Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability

Koinuma, Koji; Yamashita, Yuichi; W, Liu; Hatanaka, Hisashi; Kurashina, Kentaro; Wada, Toyoji; Takada, Shuji; Kaneda, Ruri; Yl, Choi; Si, Fujiwara; Miyakura, Yasuyuki; Nagai, Hideo; Mano, Hiroyuki

doi:10.1038/sj.onc.1209009

Cited by 88 publications

(77 citation statements)

References 30 publications

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“…Consistent with our results, another study pointed out that loss of AXIN2 in tumors can confer a survival disadvantage (Hughes and Brady, 2005). Furthermore, forced expression of AXIN2 causes rapid cell death in colon cancer cell lines (Koinuma et al, 2006). Identification of prognosis factors, especially in early stage cancer patients, is important for reducing cancer mortality because the individual at risk for tumor progression can be treated with adjuvant therapy and more frequent follow-up checks.…”

Section: Discussionsupporting

confidence: 88%

Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis

et al. 2008

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b-catenin accumulation is often found in lung tumors, but only a few patients have mutations in b-catenin gene. In addition, activated p53 downregulates b-catenin. Therefore, we postulated that alteration of the degradation complex AXIN2 (axis inhibition protein 2) and betaTrCP (b-transducin repeat-containing protein) and p53 regulation could result in b-catenin protein accumulation in lung cancer. Using the immunohistochemical and sequencing analyses, we found that patients with b-catenin accumulation without mutation were associated with patients with p53 overexpression and low AXIN2 expression (P ¼ 0.023B0.041). Alteration of AXIN2 was associated with poor survival in early stage patients (P ¼ 0.016). Low expression of AXIN2 and betaTrCP was significantly associated with promoter hypermethylation and histone deacetylation. Ectopic expression and knockdown of p53, AXIN2 and betaTrCP genes in A549 (p53 wild-type) and H1299 (p53 null) lung cancer cell lines showed cooperation between p53 and AXIN2/betaTrCP in the reduction of b-catenin expression. Our clinical and cell model findings provide new evidence that epigenetic silencing of AXIN2/betaTrCP in the degradation complex and deregulation of p53-mediated control lead to wild-type b-catenin nuclear accumulation in non-small cell lung cancer tumorigenesis. In addition, a high level of p53 downregulates the b-catenin expression, but this effect is attenuated by non-functional AXIN2 or betaTrCP in lung cancer.

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Section: Discussionsupporting

confidence: 88%

Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis

et al. 2008

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“…In contrast, colorectal carcinomas with BRAF mutation more frequently harbored AXIN2 methylation than those without. 23 In conclusion, we here obtained evidence pointing to different mechanisms of WNT/b-catenin signal activation, ie, methylation of SFRP4, MCC, and AXIN, between the serrated neoplasia pathway and the conventional adenoma-carcinoma sequence. SSA/Ps may grow into subsequent SSA/Ps with high-grade dysplasia or those with submucosal carcinoma more rapidly at least in some patients.…”

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

confidence: 53%

“…22 AXIN2 has been found to be silenced, apparently as a result of methylation of its promoter region, specifically in colorectal carcinomas with high levels of microsatellite instability. 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.…”

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confidence: 89%

“…Koinuma et al 23 noted that AXIN2 was frequently methylated in microsatellite instability associated colorectal carcinomas. In our study, AXIN2 was more highly methylated in SSA/Ps with high-grade dysplasia and those with submucosal carcinoma, as compared with tubular adenomas with high-grade dysplasia and those with submucosal carcinoma.…”

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

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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“…Interestingly, on average, the AXIN2 CGI was significantly less methylated in tumours compared with the matched apparently normal mucosa, and in only one tumour, it was more methylated than in matched apparently normal mucosa from the same person (6.8 vs 3.5%). AXIN2 methylation has been reported by others to be correlated with microsatellite instability (Koinuma et al, 2006). Microsatellite instability is strongly associated with CIMP þ status (Weisenberger et al, 2006), and CIMP þ tumours have been reported to be associated with high CGI methylation levels in the normal mucosa (Kawakami et al, 2006).…”

Section: Discussionmentioning

confidence: 98%

Profiling CpG island field methylation in both morphologically normal and neoplastic human colonic mucosa

et al. 2008

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Aberrant CpG island (CGI) methylation occurs early in colorectal neoplasia. Quantitative methylation-specific PCR profiling applied to biopsies was used to quantify low levels of CGI methylation of 18 genes in the morphologically normal colonic mucosa of neoplasia-free subjects, adenomatous polyp patients, cancer patients and their tumours. Multivariate statistical analyses distinguished tumour from mucosa with a sensitivity of 78.9% and a specificity of 100% (P ¼ 3 Â 10 À7 ). In morphologically normal mucosa, agedependent CGI methylation was observed for APC, AXIN2, DKK1, HPP1, N33, p16, SFRP1, SFRP2 and SFRP4 genes, and significant differences in CGI methylation levels were detected between groups. Multinomial logistic regression models based on the CGI methylation profiles from normal mucosa correctly identified 78.9% of cancer patients and 87.9% of non-cancer (neoplasiafree þ polyp) patients (P ¼ 4.93 Â 10 À7 ) using APC, HPP1, p16, SFRP4, WIF1 and ESR1 methylation as the most informative variables. Similarly, CGI methylation of SFRP4, SFRP5 and WIF1 correctly identified 61.5% of polyp patients and 78.9% of neoplasia-free subjects (P ¼ 0.0167). The apparently normal mucosal field of patients presenting with neoplasia has evidently undergone significant epigenetic modification. Methylation of the genes selected by the models may play a role in the earliest stages of the development of colorectal neoplasia.

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Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability

Cited by 88 publications

References 30 publications

Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis

Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis

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

Profiling CpG island field methylation in both morphologically normal and neoplastic human colonic mucosa

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