Gene Summary

Gene:CTNNB1; catenin beta 1
Aliases: CTNNB, MRD19, armadillo
Summary:The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:catenin beta-1
Source:NCBIAccessed: 09 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 09 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (13)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Colorectal CancerCTNNB1 and Colorectal Cancer View Publications1206
-CTNNB1 and Hepatocellular Carcinoma View Publications787
Liver CancerCTNNB1 and Liver Cancer View Publications512
Stomach CancerCTNNB1 mutations in Gastric Cancer View Publications460
Prostate CancerCTNNB1 and Prostate Cancer View Publications371
Ovarian CancerCTNNB1 and Ovarian Cancer View Publications333
Breast CancerCTNNB1 and Breast Cancer View Publications332
MelanomaCTNNB1 and Melanoma View Publications256
Lung CancerCTNNB1 and Lung Cancer View Publications260
Thyroid CancerCTNNB1 and Thyroid Cancer View Publications123
HepatoblastomaCTNNB1 and Hepatoblastoma View Publications69
MedulloblastomaCTNNB1 and Medullobalastoma
In an ICGC deep sequencing study of 125 medulloblastoma tumour-normal pairs, (Jones DTW et al, 2012) reported CTNNB1 mutations in 15 (12%) of cases. In an exome sequencing study of medulloblastoma (Pugh et al, 2012) reported CTNNB1 as one of 12 genes mutated at significant levels: with CTNNB1 mutations in 6/92 patients (7%); all missense mutations.
View Publications66
Adrenocortical CancerCTNNB1 and Adrenocortical Carcinoma
Assié, et al (2014) identified recurrent alterations in CTNNB1 in a GWAS study of 45 Adrenocortical carcinomas, with results verified in a further independent set of 77 samples.
View Publications34

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CTNNB1 (cancer-related)

Baker E, Jacobs C, Martinie J, et al.
Mixed Hepatocellular Carcinoma, Neuroendocrine Carcinoma of the Liver.
Am Surg. 2016; 82(11):1121-1125 [PubMed] Related Publications
We present the case of a 76-year-old male found to have a large tumor involving the left lateral lobe of the liver, presumed to be hepatocellular carcinoma (HCC). After resection, pathologic features demonstrated both high-grade HCC and high-grade neuroendocrine carcinoma (NEC). Areas of NEC stained strongly for synaptophysin, which was not present in HCC component. The HCC component stained strongly for Hep-Par 1, which was not present in the NEC component. The patient underwent genetic analysis for biomarkers common to both tumor cell types. Both tumor components contained gene mutations in CTNNB1 gene (S33F located in exon 3). They also shared mutations in PD-1, PGP, and SMO. Mixed HCC/NEC tumors have been rarely reported in the literature with generally poor outcomes. This patient has been referred for adjuvant platinum-based chemotherapy; genetic biomarker analysis may provide some insight to guide targeted chemotherapy.

Xia S, Ji R, Zhan W
Long noncoding RNA papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) inhibits proliferation and invasion of glioma cells by suppressing the Wnt/β-catenin signaling pathway.
BMC Neurol. 2017; 17(1):30 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The dysregulation of long noncoding RNAs (lncRNAs) has been identified in a variety of cancers. An increasing number of studies have found the critical role of lncRNAs in the regulation of cellular processes, such as proliferation, invasion and differentiation. Long noncoding RNA papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) is a novel lncRNA that was primarily detected in papillary thyroid carcinoma. However, the biological function and molecular mechanism of lncRNA PTCSC3 in glioma are still unknown.
METHODS: The expression level of lncRNA PTCSC3 in human microglia and glioma cell lines was examined using quantitative real-time polymerase chain reaction (qRT-PCR). The influence of lncRNA PTCSC3 on cell proliferation were studied using the cell counting kit-8, and cell cycle and apoptosis were analyzed by flow cytometry assays. The migration and invasion abilities were investigated by transwell and wound healing assays. The target genes of lncRNA PTCSC3 were explored by qRT-PCR, immunofluorescence and western blot.
RESULTS: LncRNA PTCSC3 was significantly downregulated in glioma cell lines. The overexpression of lncRNA PTCSC3 suppressed proliferation and induced apoptosis in U87 and U251 cells. Additionally, the overexpression of lncRNA PTCSC3 inhibited the migration and invasion of U87 and U251 cells. Moreover, lncRNA PTCSC3 inhibited the epithelial-mesenchymal transition of U87 cells. The study also demonstrated that LRP6, as a receptor of the Wnt/β-catenin pathway, was a target of lncRNA PTCSC3. By evaluating the expression levels of Axin1, active β-catenin, c-myc, and cyclin D1, the study indicated that lncRNA PTCSC3 inhibited the activation of the Wnt/β-cateninpathway through targeting LRP6.
CONCLUSIONS: LncRNA PTCSC3 inhibits the proliferation and migration of glioma cells and suppresses Wnt/β-catenin signaling pathway by targeting LRP6. LncRNA PTCSC3 is a potential therapeutic target for treatment of glioma.

Yang W, Ning N, Jin X
The lncRNA H19 Promotes Cell Proliferation by Competitively Binding to miR-200a and Derepressing β-Catenin Expression in Colorectal Cancer.
Biomed Res Int. 2017; 2017:2767484 [PubMed] Free Access to Full Article Related Publications
H19, a paternally imprinted noncoding RNA, has been found to be overexpressed in various cancers, including colorectal cancer (CRC), and may function as an oncogene. However, the mechanism by which H19 regulates CRC progression remains poorly understood. In this study, we aimed to assess H19 expression levels in CRC tissues, determine the effect of H19 on CRC proliferation, and explore the mechanism by which H19 regulates the proliferation of CRC. We measured H19 expression using qRT-PCR and analysed the effects of H19 on colon cancer cell proliferation via cell growth curve, cell viability assay, and colony formation assays. To elucidate the mechanism underlying these effects, we analysed the interactions between H19 and miRNAs and identified the target gene to which H19 and miRNA competitively bind using a series of molecular biological techniques. H19 expression was upregulated in CRC tissues compared with adjacent noncancerous tissues. H19 overexpression facilitated colon cancer cell proliferation, whereas H19 knockdown inhibited cell proliferation. miR-200a bound to H19 and inhibited its expression, thereby decreasing CRC cell proliferation. β-Catenin was identified as a target gene of miR-200a. H19 regulated β-catenin expression and activity by competitively binding to miR-200a. H19 promotes cell proliferation by competitively binding to miR-200a and derepressing β-catenin in CRC.

