MACC1 promotes carcinogenesis of colorectal cancer via β-catenin signaling pathway

Here we confirmed that metastasis-associated in colon cancer 1 (MACC1) and β-catenin expression were higher in colorectal cancer (CRC) cells and tissues than those in normal colonic epithelial cell line and adjacent non-tumour colorectal mucosa (ANM) tissues, respectively. MACC1 expression was significantly related to histological differentiation (p<0.001), UICC stage (p=0.029), T classification (p=0.017), and N classification (p=0.023). Cox regression analysis demonstrated that high MACC1/abnormal β-catenin expression was the strongest independent prognostic indicator for reduced overall survival in CRC patients. Significant positive correlation between MACC1 expression and abnormal β-catenin expression was found in CRC tissues. MACC1 knockdown dramatically inhibited cellular proliferation, migration, invasion, colony formation, and tumorigenesis, both in vitro and in vivo, but induced apoptosis in CRC cells. Further MACC1 over-expression increased Met, β-catenin, and its downstream genes including c-Myc, cyclin D1, and MMP9 expression, and its upstream gene phos-GSK3β (Ser9) expression. In addition, MACC1 increased vimentin and suppressed E-cadherin in HCT116 cells. Silencing of MACC1 reversed all these changes. Our results firstly suggest that MACC1 plays an important role in carcinogenesis and progression of CRC through β-catenin signaling pathway and mesenchymal-epithelial transition.     

Expression of E-cadherin, β-catenin and topoisomerase IIα in leiomyosarcomas

Introduction  

The expression of E-cadherin, β-catenin and topoisomerase II has been associated with clinical outcome of several cancers including sarcomas. We aimed to evaluate the expression of these markers in leiomyosarcomas (LMS).     

Expression of FRAT1 and β-catenin in human brain glioma and their significances

Objective: To investigate the expression of FRAT1 and β-catenin in human brain glioma, analyze the correlation between the expression and clinical pathological grades and the correlation of the two genes. Methods: FRAT1 and β-catenin were detected by immunohistochemistry in 84 human brain glioma tissues and 6 human normal brain tissues. Results: 66.7% (56/84) and 77.4% (65/84) of human brain glioma tissues expressed FRAT1 and β-catenin protein, whereas no FRAT1 and β-catenin protein expression was detected in human normal brain tissues. The expression levels of FRAT1 and β-catenin increased markedly with the ascending of pathologic grade of tumor specimens (r = 0.55, P < 0.01, r = 0.70, P < 0.01), there was a positive correlation between FRAT1 and β-catenin (r = 0.77, P < 0.01). Conclusion: FRAT1 and β-catenin over-expression maybe closely related with occurrence and development of human brain gliomas. The results provide important supplements for the research of Wnt/β-catenin pathway. Meanwhile, FRAT1 may act as a valuable biomarker for molecular diagnosis of glioma and a potential target for gene therapy of glioma.     

Expression patterns of the tumor suppressor PDCD4 and correlation with β-catenin expression in gastric cancers

The expression patterns of PDCD4, a tumor suppressor, and β-catenin were immunohistologically investigated in gastric carcinoma tissues. In normal gastric tissues, PDCD4 was strongly expressed in the cell nuclei, but weakly expressed in the cytoplasm. In gastric adenocarcinoma tissues, nuclear PDCD4 expression was decreased, while cytoplasmic PDCD4 expression was unchanged or somewhat increased. In gastric signet ring cell carcinoma tissues, PDCD4 expression patterns were different from the expression patterns of the adenocarcinoma tissues, and PDCD4 was localized in the nuclei of the carcinoma cells as a belt in the middle of the epithelial layer. The nuclear localization of PDCD4 in the adenocarcinoma tissues was correlated with the membrane localization of β-catenin, the activation of which stimulates invasion of colon cancer cells. PDCD4 expression was correlated with β-catenin expression in gastric carcinoma cell lines, but not with E-cadherin, as the binding partner in the cell membrane.     

