Nuclear beta-catenin expression as a prognostic factor in advanced colorectal carcinoma.

Department of Pathology, University of Turku, Kiinamyllynkatu 10, FIN-20520, Turku, Finland.
World Journal of Gastroenterology (Impact Factor: 2.37). 07/2008; 14(24):3866-71.
Source: PubMed


To investigate the changing pattern of beta-catenin expression and its prognostic value in advanced colorectal cancer (CRC).
Archival tumor samples were analyzed for beta-catenin using immunohistochemistry (IHC) in 95 patients with advanced CRC.
Membranous beta-catenin expression was found in the normal colorectal epithelium. Almost 100% of CRC cases showed membranous and cytoplasmic expression, and 55 (58%) cases showed nuclear expression. In univariate (Kaplan-Meier) survival analysis, only the nuclear index (NI) was a significant predictor of disease free survival (DFS) (P = 0.023; n = 35), with a NI above the median associated with longer DFS (34.2 mo) than those with a NI below the median (15.5 mo) (P = 0.045, ANOVA). The other indices were not significant predictors of DFS, and none of the three tested indices (for membranous, cytoplasmic, or nuclear expression) predicted disease-specific survival (DSS). However, when dichotomized as positive or negative nuclear expression, the former was a significant predictor of more favorable DFS (P = 0.041) and DSS (P = 0.046).
Nuclear beta-catenin expression provides additional information in predicting patient outcome in advanced CRC.