Liang S, Zhang S, Wang P, et al.
LncRNA, TUG1 regulates the oral squamous cell carcinoma progression possibly via interacting with Wnt/β-catenin signaling.
Gene. 2017; 608:49-57 [PubMed] Related Publications
Oral squamous cell carcinoma (OSCC) is one the most common cancer affecting the head and neck region, and the molecular mechanisms underlying OSCC development is largely unknown. Long non-coding RNAs (lncRNAs) are emerging as key regulators in tumor development. The present study aimed to investigate the role of lncRNA, taurine upregulated gene 1 (TUG1) in OSCC development. The mRNA and protein expression levels were determined by qRT-PCR and western blotting; flow cytometry and ELISA experiments were employed to examine the cell apoptosis; CCK-8 assay, MTT assay, colony formation assay, and cell invasion assay was used to determine cell growth, cell proliferation and cell invasion, respectively. qRT-PCR results showed that TUG1 was up-regulated in both OSCC tissues and cell lines. The high expression level of TUG1 was significantly correlated with TNM stage, lymph node metastasis and tumor grade in OSCC patients. CCK-8 assay, MTT assay, colony formation assay, and cell invasion assay results showed that knock-down of TUG1 by siRNA transfection suppressed cell growth, cell proliferation, and cell invasion in OSCC cell lines (Tca8113 and TSCCA). The cell apoptosis was induced in Tca8113 and TSCCA cells transfected with TUG1 siRNA. In addition, knock-down of TUG1 in Tca8113 and TSCCA cells significantly suppressed the mRNA and protein expression levels of β-catenin, cyclin D1, and c-myc. Wnt/β-catenin pathway activator (LiCl) reversed the TUG1 knock-down effect on cell proliferation, cell invasion and cell apoptosis in Tca8113 and TSCCA cells. In summary, knock-down of TUG1 suppressed cell growth, proliferation and invasion, and also induced apoptosis of OSCC possibly via targeting Wnt/β-catenin signaling. Our data suggest that knock-down of TUG1 may represent a novel therapeutic target for the management of OSCC.

Lu J, Xu Y, Wei X, et al.
Emodin Inhibits the Epithelial to Mesenchymal Transition of Epithelial Ovarian Cancer Cells via ILK/GSK-3β/Slug Signaling Pathway.
Biomed Res Int. 2016; 2016:6253280 [PubMed] Free Access to Full Article Related Publications
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite the anticancer capabilities of emodin observed in many cancers, including EOC, the underlying molecular mechanism remains to be elucidated. A crucial link has been discovered between the acquisition of metastatic traits and the epithelial-mesenchymal transition (EMT). The present study aimed to determine whether emodin could inhibit the EMT of EOC cells and explore the underlying mechanism. The CCK-8 assay and transwell assay showed that emodin effectively repressed the abilities of proliferation, invasion, and migration in A2780 and SK-OV-3 cells. The Western blot showed that emodin upregulated epithelial markers (E-cadherin and Claudin) while it downregulated mesenchymal markers (N-cadherin and Vimentin) and transcription factor (Slug) in a dose-dependent fashion. After transfection of siRNA-Slug, both Slug and N-cadherin were downregulated in EOC cells while E-cadherin was upregulated, which was intensified by emodin. Besides, emodin decreased the expression of ILK, p-GSK-3β, β-catenin, and Slug. Transfection of siRNA-ILK also achieved the same effects, which was further strengthened by following emodin treatment. Nevertheless, SB216763, an inhibitor of GSK-3β, could reverse the effects of emodin except for ILK expression. These findings suggest that emodin inhibited the EMT of EOC cells via ILK/GSK-3β/Slug signaling pathway.

Xu W, Chang J, Liu G, et al.
Knockdown of FOXR2 suppresses the tumorigenesis, growth and metastasis of prostate cancer.
Biomed Pharmacother. 2017; 87:471-475 [PubMed] Related Publications
Fork-head box R2 (FOXR2), a member of FOX protein family, was reported to play important roles in the development and progression of cancers. However, the expression and function of FOXR2 in prostate cancer remain unclear. In this study, we investigated the role of FOXR2 in prostate cancer and cancer progression including the molecular mechanism that drives FOXR2-mediated oncogenesis. Our results showed that FOXR2 was overexpressed in prostate cancer cell lines. The in vitro experiments demonstrated that knockdown of FOXR2 significantly repressed the proliferation, migration and invasiveness of prostate cancer cells. Furthermore, the in vivo experiments indicated that knockdown of FOXR2 significantly attenuated prostate cancer growth. Finally, knockdown of FOXR2 significantly down-regulated the protein expression levels of β-catenin, cyclinD1 and c-Myc in DU-145 cells. Taken together, our results demonstrated for the first time that FOXR2 plays a critical role in cell proliferation and invasion, at least in part, through inhibiting the Wnt/β-catenin signaling pathway during prostate cancer progression. Thus, FOXR2 may be an attractive therapeutic target for the treatment of prostate cancer.

