play a role in defining their less differentiated/'stem cell' phenotypic characteristics. Modern Pathology (2007) 20, 474-481.

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“…Sox2 has been found to be an immunogenic antigen in 41% of small cell lung cancer patients (Gure et al, 2000) and in 29% of meningioma patients (Comtesse et al, 2005). Immunohistochemistry results suggest that Sox2 is involved in invasion and metastasis of pancreatic intraepithelial neoplasia (Sanada et al, 2006), and may also be involved in gastric carcinogenesis (Li et al, 2004) and prostate cancers (Sattler et al, 2000). Furthermore, Sox2 expression has been observed in 43% of basal cell-like breast carcinomas, suggesting a role in conferring a less differentiated phenotype (Rodriguez-Pinilla et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Sox2 expression in breast tumours and activation in breast cancer stem cells

Leis¹,

Eguiara²,

et al. 2011

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The cancer stem cell (CSC) model does not imply that tumours are generated from transformed tissue stem cells. The target of transformation could be a tissue stem cell, a progenitor cell, or a differentiated cell that acquires selfrenewal ability. The observation that induced pluripotency reprogramming and cancer are related has lead to the speculation that CSCs may arise through a reprogramming-like mechanism. Expression of pluripotency genes (Oct4, Nanog and Sox2) was tested in breast tumours by immunohistochemistry and it was found that Sox2 is expressed in early stage breast tumours. However, expression of Oct4 or Nanog was not found. Mammosphere formation in culture was used to reveal stem cell properties, where expression of Sox2, but not Oct4 or Nanog, was induced. Over-expression of Sox2 increased mammosphere formation, effect dependent on continuous Sox2 expression; furthermore, Sox2 knockdown prevented mammosphere formation and delayed tumour formation in xenograft tumour initiation models. Induction of Sox2 expression was achieved through activation of the distal enhancer of Sox2 promoter upon sphere formation, the same element that controls Sox2 transcription in pluripotent stem cells. These findings suggest that reactivation of Sox2 represents an early step in breast tumour initiation, explaining tumour heterogeneity by placing the tumour-initiating event in any cell along the axis of mammary differentiation.

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Histopathologic evaluation of stepwise progression of pancreatic carcinoma with immunohistochemical analysis of gastric epithelial transcription factor SOX2: comparison of expression patterns between invasive components and cancerous or nonneoplastic intraductal components

Abstract: Ta b l e 2 P a n I Nの g r a d e間での発現頻度の比較（MUC 5 AC） p-v a l u e P a n I N g r a d e s

Cited by 31 publications

References 4 publications

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin

Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer

Sox2 expression in breast tumours and activation in breast cancer stem cells

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