Gene Summary

Gene:CDH1; cadherin 1
Aliases: UVO, CDHE, ECAD, LCAM, Arc-1, BCDS1, CD324
Summary:This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


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 (1994-2019)
Graph generated 31 August 2019 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 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (11)

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

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

Latest Publications: CDH1 (cancer-related)

Kishore C, Sundaram S, Karunagaran D
Vitamin K3 (menadione) suppresses epithelial-mesenchymal-transition and Wnt signaling pathway in human colorectal cancer cells.
Chem Biol Interact. 2019; 309:108725 [PubMed] Related Publications
Tumor recurrence and metastasis decrease the survival rate of colorectal cancer (CRC) patients. Menadione reduces the numbers and incidences of 1,2-dimethylhydrazine induced colon tumors in mouse but the mechanism of anticancer activity of menadione in colorectal cancer is not very clear. Since Wnt signaling is constitutively active in CRC and it aggravates the epithelial mesenchymal transition (EMT), the regulation of EMT and Wnt signaling by menadione (vitamin K3) was investigated in CRC cells. Menadione showed cytotoxicity against human CRC cells (SW480 and SW620) and human primary colon cancer cells but was relatively ineffective against the cells from human normal colon (CRL-1790) and human primary colon epithelial cells. Menadione suppressed invasion, migration and epithelial-mesenchymal transition in human CRC cells by upregulating the expression of E-cadherin (CDH1), ZO-1 and downregulating that of N-cadherin (CDH2), Vimentin (VIM), ZEB1, MMP2 and MMP9. Menadione decreased TOPFlash/FOPFlash luciferase activity and expression of several downstream targets of Wnt signaling and coactivators such as β-catenin (CTNNB1), TCF7L2, Bcl9l, p300 (EP300) and cyclin D1 (CCND1) was suppressed. Menadione induced differentiation and increased apoptotic cell population in SubG0 phase of cell cycle in SW480 and SW620 cells. The ability of menadione to suppress EMT, migration, invasion, Wnt signaling, cell proliferation and induce Sub G0 arrest, highlights its potential to be considered for intensive preclinical and clinical investigation in CRC.

Kumar KJS, Vani MG, Hsieh HW, et al.
Antcin-A Modulates Epithelial-to-Mesenchymal Transition and Inhibits Migratory and Invasive Potentials of Human Breast Cancer Cells via p53-Mediated miR-200c Activation.
Planta Med. 2019; 85(9-10):755-765 [PubMed] Related Publications
Antcin-A (ATA) is a steroid-like phytochemical isolated from the fruiting bodies of a precious edible mushroom

Xie R, Okita Y, Ichikawa Y, et al.
Role of the kringle-like domain in glycoprotein NMB for its tumorigenic potential.
Cancer Sci. 2019; 110(7):2237-2246 [PubMed] Free Access to Full Article Related Publications
Glycoprotein NMB (GPNMB) is highly expressed in many types of malignant tumors and thought to be a poor prognostic factor in those cancers, including breast cancer. Glycoprotein NMB is a type IA transmembrane protein that has a long extracellular domain (ECD) and a short intracellular domain (ICD). In general, the ECD of a protein is involved in protein-protein or protein-carbohydrate interactions, whereas the ICD is important for intracellular signaling. We previously reported that GPNMB contributes to the initiation and malignant progression of breast cancer through the hemi-immunoreceptor tyrosine-based activation motif (hemITAM) in its ICD. Furthermore, we showed that the tyrosine residue in hemITAM is involved in induction of the stem-like properties of breast cancer cells. However, the contribution of the ECD to its tumorigenic function has yet to be fully elucidated. In this study, we focused on the region, the so-called kringle-like domain (KLD), that is conserved among species, and made a deletion mutant, GPNMB(ΔKLD). Enhanced expression of WT GPNMB induced sphere and tumor formation in breast epithelial cells; in contrast, GPNMB(ΔKLD) lacked these activities without affecting its molecular properties, such as subcellular localization, Src-induced tyrosine phosphorylation at least in overexpression experiments, and homo-oligomerization. Additionally, GPNMB(ΔKLD) lost its cell migration promoting activity, even though it reduced E-cadherin expression. Although the interaction partner binding to KLD has not yet been identified, we found that the KLD of GPNMB plays an important role in its tumorigenic potential.

Pradhan N, Parbin S, Kausar C, et al.
Paederia foetida induces anticancer activity by modulating chromatin modification enzymes and altering pro-inflammatory cytokine gene expression in human prostate cancer cells.
Food Chem Toxicol. 2019; 130:161-173 [PubMed] Related Publications
Aberrant epigenetic modifications are responsible for tumor development and cancer progression; however, readily reversible. Bioactive molecules from diets are promising to cure cancer by modulating epigenetic marks and changing immune response. These compounds specifically target the activity of DNMTs and HDACs to cure various human cancers. In view of this, we investigated the anticancer and epigenetic regulatory activities of an edible-plant Paederia foetida. The efficacy of methanolic extract of P. foetida leaves (MEPL) was tested for the modulation of epigenetic factors in gene silencing, i.e. DNMT and HDAC and expression pattern of certain tumor-suppressor genes. After treatment of prostate cancer cells (PC-3 and DU-145) with MEPL, lupeol and β-sitosterol; induction of apoptosis, decrease in cellular-viability and inhibition of cellular-migration were noticed. Simultaneously there was inhibition of DNMT1, HDACs and pro-inflammatory, IL-6, IL1-β, TNF-α and anti-inflammatory, IL-10 genes in cancer and THP1 cell lines. The DNMT1 protein content, enzyme activity and Bcl2 expression decreased significantly; however, expression of E-cadherin (CDH1) and pro-apoptotic gene Bax increased significantly after the treatment of cells with drugs. We conclude plant-derived compounds can be considered to target epigenetic machineries involved with malignant transformation and can open new avenues for cancer therapeutics provoking immune response.