Matsumoto S, Fujii S, Kikuchi A
Arl4c is a key regulator of tubulogenesis and tumourigenesis as a target gene of Wnt-β-catenin and growth factor-Ras signalling.
J Biochem. 2017; 161(1):27-35 [PubMed] Related Publications
Epithelial tubular morphogenesis (tubulogenesis) is a fundamental morphogenetic process of many epithelial organs. In this developmental process, epithelial cells migrate, proliferate, polarize and differentiate towards surrounding mesenchymal tissue to form tubule structures. Although epithelial tissue structures are basically stable in the postnatal period, epithelial cells regain highly proliferative and invasive potentials within mesenchymal tissue during tumour formation (tumourigenesis). Therefore, there must be a common molecular basis orchestrating the cellular behaviours involved in both tubulogenesis and tumourigenesis. ADP-ribosylation factor (Arf)-like protein 4c (Arl4c), which belongs to the small GTP-binding protein family, is expressed by the simultaneous activation of Wnt-β-catenin and growth factor-Ras-mitogen-activated protein kinase signalling, was identified as an essential regulator of tubulogenesis. Arl4c expression was also involved in the tumour formation of colorectal and lung cancers. In this review, we focus on Arl4c as a novel Wnt signal target molecule that links epithelial tubulogenesis to tumourigenesis.

Rodriguez-Salas N, Dominguez G, Barderas R, et al.
Clinical relevance of colorectal cancer molecular subtypes.
Crit Rev Oncol Hematol. 2017; 109:9-19 [PubMed] Related Publications
Colorectal cancer (CRC) is characterized by alteration of critical pathways such TP53 inactivation, BRAF, PI3CA mutations, APC inactivation, KRAS, TGF-β, CTNNB mutations, disregulation of Epithelial to mesnechymal transition (EMT) genes, WNT signaling activation, MYC amplification, and others. Differences in these molecular events results in differences in phenotypic characteristics of CRC, that have been studied and classified by different models of molecular subtypes. It could have potential applications to prognosis, but also to therapeutical approaches of the CRC patients. We review and summarized the different molecular classifications and try to clarify their clinical and therapeutical relevance.

Zhang H, Zhao JH, Suo ZM
Knockdown of HOXA5 inhibits the tumorigenesis in esophageal squamous cell cancer.
Biomed Pharmacother. 2017; 86:149-154 [PubMed] Related Publications
Homeobox A5 (HOXA5) is a member of the homeobox (HOX) family and was upregulated in many types of tumors. However, its expression and role in esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, the aim of this study was to investigate the expression and function of HOXA5 in ESCC. Our results showed that HOXA5 was highly expressed in ESCC cell lines. The in vitro experiments demonstrated that knockdown of HOXA5 significantly inhibited the proliferation, migration and invasion of ESCC cells. Furthermore, the in vivo experiments showed that knockdown of HOXA5 significantly inhibited the tumor growth of ESCC in mice xenograft model. Finally, sh-HOXA5 inhibited the expression of β-catenin, cyclin D1 and c-Myc in ESCC cells. Taken together, these data revealed that knockdown of HOXA5 suppressed the proliferation and metastasis partly by interfering with Wnt/β-catenin signaling pathway in ESCC cells. Therefore, these findings suggest that HOXA5 may be a potential therapeutic target for the treatment of ESCC.

Zhang S, Wang Z, Shan J, et al.
Nuclear expression and/or reduced membranous expression of β-catenin correlate with poor prognosis in colorectal carcinoma: A meta-analysis.
Medicine (Baltimore). 2016; 95(49):e5546 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The differential subcellular localizations of β-catenin (including membrane, cytoplasm, and nucleus) play different roles in the progression of colorectal cancer (CRC). However, the correlation between each subcellular localization of β-catenin and the prognosis of CRC patients remains undetermined.
METHODS: Systematic strategies were applied to search for eligible published studies in the PubMed, Embase, and Web of Science databases. The correlation between each subcellular localizations of β-catenin expression and patients' clinicopathological features or prognosis was analyzed.
RESULTS: Finally, this meta-analysis, including 6238 cases from 34 studies, revealed that β-catenin overexpression in the nucleus (HR: 1.50[95% CI: 1.08-2.10]) or reduced expression of β-catenin in the membrane (HR: 1.33[95% CI: 1.15-1.54]) significantly correlated with lower 5-year overall survival (OS). Conversely, overexpression of β-catenin in the cytoplasm (HR: 1.00[95% CI: 0.85-1.18]) did not show significant association with 5-year OS.
CONCLUSION: This study suggested that β-catenin overexpression in the nucleus or reduced expression in the membrane, but not its overexpression in cytoplasm, could serve as a valuable prognostic predictor for CRC. However, additional large and well-designed prospective studies are required to verify our results.

Ma X, Wang X, Yang C, et al.
DANCR Acts as a Diagnostic Biomarker and Promotes Tumor Growth and Metastasis in Hepatocellular Carcinoma.
Anticancer Res. 2016; 36(12):6389-6398 [PubMed] Related Publications
BACKGROUND: Long non-coding RNA differentiation antagonizing non-protein coding RNA (DANCR) is considered to be an oncogene in many cancer types. However, the role of DANCR in diagnosis and progression of hepatocellular carcinoma (HCC) is still unknown.
PATIENTS AND METHODS: In this study, 146 participants including healthy volunteers (HVs) and patients with chronic hepatitis B (CHB), cirrhosis and HCC were recruited.
RESULTS: Firstly, quantitative reverse transcription-PCR analysis showed that DANCR was up-regulated in tumor tissues and plasma of patients with HCC, and its expression was highly correlated with microvascular and liver capsule invasion of HCC. Receiver operating characteristic analysis showed that plasma DANCR exhibited significantly increased discriminatory power for differentiating patients with HCC from HVs and non-HCC patients compared to alpha fetoprotein, which has been used as a biomarker for HCC diagnosis. Furthermore, knockdown of DANCR repressed the β-catenin pathway and inhibited HCC cell proliferation and metastasis both in vitro and in vivo.
CONCLUSION: This study revealed, for the first time, the importance of DANCR in clinical diagnosis and disease progression of HCC.