Comparison of Osteopontin, β-catenin and hnRNP B1 Expression in Lung Carcinomas

This study was performed to compare osteopontin (OPN), β-catenin and heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1) immunreactivities in small cell lung carcinomas (SCLC) and non-small cell lung carcinomas (NSCLC). Correlation of these three antibodies with grade and clinicopathologic stage of the tumor in NSCLC was also investigated. Twenty-nine SCLC, 6 large cell carcinoma, 36 adenocarcinoma and 30 squamous cell carcinoma (SCC), totally 101 cases, were included in this study. OPN, β-catenin and hnRNP B1 expressions were immunohistochemically evaluated. OPN positivity was 6.9% in SCLC and 67% in NSCLC. When NSCLC types were individually considered, OPN positivity was 66.7% in large cell carcinoma, 80% in SCC and 55.6% in adenocarcinomas. β-catenin positivity was observed in 48.6% of NSCLC and none of SCLC cases. These results were statistically significant (p < 0.05). Neither grade nor stage of NSCLC was correlated with osteopontin, β-catenin or hnRNP B1 immunreactivity. We observed that OPN and β-catenin are useful in differentiating SCLC from NSCLC. This may be helpful in small lung biopsies where morphology is obscured by crush artifacts.     

Determination of β-catenin Expression in Breast Cancer and Its Relationship with Clinicopathologic Parameters

Background: Abnormal activation of the β-catenin signaling pathway is involved in various malignancies, including breast carcinoma.Aberrant expression of β-catenin has been associated with more aggressive behaviors of breast cancer in some previous studies. . In the present study, we intend to evaluate the β-catenin expression in breast cancer specimens and study its relationship with clinicopathological parameters. Materials and method: In this cross-sectional study,88 samples diagnosed as invasive ductal breast carcinoma from 2007 to 2017 were evaluated. The slides and paraffin blocks were retrieved from the archive of pathology department. Patients’ clinical characteristics and other information were also extracted from medical documents. Sections from related paraffin blocks through the tissue microarray method were provided, and immunohistochemistry staining for β-catenin was done. Then different patterns of β-catenin expression and the relationship between different patterns and clinicopathological parameters were investigated. Results: Of the 88 breast cancer samples, 94% were female, and 6% were male. In 70% of the samples, normal membrane expression of β-catenin was observed. Whereas in 30% of them, aberrant expression of β-catenin was observed. A close significant relationship was observed between aberrant β-catenin expression and age over 50 years (p-value: 0.093) and negative HER2 (p-value: 0.07). Conclusion: In the present study, a correlation was observed between aberrant β-catenin expression and age over 50 years in patients and HER2 negativity, although this association was not statistically significant.     

APC and β-catenin protein expression patterns in HNPCC-related endometrial and colorectal cancers

Objective: The adenomatous polyposis coli (APC) and β-catenin (CTNNB1) genes are the two major components of the Wnt signaling pathway that has been shown to play an important role in the formation of certain cancers. The overactivation of the pathway, which results in abnormal accumulation of β-catenin protein in nuclei, contributes to most colorectal cancers (CRCs), both sporadic and hereditary, as well as sporadic endometrial cancers (ECs). Here, we studied the involvement of APC and β-catenin in hereditary nonpolyposis colorectal cancer (HNPCC)-related ECs, and compared the expression patterns to those in HNPCC-related CRCs. Materials and methods: Nineteen ECs and 31 CRCs derived from HNPCC patients were immunohistochemically stained with anti-APC- and anti-β-catenin –antibodies. Results: Tumor-specific loss of APC was observed in 16 of endometrial cancers (3 of 19) and in 39 of colorectal cancers (12 of 31). Consistently, the loss of APC expression was associated with nuclear β-catenin staining. Altogether, aberrant β-catenin localization was observed in 53 of ECs (10 of 19) as compared to 84 of CRCs (26 of 31) (P=0.02).Conclusion: Our results suggest a frequent overactivation of the Wnt signaling pathway in hereditary endometrial cancer. In accordance with studies on sporadic cancers, abnormal accumulation of β-catenin protein in nuclei occurred much less frequently in HNPCC-related ECs than CRCs, which may reflect organ-specific differences in their pathogenesis.     

Prognostic significance of Wnt-1, β-catenin and E-cadherin expression in advanced colorectal carcinoma

Wnt/β-catenin pathway plays an important role in initiation and progression of colorectal oncogenesis. The aim of this study was to determine expression and localization of E-cadherin, β-catenin and Wnt-1 proteins in colorectal tumors. Expression of β-catenin, E-cadherin and Wnt-1 was determined by immunohistochemistry on advanced colorectal cancers. Abnormal expression of E-cadherin, β-catenin, Wnt-1 was observed. Additionally, we revealed correlations between levels of studied proteins and histoclinical data. In multivariate analysis nuclear β-catenin, higher carcinoembryonic antigen serum level before treatment, female sex and tumor localized in colon or rectum were independent unfavorable prognostic factors. These findings support the hypothesis that Wnt/β-catenin pathway plays an important role in advanced colorectal carcinoma.     

