Paneth cell differentiation in colonic epithelial neoplasms: evidence for the role of the Apc/β-catenin/Tcf pathway

Joo, Mee; Shahsafaei, Aliakbar; Odze, Robert D.

doi:10.1016/j.humpath.2008.12.003

Cited by 57 publications

(65 citation statements)

References 27 publications

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Section: Discussionmentioning

confidence: 99%

“…18,25 However, the role of WNT/b-catenin signaling in the tumorigenesis of SSA/Ps is still controversial. 13,14,22,25,26 In previous reports, 18-100% of adenomas and 78% of adenocarcinomas of the colorectum displayed nuclear b-catenin immunoreactivity. 14,22,25 Various investigators have reported that nuclear b-catenin expression was observed in 0-60% of SSA/Ps, 7,9,13,14,22,25,26 43-100% of SSA/Ps with high-grade dysplasia, 9,13,14 and 60% of SSA/Ps with submucosal carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5] Loss of APC function by gene mutation or methylation is the reason for b-catenin translocation into the nucleus in the conventional adenomacarcinoma sequence. 18,25 The majority (60-91%) of conventional tubular adenomas or adenocarcinomas have APC mutations, 15,16 but to our knowledge no mutational study of APC has been conducted in SSA/Ps, although methylation of APC has been reported to be more frequent in tubular adenomas (56-65%) than SSA/Ps (22-25%). 8,20 In the present work, APC was not methylated in our SSA/P series, suggesting that methylation of APC is not responsible for nuclear translocation of b-catenin.…”

Section: Modern Pathology (2015) 28 146-158mentioning

confidence: 99%

“…23 An association of CTNNB1 mutations with microsatellite instability status was previously suggested in colorectal carcinomas. 24 Although the conventional adenoma-carcinoma pathway is associated with activation of the WNT/bcatenin signaling pathway, 15,16,18,25 any contribution to serrated neoplasia remains controversial. 13,14,22,25,26 The aim of this study was thus to elucidate the potential roles of WNT/b-catenin signaling in association with MLH1 methylation or BRAF/KRAS mutations in the serrated neoplasia pathway, in comparison with the conventional adenoma-carcinoma sequence.…”

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confidence: 99%

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Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum

et al. 2015

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Sessile serrated adenoma/polyp (SSA/P) is considered as an early precursor in the serrated neoplasia pathway leading to colorectal cancer development. The conventional adenoma-carcinoma sequence is associated with activation of the WNT signaling pathway, although its role in serrated lesions is still controversial. To clarify differences in WNT signaling activation in association with MLH1 methylation or BRAF/KRAS mutations between serrated and conventional routes, we performed b-catenin immunostaining, methylation-specific PCR for MLH1 and WNT signaling associated genes such as AXIN2, APC, and MCC and secreted frizzled-related proteins (SFRPs), and direct sequencing of BRAF/KRAS in 27 SSA/Ps, 14 SSA/Ps with high-grade dysplasia and 9 SSA/Ps with submucosal carcinoma, as well as 19 conventional adenomas, 26 adenomas with high-grade dysplasia and 25 adenomas with submucosal carcinoma. Nuclear b-catenin labelings were significantly lower in the serrated series than in their adenoma counterparts, and a significant increment in those labelings was found from SSA/Ps to those with high-grade dysplasia or submucosal carcinoma. The frequency of MLH1 and SFRP4 methylation was significantly higher in SSA/P series, as compared with corresponding adenoma series. AXIN2 and MCC were more frequently methylated in SSA/Ps with high-grade dysplasia and those with submucosal carcinoma than in adenoma counterparts. Stepwise increment of AXIN2 and MCC methylation was identified from SSA/Ps through those with high-grade dysplasia to those with submucosal carcinoma. A significant correlation was seen between nuclear b-catenin expression and methylation of AXIN2 or MCC in the SSA/P series. BRAF mutation was more frequent, whereas KRAS mutation was less frequent in the SSA/P series as compared with the adenoma series. There was an inverse association of BRAF mutation with AXIN2 methylation in SSA/P series. In conclusion, WNT/b-catenin signal activation mediated by the methylation of SFRP4, MCC, and AXIN2 may make different contributions to colorectal neoplasia between the serrated and conventional routes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Modern Pathology (2015) 28 146-158mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum

et al. 2015

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“…To understand mechanistically how Jak3 might be facilitating barrier functions, our data showed that Jak3 redistributed to basolateral surfaces in differentiated human IECs, Jak3 interacted with ␤-catenin, Jak3 activations were necessary for these interactions, and knockdown of Jak3 decreased TEER and AJ localizations of ␤-catenin. Expression of ␤-catenin at AJ is essential for the differentiation and barrier functions of colonic mucosa (49,50). Altogether, these point to an essential role of Jak3 not only in mucosal differentiation but also in facilitating barrier functions through its interactions with ␤-catenin (Fig.…”

Section: Discussionmentioning

confidence: 99%