Robinson LC, Santagata S, Hankinson TC
Potential evolution of neurosurgical treatment paradigms for craniopharyngioma based on genomic and transcriptomic characteristics.
Neurosurg Focus. 2016; 41(6):E3 [PubMed] Related Publications
The recent genomic and transcriptomic characterization of human craniopharyngiomas has provided important insights into the pathogenesis of these tumors and supports that these tumor types are distinct entities. Critically, the insights provided by these data offer the potential for the introduction of novel therapies and surgical treatment paradigms for these tumors, which are associated with high morbidity rates and morbid conditions. Mutations in the CTNNB1 gene are primary drivers of adamantinomatous craniopharyngioma (ACP) and lead to the accumulation of β-catenin protein in a subset of the nuclei within the neoplastic epithelium of these tumors. Dysregulation of epidermal growth factor receptor (EGFR) and of sonic hedgehog (SHH) signaling in ACP suggest that paracrine oncogenic mechanisms may underlie ACP growth and implicate these signaling pathways as potential targets for therapeutic intervention using directed therapies. Recent work shows that ACP cells have primary cilia, further supporting the potential importance of SHH signaling in the pathogenesis of these tumors. While further preclinical data are needed, directed therapies could defer, or replace, the need for radiation therapy and/or allow for less aggressive surgical interventions. Furthermore, the prospect for reliable control of cystic disease without the need for surgery now exists. Studies of papillary craniopharyngioma (PCP) are more clinically advanced than those for ACP. The vast majority of PCPs harbor the BRAF(v600e) mutation. There are now 2 reports of patients with PCP that had dramatic therapeutic responses to targeted agents. Ongoing clinical and research studies promise to not only advance our understanding of these challenging tumors but to offer new approaches for patient management.

Martinez-Gutierrez JC, D'Andrea MR, Cahill DP, et al.
Diagnosis and management of craniopharyngiomas in the era of genomics and targeted therapy.
Neurosurg Focus. 2016; 41(6):E2 [PubMed] Related Publications
Craniopharyngiomas are rare intracranial neoplasms that pose clinical challenges due to their location adjacent to vital structures. The authors have previously shown high mutation rates of BRAF V600E in papillary craniopharyngioma and of CTNNB1 in adamantinomatous craniopharyngioma. These activating driver mutations are potential therapeutic targets, and the authors have recently reported a significant response to BRAF/MEK inhibition in a patient with multiply recurrent PCP. As these targetable mutations warrant prospective research, the authors will be conducting a national National Cancer Institute-sponsored multicenter clinical trial to investigate BRAF/MEK inhibition in the treatment of craniopharyngioma. In this new era of genomic discovery, the treatment paradigm of craniopharyngioma is likely to change.

Liu B, Pan CF, He ZC, et al.
Long Noncoding RNA-LET Suppresses Tumor Growth and EMT in Lung Adenocarcinoma.
Biomed Res Int. 2016; 2016:4693471 [PubMed] Free Access to Full Article Related Publications
Recently, many studies showed that long noncoding RNAs (lncRNAs) are involved in tumor progression. It is reported that lncRNA-LET is downregulated and has antitumor effect on several types of cancer. This study focuses on the role of lncRNA-LET on lung adenocarcinoma (LAC) progression. RT-PCR results indicated that frequent downregulation of lncRNA-LET in LAC tissues was related to clinicopathologic factors. lncRNA-LET knockdown significantly promoted LAC cell proliferation, invasion, and migration while lncRNA-LET overexpression obviously inhibited LAC cell proliferation, invasion, and migration, indicating a tumor inhibition of lncRNA-LET in LAC progression. Besides, lncRNA-LET inhibited EMT and negatively regulated Wnt/β-catenin pathway in part. Our study suggests that lncRNA-LET exhibits an important tumor-suppressive effect on LAC progression by inhibiting EMT and Wnt/β-catenin pathway, which provides potential therapeutic targets for LAC.

Zhang JJ, Chen JT, Hua L, et al.
miR-98 inhibits hepatocellular carcinoma cell proliferation via targeting EZH2 and suppressing Wnt/β-catenin signaling pathway.
Biomed Pharmacother. 2017; 85:472-478 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a highly aggressive solid malignancy in the word. Aberrant microRNA (miRNA) expression is involved in human diseases including cancer. In the current study, we explore the function of miR-98 in HCC cell proliferation. We found that expression level of miR-98 was significantly decreased in HCC tissues and cells lines compared with adjacent non-tumor issues and human hepatic cell line LO2. Increased expression of miR-98 suppressed HCC cell proliferation and arrested HCC cell cycle in G0/G1 phase. While, suppressed expression of miR-98 showed the opposite effect. Bioinformatics analysis revealed EZH2, a putative tumor promoter as a potential target of miR-98. Additionally, luciferase reporter assay revealed that miR-98 directly binds to the 3'-untranslated region (3'-UTR) of EZH2 mRNA. Furthermore, we demonstrated that miR-98 could reduce the Wnt/β-catenin signal pathway by suppressing EZH2 directly. Moreover, inhibition of EZH2 abrogated the effect of miR-98 inhibitor on HCC cell proliferation. Taken together, these results suggested that miR-98 functioned as a potential tumor suppressor by regulating Wnt/β-catenin signal pathway through direct suppression of EZH2 expression and might sever as a potential therapeutic target for HCC patients.

Hattori T, Sentani K, Naohide O, et al.
Clinicopathological significance of SPC18 in colorectal cancer: SPC18 participates in tumor progression.
Cancer Sci. 2017; 108(1):143-150 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. In order to identify novel prognostic markers or therapeutic targets for CRC, we searched for candidate genes in our comprehensive gene expression libraries, and focused on SEC11A, which encodes the SPC18 protein. SPC18 plays a key role in the endoplasmic reticulum-Golgi secretory pathway and presumably regulates the secretion of various secretory proteins. An immunohistochemical analysis of SPC18 in 137 CRC tissue samples demonstrated that 79 (58%) CRC cases were positive for SPC18. SPC18-positive CRC cases were more advanced in terms of N classification (P = 0.0315) and tumor stage (P = 0.0240) than SPC18-negative CRC cases. Furthermore, the expression of SPC18 was an independent prognostic classifier for CRC patients. The cell growth and invasiveness of SPC18 siRNA-transfected CRC cell lines was less than that of the negative control siRNA-transfected cell lines. The levels of phosphorylated epidermal growth factor receptor, Erk and Akt were lower in SPC18 siRNA-transfected CRC cells than in control cells. The expression of SPC18 was colocalized with β-catenin nuclear localization and MMP7 at the invasive front. An immunohistochemical analysis of human colorectal polyp specimens revealed a sequential increase in the expression of SPC18 through the conventional adenoma-carcinoma pathway, while SPC18 was not expressed or was expressed to a lesser extent in serrated pathway-related tumors. These results suggest that SPC18 is involved in tumor progression, and is an independent prognostic classifier in patients with CRC.

