Nuclear expression and/or reduced membranous expression of β-catenin correlate with poor prognosis in colorectal carcinoma

Zhang, Shizhen; Wang, Zhen; Shan, Jixiu; Yu, Xiaoqing; Li, Ling; Li, Rui; Lin, Dong; Guan, Siqi; Wang, Xiaochen

doi:10.1097/md.0000000000005546

Cited by 14 publications

(11 citation statements)

References 58 publications

(55 reference statements)

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“…Prior work in SBA has noted abnormal nuclear accumulation of b-catenin as a marker of WNT activation in 20% to 41% of cases, and in one study correlated with worse overall survival (26,27). In colorectal cancer, despite near universal alterations in the APC gene, abnormal b-catenin expression is observed in a limited number of cases, often heterogenous within a tumor, and of unclear prognostic significance (28,29). Thus, as in colorectal cancer, additional factors besides single alterations in the WNT pathway genes are likely involved with downstream WNT-related protein expression.…”

Section: Discussionmentioning

confidence: 99%

DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway

Adam

Lucas

Fowler

et al. 2019

Clinical Cancer Research

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Purpose: Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease. Experimental Design: Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with ERBB2 kinase activating mutations were tested for sensitivity to anti-ERBB2 agents in vivo and in vitro. Biochemical changes were measured by reverse-phase protein arrays. Results: WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although APC mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. ERBB2 mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank HR ¼ 2.4, P ¼ 0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC 50 < 2.5 nmol/L). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, whereas it had no effect in an SBA wild-type ERBB2 model. Conclusions: The in vitro and in vivo models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating ERBB2 mutations in patients with SBA that harbor these alterations.

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Section: Discussionmentioning

confidence: 99%

DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway

Adam

Lucas

Fowler

et al. 2019

Clinical Cancer Research

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“…Membranous expression of β-catenin exerts a restrictive effect on tumor cell movement and growth. Loss of β-catenin expression on the cell surface is an EMT associated event and increases cell motility, growth, and transformation and thus promote tumorigenesis [ 36 , 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

Slug Is A Surrogate Marker of Epithelial to Mesenchymal Transition (EMT) in Head and Neck Cancer

Steinbichler

Dudás

Ingruber

et al. 2020

JCM

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Background: Epithelial to mesenchymal transition (EMT) promotes therapy resistance in head and neck cancer (HNC) cells. In this study, EMT was quantified in HNC tumor samples by the cellular co-localization of cytokeratin/vimentin, E-cadherin/β-catenin and by Slug expression. Methods: Tissue samples from HNC patients were stained with antibody pairs against cytokeratin/vimentin and E-cadherin/β-catenin. Epithelial–mesenchymal co-localization was quantified using immunofluorescence multichannel image cytometry. Double positivity was confirmed using confocal microscopy. Slug was semi-quantified by 2 specialists and quantified by bright field image cytometry. Results: Tumor samples of 102 patients were investigated. A loss of E-cadherin positive cells (56.9 ± 2.6% vs. 97.9 ± 1.0%; p < 0.0001) and E-cadherin/β-catenin double positive cells (15.4 ± 5.7% vs. 85.4 ± 1.2%; p < 0.0001) was observed in tumor samples. The percentage of Slug positive cells was increased in tumor samples (12.1 ± 3.6% vs. 3.2 ± 2.6%; p = 0.001). Ordinal Slug scores judged by two specialists closely correlated with percentage of Slug-positive cells (Spearman’s rho = 0.81; p < 0.001). Slug score correlated negatively with the percentage of E-cadherin positive cells (r = 0.4; p = 0.006), the percentage of E-cadherin/β-catenin positive cells (r = 0.5; p = 0.001) and positively with cytokeratin/vimentin positive cells (r = 0.4, p = 0.003). Conclusion: EMT can be assessed in HNC tumor probes by cytokeratin/vimentin co-expression and loss of E-cadherin/β-catenin co-expression. Slug score provides a convenient surrogate marker for EMT.

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“…For example, in studies to localize AJ proteins in colorectal tumors, membrane-bound ␤-catenin was intensely reduced, although it was difficult to discern whether or not there was an increase in ␤-catenin in the nucleus because of the different tumor stages that were detected and excessive disruption of tissue architecture through-out these tissues. Nonetheless, several studies have also shown that loss of membrane-bound E-cadherin and ␤-catenin is closely associated with a poorer prognosis in colorectal cancer patients (1,5,37). In addition, we have evidence that the absence of ClC-2 along with disruption of AJs promote colitisassociated tumorigenicity through increased activation of TCF/ LEF1 target genes.…”

Section: Discussionmentioning

confidence: 54%

Knockout of ClC-2 reveals critical functions of adherens junctions in colonic homeostasis and tumorigenicity

Jin

Ibrahim

Magness

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Adherens junctions (AJs), together with tight junctions (TJs), form an apical junctional complex that regulates intestinal epithelial cell-to-cell adherence and barrier homeostasis. Within the AJ, membrane-bound E-cadherin binds β-catenin, which functions as an essential intracellular signaling molecule. We have previously identified a novel protein in the region of the apical junction complex, chloride channel protein-2 (ClC-2), that we have used to study TJ regulation. In this study, we investigated the possible effects of ClC-2 on the regulation of AJs in intestinal mucosal epithelial homeostasis and tumorigenicity. Mucosal homeostasis and junctional proteins were examined in wild-type (WT) and ClC-2 knockout (KO) mice as well as associated colonoids. Tumorigenicity and AJ-associated signaling were evaluated in a murine colitis-associated tumor model and in a colorectal cancer cell line (HT-29). Colonic tissues from ClC-2 KO mice had altered ultrastructural morphology of intercellular junctions with reduced colonocyte differentiation, whereas jejunal tissues had minimal changes. Colonic crypts from ClC-2 KO mice had significantly higher numbers of less-differentiated forms of colonoids compared with WT. Furthermore, the absence of ClC-2 resulted in redistribution of AJ proteins and increased β-catenin activity. Downregulation of ClC-2 in colorectal cells resulted in significant increases in proliferation associated with disruption of AJs. Colitis-associated tumors in ClC-2 KO mice were significantly increased, associated with β-catenin transcription factor activation. The absence of ClC-2 results in less differentiated colonic crypts and increased tumorigenicity associated with colitis via dysregulation of AJ proteins and activation of β-catenin-associated signaling. NEW & NOTEWORTHY Disruption of adherens junctions in the absence of chloride channel protein-2 revealed critical functions of these junctional structures, including maintenance of colonic homeostasis and differentiation as well as driving tumorigenicity by regulating β-catenin signaling.

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Nuclear expression and/or reduced membranous expression of β-catenin correlate with poor prognosis in colorectal carcinoma

Abstract: Supplemental Digital Content is available in the text

Cited by 14 publications

References 58 publications

DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway

DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway

Slug Is A Surrogate Marker of Epithelial to Mesenchymal Transition (EMT) in Head and Neck Cancer

Knockout of ClC-2 reveals critical functions of adherens junctions in colonic homeostasis and tumorigenicity

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