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Available from: Abdelbaset Buhmeida, Apr 13, 2015
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    • "Lugli et al. studied more than 1000 colorectal tumours initially treated with surgery, showing that an increase in nuclear β-catenin and a loss of membranous E-cadherin expression were independent prognostic factors for poor survival [7]. However, other reports have shown that increased nuclear β-catenin confers an advantage in survival [8]. "
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    ABSTRACT: Preoperative chemoradiotherapy (CRT) is the cornerstone of treatment for locally advanced rectal cancer (LARC). Although high local control is achieved, overall rates of distant control remain suboptimal. Colorectal carcinogenesis is associated with critical alterations of the Wnt/beta-catenin pathway involved in proliferation and survival. The aim of this study was to assess whether CRT induces changes in the expression of beta-catenin/E-cadherin, and to determine whether these changes are associated with survival. The Immunohistochemical expression of nuclear beta-catenin and membranous E-cadherin was prospectively analysed in tumour blocks from 98 stage II/III rectal cancer patients treated with preoperative CRT. Tumour samples were collected before and after CRT treatment. All patients were treated with pelvic RT (46-50 Gy in 2 Gy fractions) and 5-fluorouracil (5FU) intravenous infusion (225 mg/m2) or capecitabine (825 mg/m2) during RT treatment, followed by total mesorectal excision (TME). Disease-free survival (DFS) was analysed using the Kaplan-Meier method and a multivariate Cox regression model was employed for the Multivariate analysis. CRT induced significant changes in the expression of nuclear beta-catenin (49% of patients presented an increased expression after CRT, 17% a decreased expression and 34% no changes; p = 0.001). After a median follow-up of 25 months, patients that overexpressed nuclear beta-catenin after CRT showed poor survival compared with patients that experienced a decrease in nuclear beta-catenin expression (3-year DFS 92% vs. 43%, HR 0.17; 95% CI 0.03 to 0.8; p = 0.02). In the multivariate analysis for DFS, increased nuclear beta-catenin expression after CRT almost reached the cut-off for significance (p = 0.06). In our study, preoperative CRT for LARC induced significant changes in nuclear beta-catenin expression, which had a major impact on survival. Finding a way to decrease CRT resistance would significantly improve LARC patient survival.
    BMC Cancer 03/2014; 14(1):192. DOI:10.1186/1471-2407-14-192 · 3.36 Impact Factor
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    • "The wnt/β-catenin signaling pathway is an emerging target for cancer research; studies indication the pathway may play a role in cancer invasion and progression by interacting with the tumor microenvironment and oncogenesis [13]. Wnt/β-catenin has been widely studied as a prognostic factor for CRC, and it may also be involved in the mechanism of cancer invasion [14,15]. However, research has focused on aberrant nuclear β-catenin rather than wnt3a, despite the role of wnt3a as a major initiating factor in the wnt/β-catenin pathway. "
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    ABSTRACT: The wnt/ beta-catenin signaling pathway is known to affect in cancer oncogenesis and progression by interacting with the tumor microenvironment. However, the roles of wnt3a and wnt5a in colorectal cancer (CRC) have not been thoroughly studied. In the present study, we investigated the expression of wnt protein and the concordance rate in primary tumor and metastatic sites in CRC. To determine the relationship of wnt proteins with invasion related protein, we also analyzed the association between wnt protein expression and the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor receptor-2 (VEGFR-2). Tumor tissue was obtained from eighty-three paraffin- embedded blocks which were using resected tissue from both the primary tumor and metastatic sites for each patient. We performed immunohistochemical staining for wnt3a, wnt5a, beta-catenin, MMP-9 and VEGFR-2. Wnt3a, wnt5a, beta-catenin, and MMP-9 expression was high; the proteins were found in over 50% of the primary tumors, but the prevalence was lower in tissue from metastatic sites. The concordance rates between the primary tumor and metastatic site were 76.2% for wnt5a and 79.4% for wnt3a and beta-catenin, but VEGFR-2 was expressed in 67.4% of the metastatic sites even when not found in the primary tumor. Wnt3a expression in primary tumors was significantly associated with lymph node involvement (p = 0.038) and MMP-9 expression in the primary tumor (p = 0.0387), mesenchyme adjacent to tumor (p = 0.022) and metastatic site (p = 0.004). There was no other relationship in the expression of these proteins. Vascular invasion in primary tumor tissue may be a potential prognostic marker for liver metastasis, but no significant association was observed among the wnt protein, MMP-9, and VEGFR-2 for peritoneal seeding. In survival analysis, beta-catenin expression was significantly correlated with overall survival (p = 0.05). Wnt3a and wnt5a expression had a concordance rate higher than 60% with a high concordance rate between the primary tumor and metastatic site. Wnt3a expression is associated with the expression of MMP-9 in primary tumor tissue adjacent mesenchymal tissue, and at the metastatic site. As a prognostic marker, only beta-catenin expression showed significant relation with survival outcome.
    BMC Cancer 02/2014; 14(1):125. DOI:10.1186/1471-2407-14-125 · 3.36 Impact Factor
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    • "Wnt/β-catenin pathway plays a critical role in CRC development [25]. The majority of CRC harbor mutations of adenomatous polyposis coli (APC) gene or β-catenin gene, resulting in Wnt-independent cytoplasmic and nuclear β-catenin accumulation [26]–[27]. Furthermore, Wnt/β-catenin pathway can be regulated by other additional cues, such as protein interactions, microenvironments, and signaling pathways [28]–[32]. It has been reported that many proteins in the S100 family, such as S100A6, S100B and S100P, negatively regulate cacyBP/SIP-mediated β-catenin degradation [33]–[35], while S100A7 inhibits tumorigenesis via down-regulation of the β-catenin [36]. "
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    ABSTRACT: S100A8 and S100A9, two members of the S100 protein family, have been reported in association with the tumor cell differentiation and tumor progression. Previous study has showed that their expression in stromal cells of colorectal carcinoma (CRC) is associated with tumor size. Here, we investigated the clinical significances of S100A8 and S100A9 in tumor cells of CRC and their underlying molecular mechanisms. Expression of S100A8 and S100A9 in colorectal carcinoma and matching distal normal tissues were measured by reverse transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry and western blot. CRC cell lines treated with the recombinant S100A8 and S100A9 proteins were used to analyze the roles and molecular mechanisms of the two proteins in CRC in vitro. S100A8 and S100A9 were elevated in more than 50% of CRC tissues and their expression in tumor cells was associated with differentiation, Dukes stage and lymph node metastasis. The CRC cell lines treatment with recombinant S100A8 and S100A9 proteins promoted the viability and migration of CRC cells. Furthermore, the two recombinant proteins also resulted in the increased levels of β-catenin and its target genes c-myc and MMP7. β-catenin over-expression in CRC cells by Adβ-catenin increased cell viability and migration. β-catenin knock-down by Adsiβ-catenin reduced cell viability and migration. Furthermore, β-catenin knockdown also partially abolished the promotive effects of recombinant S100A8 and S100A9 proteins on the viability and migration of CRC cells. Our work demonstrated that S100A8 and S100A9 are linked to the CRC progression, and one of the underlying molecular mechanisms is that extracellular S100A8 and S100A9 proteins contribute to colorectal carcinoma cell survival and migration via Wnt/β-catenin pathway.
    PLoS ONE 04/2013; 8(4):e62092. DOI:10.1371/journal.pone.0062092 · 3.23 Impact Factor
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