Zhu YW, Yan JK, Li JJ, et al.
Knockdown of Radixin Suppresses Gastric Cancer Metastasis In Vitro by Up-Regulation of E-Cadherin via NF-κB/Snail Pathway.
Cell Physiol Biochem. 2016; 39(6):2509-2521 [PubMed] Related Publications
BACKGROUND/AIMS: Radixin has recently been shown to correlate with the metastasis of gastric cancer, but the pathogenesis is elusive. Adhesion proteins contribute to the regulation of metastasis, and thus this study sought to investigate the role of radixin in the migration, invasion and adhesion of gastric cancer cells, as well as its interaction with adhesion proteins in vitro.
METHODS: Radixin stable knockdown human gastric carcinoma SGC-7901 cells were constructed. Alterations in the migration, invasion and adhesion ability were examined by matrigel-coated plate and transwell assays. The expression pattern of adhesion proteins, including E-cadherin, β-catenin and claudin-1, was determined by quantitative real-time PCR and western blot. Possible involvement of NF-κB/snail pathway was also evaluated.
RESULTS: Stable knockdown of radixin significantly suppressed migration and invasion, but enhanced adhesion in SGC-7901 cells. The expression of E-cadherin was manifestly increased in radixin knockdown cells, whereas the expression of β-catenin and claudin-1 was unchanged. The nuclear exclusion of NF-κB followed by conspicuous reduction of snail expression was involved in the regulation of E-cadherin expression.
CONCLUSIONS: Radixin knockdown suppresses the metastasis of SGC-7901 cells in vitro by up-regulation of E-cadherin. The NF-κB/snail pathway contributes to the regulation of E-cadherin in response to depletion of radixin.

Liang J, Zhou H, Peng Y, et al.
β-Catenin Expression Negatively Correlates with WIF1 and Predicts Poor Clinical Outcomes in Patients with Cervical Cancer.
Biomed Res Int. 2016; 2016:4923903 [PubMed] Free Access to Full Article Related Publications
Aberrant activation of the canonical Wnt pathway plays a significant role in cervical cancer (CC). However, limited data show the correlation between the cancer clinicopathological characteristics and the key molecules such as β-catenin and Wnt inhibitory factor 1 (WIF1). In this study, β-catenin and WIF1 expression were analyzed by immunohistochemistry for 196 patients with CC, 39 with cervical intraepithelial neoplasia (CIN), and 41 with normal cervical epithelium (NCE). Significant overexpression of β-catenin was detected in CC (67.9%) when compared to CIN (43.6%) or NCE (34.1%), p < 0.01, while low WIF1 expression was detected in CC (24.0%) when compared to CIN (59.0%) or NCE (58.5%), p < 0.001. Negative correlation was shown between β-catenin and WIF1 expression (r = -0.637, p < 0.001). In addition, multivariate analysis revealed that both lymph node metastasis and β-catenin expression were the independent prognostic factors not only for disease-free survival (HR = 5.029, p < 0.001; HR = 2.588, p = 0.035, resp.), but also for overall survival (HR = 5.058, p < 0.001; HR = 2.873, p = 0.031, resp.). Our findings indicate that, besides lymph node metastasis, β-catenin expression may also be a poor prognostic factor for CC while WIF1 could be a potential drug target for treatment of advanced CC.

Yu J, Li H
The expression of FAT1 is associated with overall survival in children with medulloblastoma.
Tumori. 2017; 103(1):44-52 [PubMed] Related Publications
PURPOSE: The FAT1 gene is involved in some cancers; however, its role in medulloblastoma is less clear. This study investigated the effects of FAT1 expression on the prognosis of medulloblastoma patients.
METHODS: Whole exome sequencing was undertaken in 40 medulloblastoma patient samples. FAT1 mRNA and protein expression levels in normal and brain tumor tissues were determined by fluorescence quantitative PCR and immunohistochemistry, respectively. The association of FAT1 expression with overall survival (OS) was examined by Kaplan-Meier curve analysis with a log-rank test. Following lentiviral-mediated FAT1 knockdown using shRNA in Daoy cells, proliferation, Wnt signaling, and β-catenin protein expression were determined.
RESULTS: Eight FAT1 missense mutations were detected in 7 patients. FAT1 mRNA expression in tumors was significantly lower than in adjacent normal tissue (p = 0.043). The OS of patients with high FAT1 protein expression was significantly longer than that of patients with low FAT1 protein expression (median survival time: 24.3 vs 4.8 months, respectively; p = 0.002). shFAT1 cells had significantly higher proliferation rates than shControl cells (p≤0.028). Furthermore, the mRNA expression of LEF1, β-catenin, and cyclin D1 was significantly upregulated in shFAT1-Daoy cells (p≤0.018).
CONCLUSIONS: Low FAT1 expression was associated with poor prognosis in children with medulloblastoma. Furthermore, FAT1 may act on Wnt signaling pathway to exert its antitumor effect.