The expression and clinical significance of β-catenin and colorectal cancer stem cells marker EpCAMhigh/CD44+ in colorectal cancer

Objective

The aim of the study was to explore the role of Wnt/β-catenin signalling pathway in the maintenance, invasion and metastasis of colorectal cancer stem cells.

Methods

Double immunohistochemical staining was used to detect the expression of EpCAM^high/CD44⁺ which is regarded as the marker of colorectal cancer stem cells in 80 cases of colorectal cancer and their corresponding liver metastases. The SP method of immunohistochemistry was used to detect the expression of the key protein β-catenin in the Wnt pathway in these tissue. The expression and correlation of β-catenin and EpCAM^high/CD44⁺ in colorectal cancer were analyzed and their role on the biological behavior of colorectal cancer was explored.

Results

The abnormal expression of β-catenin was significantly higher in colorectal cancer than in the paraneoplastic normal intestinal mucosa [55% (44/80) vs 10% (2/20), P < 0.05]. The positive expression of EpCAM^high/CD44⁺ was significantly higher in colorectal cancer than in the paraneoplastic normal intestinal mucosa [66.25% (53/80) vs 0% (0/20), P < 0.05]. In the 80 cases of colorectal cancer, the abnormal expression of β-catenin has no correlation with gender (P = 0.079), age (P = 0.416) and the magnitude (P = 0.816) of the tumor (P > 0.05), but it was significantly correlated with degree of differentiation (P = 0.001), depth of invasion (P = 0.001), clinical stage (P = 0.000) and metastasis (P = 0.000). In the colorectal cancer, the expression of EpCAM^high/CD44⁺ cells has no correlation with gender (P = 0.934) and the magnitude (P = 0.160) of the tumor (P > 0.05), but was significantly correlated with age (P = 0.021), degree of differentiation (P = 0.013), depth of invasion (P = 0.000), clinical stage (P = 0.000) and metastasis (P = 0.000). In the corresponding liver metastases, we could also detecte EpCAM^high/CD44⁺ cells. In cases with abnormal expression of β-catenin, the positive expression rate of EpCAM^high/CD44⁺ was significantly higher than those with normal expression of β-catenin (84.1% vs 44.4%), and the difference was statistically significant (P < 0.05).

Conclusion

The abnormal activation of Wnt/β-catenin signalling pathway may prompt the abnormal proliferation of the colorectal cancer stem cells, which leads to the recurrence and metastasis of the cancer.     

Alterations of E-cadherin and β-catenin in gastric cancer

Background  

The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression.     

Roles of cyclin-dependent kinase 8 and β-catenin in the oncogenesis and progression of gastric adenocarcinoma

Gastric adenocarcinoma is a common cause of cancer-related death. The Wnt/β-catenin pathway plays an important role in various cancers. However, relatively little is known about the regulatory mechanism of β-catenin in stomach cancer. To determine the patterns of cyclin-dependent kinase (CDK) 8 and β-catenin expression and the relationship between CDK8 and β-catenin, we conducted a study of immuno-histochemical staining of tumor tissues (12 adenomas, 24 early gastric carcinomas, 24 advanced gastric carcinomas and 21 metastatic lymph nodes), together with Western blot analysis and CDK8 interference studies using gastric cancer cell lines. Gastric adenocarcinomas with CDK8 expression had distinct clinical, prognostic and molecular attributes. CDK8 expression and the delocalization of β-catenin expression showed a significant positive correlation with carcinogenesis and tumor progression, especially lymph node metastasis. Immunohisto-chemically, CDK8 expression in gastric adenocarcinoma was independently associated with β-catenin activation (p<0.05). β-catenin expression was suppressed by CDK8 interference in the gastric adenocarcinoma cell lines, SNU-601 and SNU-638. These data support the potential link between CDK8 and β-catenin, and suggest that CDK8 detection and β-catenin delocalization could be related to a poor prognosis. Moreover, the interference of CDK8 could be a promising therapeutic modality for gastric adenocarcinoma.     