Meurgey A, Descotes F, Mery-Lamarche E, Devouassoux-Shisheboran M
Lack of mutation of DICER1 and FOXL2 genes in microcystic stromal tumor of the ovary.
Virchows Arch. 2017; 470(2):225-229 [PubMed] Related Publications
Microcystic stromal tumors (MCST), first described in 2009 by Irving et al., are rare ovarian neoplasms. The entity was introduced into the 2014 WHO classification of tumors of female reproductive organs in the group of sex cord-stromal tumors, which is rather heterogeneous. We studied three cases of ovarian tumor with the characteristic morphological features and immunohistochemical marker profiles of MCST. The three tumors showed micro, and macrocystic patterns with solid areas, and were composed of small round to spindle-shaped cells, without atypia. The tumors diffusely and strongly expressed CD10, FOXL2, and nuclear β-catenin, but without immmunoreactivity for hormone receptors, calretinin, or inhibin. Genome analyses showed no somatic mutation of exon 1 of the FOXL2 gene and of exons 24 and 25 of DICER1 gene, the latter not having been reported previously. The patients are well, without evidence of tumor progression 1 to 10 years after diagnosis.The absence of FOXL2 and DICER1 gene mutation, along with strong FOXL2 immunoreactivity provides additional evidence to place MCST within pure gonadal stromal rather than sex cord ovarian tumors.

Wang Y, Chen C, Wang X, et al.
Lower DSC1 expression is related to the poor differentiation and prognosis of head and neck squamous cell carcinoma (HNSCC).
J Cancer Res Clin Oncol. 2016; 142(12):2461-2468 [PubMed] Related Publications
PURPOSE: Although desmocollins have an important position in cancer-related research, there are little reports about the relations between cancers and desmocollin 1 (DSC1). The present study was designed to investigate the correlations between DSC1 and head and neck squamous cell carcinoma (HNSCC).
METHODS: First we analyzed the GEO database; then, HNSCC and pericarcinous tissues were collected to verify the results. DSC1 expression was detected by western blot and real-time PCR. The co-expression genes of DSC1 were extracted from Cancer Cell Line Encyclopedia database (CCLE database), and their correlation was analyzed in The Cancer Genome Atlas HNSCC database (TCGA HNSCC database). Next the gene ontology analysis (GO) was carried out. Moreover, we suppressed DSC1 in FaDu cell to investigate the internal mechanism.
RESULTS: GEO database showed that DSC1 was higher in HNSCC and patients with higher DSC1 had unfavorable prognosis. The results of the samples showed that DSC1 was significantly higher in HNSCC than in normal tissue, which was consistent with the results of GEO database. The co-expression genes of DSC1 were extracted from CCLE database and verified in TCGA HNSCC database. It revealed that DSC1 was related to cell signal transduction. In FaDu/siDSC1 cells, the proliferation and migration were decreased compared to FaDu cells, and the expression levels of β-catenin, c-myc and cyclin D1 down-regulated significantly.
CONCLUSIONS: The increased expression of DSC1 can promote the occurrence of HNSCC and is associated with tumor. The increased expression of DSC1 also indicates a poor prognosis of the patients with HNSCC.

Ma SS, Henry CE, Llamosas E, et al.
Validation of specificity of antibodies for immunohistochemistry: the case of ROR2.
Virchows Arch. 2017; 470(1):99-108 [PubMed] Related Publications
The Wnt signalling receptor receptor tyrosine kinase-like orphan receptor 2 (ROR2) is implicated in numerous human cancers. However, there have been conflicting reports regarding ROR2 expression, some studies showing upregulation and others downregulation of ROR2 in the same cancer type. The majority of these studies used immunohistochemistry (IHC) to detect ROR2 protein, without validation of the used antibodies. There appears to be currently no consensus on the antibody best suited for ROR2 detection or how ROR2 expression changes in various cancer types. We examined three commercially available ROR2 antibodies and found that only one bound specifically to ROR2. Another antibody cross-reacted with other proteins, and the third failed to detect ROR2 at all. ROR2 detection by IHC on 107 patient samples using the ROR2 specific antibody showed that the majority of colorectal cancers show loss of ROR2 protein. We found no association between ROR2 staining and poor patient survival, as had been previously reported. These results question the previously reported association between ROR2 and poor patient survival in colorectal cancer. Future studies should use fully validated antibodies when detecting ROR2 protein, as non-specific staining can lead to irrelevant observations and misinterpretations.

Sideris M, Moorhead J, Diaz-Cano S, et al.
KRAS Mutant Status, p16 and β-catenin Expression May Predict Local Recurrence in Patients Who Underwent Transanal Endoscopic Microsurgery (TEMS) for Stage I Rectal Cancer.
Anticancer Res. 2016; 36(10):5315-5324 [PubMed] Related Publications
BACKGROUND/AIM: Transanal endoscopic microsurgery (TEMS) is emerging as an alternative treatment for rectal cancer Stage I. There remains a risk of local recurrence. The Aim of the study was to study the effect of biomarkers in local recurrence for Stage I rectal cancer following TEMS plus or minus radiotherapy.
MATERIALS AND METHODS: This is a case control study where we compared 10 early rectal cancers that had recurred, against 19 cases with no recurrence, total 29 patients (age=28.25-86.87, mean age=67.92 years, SD=14.91, Male, N=18, Female, N=11). All patients underwent TEMS for radiological Stage I rectal cancer (yT1N0M0 or yT2N0M0) established with combination of magnetic resonance imaging (MRI) and endorectal ultrasound. We prospectively collected all data on tumour histology, morphological features, as well as follow-up parameters. Molecular analysis was performed to identify their status on BRAF, KRAS, p16 O(6)-methylguanine-DNA methyltransferase (MGMT) and β-catenin.
RESULTS: Out of 29 specimens analyzed, 19 were KRAS wild type (65.9%) and 10 mutant (34.5%). Recurrence of the tumour was noted in 10 cases (34.5%) from which 60% were pT1 (N=6) and 40% pT2 (N=4). There was a statistically significant association between KRAS mutant status and local recurrence (N=6, p=0.037). P16 expression greater than 5% (mean=10.8%, min=0, max=95) is linked with earlier recurrence within 11.70 months (N=7, p=0.004). Membranous β-catenin expression (N=12, 48%) was also related with KRAS mutant status (p=0.006) but not with survival (p>0.05). BRAF gene was found to be wild type in all cases tested (N=23).
CONCLUSION: KRAS/p16/β-catenin could be used as a combined biomarker for prediction of local recurrence and stratification of the risk for further surgery.

Vesely DL
Heart Peptide Hormones: Adjunct and Primary Treatments of Cancer.
Anticancer Res. 2016; 36(11):5693-5700 [PubMed] Related Publications
Four heart hormones, namely atrial natriuretic peptide (ANP), long-acting natriuretic peptide (LANP), vessel dilator and kaliuretic peptide reduce up to 97% of cancer cells in vitro. These four cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, two-thirds of human breast carcinomas and up to 86% of human small-cell lung carcinomas growing in athymic mice. ANP given intravenously for 3 hours after 'curative' lung surgery as an adjunct to surgery results in a 2-year relapse-free survival of 91% compared to 75% for those treated with surgery alone. The anticancer mechanisms of action of these peptides involve binding to receptors on the cancer cells, followed by 95% inhibition of the conversion of inactive to active rat sarcoma-bound guanosine triphosphate (RAS)-mitogen-activated protein kinase (MAPK) kinases 1/2 (MEK 1/2) (98% inhibition)-extracellular signal-related kinases 1/2 (ERK1/2) (96% inhibition) cascade in cancer cells. They are dual inhibitors of vascular endothelial growth factor (VEGF) and its VEGF2 receptor (up to 89%). They also inhibit MAPK9, i.e. c-JUN-N-terminal kinase 2. One of the downstream targets of VEGF is β-catenin, which these peptides inhibit by up to 88%. These four peptide hormones inhibit the Wingless-related integration site (WNT) pathway 68% and WNT secreted-Frizzled protein is reduced by up to 84%. Signal transducer and activator of transcription 3 (STAT3), a final 'switch' that activates gene expression that leads to malignancy, is specifically reduced up to 88% by these peptides but they do not affect STAT1. There is crosstalk between the RAS-MEK 1/2-ERK 1/2 kinase cascade, VEGF, β-catenin, JNK, WNT, and STAT pathways and each of these pathways and their crosstalk is inhibited by these peptide hormones. They enter the nucleus of cancer cells where they inhibit the proto-oncogenes c-FOS (by up to 82%) and c-JUN (by up to 61%).
CONCLUSION: These multiple kinase inhibitors have both adjunct and primary anticancer effects.

Pires BR, DE Amorim ÍS, Souza LD, et al.
Targeting Cellular Signaling Pathways in Breast Cancer Stem Cells and its Implication for Cancer Treatment.
Anticancer Res. 2016; 36(11):5681-5691 [PubMed] Related Publications
Breast cancer is a public health problem both in developing and developed countries. The breast cancer stem cell (BCSC) hypothesis has grown in the cancer research community. These BCSCs comprise of a small subpopulation of cells within the tumor mass which exhibit stem cell-like characteristics and have emerged as being responsible for tumor development, recurrence and metastasis in BC. The complexity of control of gene expression in BCSC is commonly driven by a myriad of signaling pathways triggered by extracellular signals, mutations and epigenetic control. Thus, some signaling pathways have been highlighted in BC, especially those linked to stem cell phenotype, such as nuclear factor-kappa B, signal transducer and activator of transcription 3, wingless-type MMTV integration site family (Wnt)/β-catenin, Hedgehog and NOTCH. Moreover, these BCSCs can also be influenced by the tumor microenvironment, for instance, hypoxic areas. Given the importance of signaling pathways and tumor microenvironment for breast cancer, this review focuses on the relationship between cellular signaling and BCSCs and its therapeutic implications.

Ohtsuka M, Ling H, Ivan C, et al.
H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer.
EBioMedicine. 2016; 13:113-124 [PubMed] Free Access to Full Article Related Publications
The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unexplored. Here, we analyzed a large panel of lncRNA candidates with The Cancer Genome Atlas (TCGA) CRC dataset, and identified H19 as the most significant lncRNA associated with CRC patient survival. We further validated such association in two independent CRC cohorts. H19 silencing blocked G1-S transition, reduced cell proliferation, and inhibited cell migration. We profiled gene expression changes to gain mechanism insight of H19 function. Transcriptome data analysis revealed not only previously identified mechanisms such as Let-7 regulation by H19, but also RB1-E2F1 function and β-catenin activity as essential upstream regulators mediating H19 function. Our experimental data showed that H19 affects phosphorylation of RB1 protein by regulating gene expression of CDK4 and CCND1. We further demonstrated that reduced CDK8 expression underlies changes of β-catenin activity, and identified that H19 interacts with macroH2A, an essential regulator of CDK8 gene transcription. However, the relevance of H19-macroH2A interaction in CDK8 regulation remains to be experimentally determined. We further explored the clinical relevance of above mechanisms in clinical samples, and showed that combined analysis of H19 with its targets improved prognostic value of H19 in CRC.

Mussi CE, Colombo P, Lo Russo C, et al.
Sporadic desmoid tumors of the abdominal wall: the results of surgery.
Tumori. 2016; 102(6):582-587 [PubMed] Related Publications
PURPOSE: Before the wait-and-see policy became the standard approach in abdominal wall desmoid tumors, surgery was performed on a systematic basis. Surgery remains indicated for progressing tumors but its extent is debatable. The abdominal wall is a common site of origin of sporadic desmoids, usually associated with a favorable prognosis. We analyzed the results of surgery at this specific site.
METHODS: Data from 33 patients affected by sporadic desmoid tumors of the abdominal wall (31 primary, 2 recurrent) consecutively treated at our cancer center between January 2000 and September 2013 were retrospectively studied.
RESULTS: Twenty-nine patients underwent surgery upfront and 1 after progression during the initial wait-and-see period. Prosthetic reconstruction of the abdominal wall was required in 28 patients. The average hospital stay was 5 days. Three patients developed surgical complications. Local recurrence-free survival was 90% at 5 and 10 years. Three patients had an uneventful childbirth during the follow-up after surgery.
CONCLUSIONS: Desmoid tumors of the abdominal wall have a favorable prognosis after surgical resection, which remains a safe and effective treatment. Wild-type tumors are common, whereas the incidence of S45F mutation in the beta-catenin gene is lower than in other anatomic sites. Upfront surgery may be considered in selected women who wish to bear a child.