Expression of GST-π gene in human esophageal carcinogenesis

Objective: To investigate the possible role of GST-π in esophageal carcinogenesis. Methods: GST-π expression at mRNA level was studied by in situ hybridization (ISH) and at protein level by immunohistochemistry (IHC). GST-π expression in normal epithelial cells (NC) of the esophagus, hyperplastic cells (HC), dysplastic cells (DC) from grade I to III, carcinoma in situ (CIS) and all the cells in squamous cell carcinomas (SCC) were examined in the same esophageal cancer specimens (n=48) which provided a model reflecting the process of esophageal carcinogenesis. Results: The positive rate of IHC staining was 87.5% for NC, 95.3% for HC, 55.9% for DC (grade I: 73.9%, grade II: 47.4%, grade III: 41.2%), 36.4% for CIS and 45.8% for SCC. The positive rate of GST-π mRNA expression was 81.2% for NC, 94.4% for HC, 61.9% for DC (grade I: 76.5%, grade II: 61.5%, grade III: 41.7%), 44.4% for CIS and 83.3% for grade I SCC, 30.0% for grade II SCC and 0% for grade III SCC. There was no statistically significant difference in GST-π expression at the mRNA and the protein level. Conclusion: There is a decreasing tendency of GST-π expression from dysplasia to CIS and SCC. The decrease in GST-π expression is an early event in esophageal carcinogenesis. This work was supported by a grant from the Key Project of Henan Province Science Foundation (No. 961001)     

Prognostic Value of β-catenin Expression in Breast Cancer Patients: a Meta-analysis

Background: β-catenin plays a crucial role in the progression of breast cancer (BC) and a prognostic role ofin BC patients has been widely reported. However, controversy still remains. Materials and Methods: Identicalsearch strategies were used to search relevant literature in electronic databases updated to July 1, 2014. Individualhazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled HRs with 95%CIs were usedto evaluate the strength of association between positive β-catenin expression in different subcellular locations andsurvival results of BC patients. Subgroup and meta-regression analyses were performed to explore heterogeneity.Funnel plots of Begg’s and Egger’s linear regression test were used to investigate publication bias. Heterogeneityand sensitivity were also assessed. All the work was completed using STATA. Results: A total of 2,204 patientsfrom 12 evaluative studies were finally included. Pooled HRs and 95%CIs suggested that β-catenin expression incytoplasm/nucleus had an unfavorable impact on both overall survival (OS) (HR: 1.93, 95%CI: 1.40-2.65) anddisease free survival (DFS)/ recurrent free survival (RFS) (HR: 1.60, 95%CI: 1.20-2.13) in BC patients. However,here was no significant association between β-catenin expression in the membranes with OS (HR: 0.65, 95%CI:0.42-1.02) or DFS/RFS (HR: 0.66, 95%CI: 0.38-1.13). Publication bias was absent in all of the four outcomes.Sensitivity analysis revealed that the results of this meta-analysis were robust. Conclusions: Positive β-cateninexpression in cytoplasm/nucleus rather than in membrane is a significant prognostic factor in patients with BCwho have been surgically treated.     

Nuclear expression of β-catenin predicts the efficacy of meloxicam treatment for patients with sporadic desmoid tumors

This study aimed to determine the prevalence of β-catenin nuclear positivity as a prognostic factor in patients with desmoid tumors (DTs) treated with meloxicam, a cyclooxygenase-2 (COX-2) selective inhibitor. Between 2003 and 2012, consecutive 31 patients with extraabdominal, sporadic DTs were prospectively treated with meloxicam as a systemic medical therapy. Immunohistochemistry was performed on formalin-fixed material to quantify the nuclear expression of β-catenin and Ki-67, and cytoplasmic expression of COX-2. All clinicopathological characteristics including the intensity of immunohistochemical staining were analyzed with respect to their prognostic value for meloxicam treatment. Of the 31 patients with meloxicam treatment, there was 1 with complete remission (CR), 7 with partial remission (PR), 12 with stable disease (SD), and 11 with progressive disease (PD). Higher nuclear expression of β-catenin was significantly associated with a poor response (PD/SD) (p?=?0.017). The positivity of COX-2 and Ki-67 and none of the other clinical variables were associated with prognosis. The nuclear expression of β-catenin can predict the efficacy of meloxicam treatment for patients with sporadic DTs.