Chen Z, Tang J, Cai X, et al.
HBx mutations promote hepatoma cell migration through the Wnt/β-catenin signaling pathway.
Cancer Sci. 2016; 107(10):1380-1389 [PubMed] Free Access to Full Article Related Publications
HBx mutations (T1753V, A1762T, G1764A, and T1768A) are frequently observed in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Aberrant activation of the Wnt/β-catenin signaling pathway is involved in the development of HCC. However, activation of the Wnt/β-catenin signaling pathway by HBx mutants has not been studied in hepatoma cells or HBV-associated HCC samples. In this study, we examined the effects of HBx mutants on the migration and proliferation of HCC cells and evaluated the activation of Wnt/β-catenin signaling in HBx-transfected HCC cells and HBV-related HCC tissues. We found that HBx mutants (T, A, TA, and Combo) promoted the migration and proliferation of hepatoma cells. The HBx Combo mutant potentiated TOP-luc activity and increased nuclear translocation of β-catenin. Moreover, the HBx Combo mutant increased and stabilized β-catenin levels through inactivation of glycogen synthase kinase-3β, resulting in upregulation of downstream target genes such as c-Myc, CTGF, and WISP2. Enhanced activation of Wnt/β-catenin was found in HCC tissues with HBx TA and Combo mutations. Knockdown of β-catenin effectively abrogated cell migration and proliferation stimulated by the HBx TA and Combo mutants. Our results indicate that HBx mutants, especially the Combo mutant, allow constitutive activation of the Wnt signaling pathway and may play a pivotal role in HBV-associated hepatocarcinogenesis.

Basturk O, Chung SM, Hruban RH, et al.
Distinct pathways of pathogenesis of intraductal oncocytic papillary neoplasms and intraductal papillary mucinous neoplasms of the pancreas.
Virchows Arch. 2016; 469(5):523-532 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is classified as a variant of intraductal papillary mucinous neoplasm (IPMN) in the WHO guidelines. However, the neoplastic cells of IOPNs are unique, with distinctive architecture/oncocytic cytoplasm. Although molecular/immunohistochemical features of other IPMN variants have been extensively studied, those of IOPNs have not been well characterized. Expression profile of antibodies associated with genetic alterations previously described for ductal adenocarcinomas (DAs) and IPMNs (SMAD4/β-catenin/p53/mesothelin/claudin-4) as well as antibodies to mucins and differentiation markers [MUC1/MUC2/MUC5AC/MUC6/CDX2/hepatocyte paraffin-1 (HepPar-1)] was investigated in 24 IOPNs and 22 IPMNs to assess the similarities/differences between these tumors. Expression of mesothelin and claudin-4 was dissimilar between these tumor types: A higher proportion of IOPNs labeled with mesothelin [21/24 (87.5 %) of IOPNs, 6/22 (27 %) of IPMNs, p < 0.001], while the reverse was true for claudin-4 [2/23 (9 %) of IOPNs, 9/22 (41 %) of IPMNs, p = 0.01]. The results of immunolabeling for SMAD4/β-catenin/p53 were similar in both: None of the cases showed SMAD4 loss in the intraductal components, and only 1/21 (5 %) of IOPNs and 2/22 (9 %) of IPMNs revealed abnormal β-catenin expression (p = 0.49). Nuclear p53 accumulation was seen mostly in architecturally complex/high-grade dysplasia areas in both. Immunolabeling for MUC proteins showed that almost all lesions expressed MUC5AC. Twelve of the 24 (50 %) IOPNs and 6/22 (27 %) of IPMNs (p = 0.11) labeled for MUC1, whereas 7/24 (29 %) of IOPNs and 10/22 (45 %) of IPMNs labeled for MUC2 (p = 0.25). MUC6 was expressed in 8/9 (89 %) of IOPNs (strong) and 6/21 (29 %) of IPMNs (weak) (p = 0.002). Fourteen of the 23 (61 %) IOPNs and 4/22 (18 %) of IPMNs labeled for HepPar-1 (p = 0.003). These results show that IOPNs have distinct immunoprofile and provide support for the proposition that IOPN is a distinct entity developing through a mechanism different from other pancreatic ductal neoplasms.

Pietsch T, Haberler C
Update on the integrated histopathological and genetic classification of medulloblastoma - a practical diagnostic guideline.
Clin Neuropathol. 2016 Nov/Dec; 35(6):344-352 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
The revised WHO classification of tumors of the CNS 2016 has introduced the concept of the integrated diagnosis. The definition of medulloblastoma entities now requires a combination of the traditional histological information with additional molecular/genetic features. For definition of the histopathological component of the medulloblastoma diagnosis, the tumors should be assigned to one of the four entities classic, desmoplastic/nodular (DNMB), extensive nodular (MBEN), or large cell/anaplastic (LC/A) medulloblastoma. The genetically defined component comprises the four entities WNT-activated, SHH-activated and TP53 wildtype, SHH-activated and TP53 mutant, or non-WNT/non-SHH medulloblastoma. Robust and validated methods are available to allow a precise diagnosis of these medulloblastoma entities according to the updated WHO classification, and for differential diagnostic purposes. A combination of immunohistochemical markers including β-catenin, Yap1, p75-NGFR, Otx2, and p53, in combination with targeted sequencing and copy number assessment such as FISH analysis for MYC genes allows a precise assignment of patients for risk-adapted stratification. It also allows comparison to results of study cohorts in the past and provides a robust basis for further treatment refinement.

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