Xing R, Zhou Y, Yu J, et al.
Whole-genome sequencing reveals novel tandem-duplication hotspots and a prognostic mutational signature in gastric cancer.
Nat Commun. 2019; 10(1):2037 [PubMed] Free Access to Full Article Related Publications
Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.

Kim E, Lisby A, Ma C, et al.
Promotion of growth factor signaling as a critical function of β-catenin during HCC progression.
Nat Commun. 2019; 10(1):1909 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. β-catenin is widely thought to be a major oncogene in HCC based on the frequency of mutations associated with aberrant Wnt signaling in HCC patients. Challenging this model, our data reveal that β-catenin nuclear accumulation is restricted to the late stage of the disease. Until then, β-catenin is primarily located at the plasma membrane in complex with multiple cadherin family members where it drives tumor cell survival by enhancing the signaling of growth factor receptors such as EGFR. Therefore, our study reveals the evolving nature of β-catenin in HCC to establish it as a compound tumor promoter during the progression of the disease.

Song W, Gu Y, Lu S, et al.
LncRNA TRERNA1 facilitates hepatocellular carcinoma metastasis by dimethylating H3K9 in the CDH1 promoter region via the recruitment of the EHMT2/SNAI1 complex.
Cell Prolif. 2019; 52(4):e12621 [PubMed] Related Publications
OBJECTIVES: Long non-coding RNAs (LncRNAs) play an important role in hepatocellular carcinoma development, however, as a crucial driver of hepatocellular carcinoma (HCC) metastasis, their functions in tumour metastasis remain largely unknown.
MATERIALS AND METHODS: The lncRNA TRERNA1 expression levels were detected in HCC by quantitative real-time PCR (qPCR). The function of TRERNA1 was examined by wound-healing assays, transwell assays and tail vein injection experiments. The potential regulatory mechanisms of TRERNA1 on its target genes were explored by ChIP, RIP, IP and WB assays.
RESULTS: Elevated TRERNA1 levels promoted HCC cell migration and invasion in vitro and in vivo. TRERNA1 recruited EHMT2 to dimethylate H3K9 in the CDH1 promoter region. Furthermore, EHMT2 bound to SNAI1 to suppress CDH1 expression in HCC cells. After inhibiting TRERNA1, the expression level of CDH1 was restored and was involved in the regulation of the EHMT2/SNAI1 complex. The level of TRERNA1 was positively correlated with tumour metastasis and was negatively correlated with the expression of CDH1 in HCC tissues.
CONCLUSIONS: For the first time, the current study reveals that TRERNA1 promotes cell metastasis and the invasion of HCC via the recruitment of EHMT2 and/or the EHMT2/SNAI1 complex to suppress CDH1. These data identify a novel mechanism that regulates TRERNA1 in metastatic HCC and provides a potential targeted therapy for HCC patients.

Hou H, Yu X, Cong P, et al.
Six2 promotes non-small cell lung cancer cell stemness via transcriptionally and epigenetically regulating E-cadherin.
Cell Prolif. 2019; 52(4):e12617 [PubMed] Related Publications
OBJECTIVES: The roles and related mechanisms of six2 in regulating non-small cell lung cancer (NSCLC) cells progression are unclear. This work aimed to explore the roles of six2 in NSCLC cell stemness.
MATERIALS AND METHODS: Kaplan-Meier plotter analysis was used to examine the correlation between six2 expression and the survival of NSCLC patients. Quantitative reverse transcription PCR and Western blot were performed to detect six2 expression in clinical samples. Moreover, transwell migration, tumour spheroid formation and in vivo tumour formation assays were used to examine the effects of six2 on NSCLC cell progression. Additionally, methylation analysis was carried out to measure E-cadherin methylation level in different cells. Finally, cell viability assay was performed to explore the effects of six2 on chemotherapeutic sensitivity of NSCLC cells.
RESULTS: Lung cancer patients with a higher six2 expression level displayed a shorter overall survival. Six2 expression was higher in lung cancer tissues than in normal adjacent tissues. Additionally, six2 knockdown suppressed NSCLC cell stemness. Mechanistically, six2 overexpression inhibited epithelial marker E-cadherin expression via stimulating its promoter methylation. And E-cadherin knockdown rescued six2 knockdown-induced decrease of NSCLC cancer cell stemness. Notably, six2 knockdown enhanced cisplatin sensitivity in parental NSCLC cells and attenuated cisplatin resistance in cisplatin-resistant NSCLC cells.
CONCLUSIONS: Our results suggest that six2 facilitates NSCLC cell stemness and attenuates chemotherapeutic sensitivity via suppressing E-cadherin expression.

Autenshlyus AI, Golovanova AV, Studenikina AA, et al.
Personalized Approach to Assessing mRNA Expression of Histidine-Rich Glycoprotein and Immunohistochemical Markers in Diseases of the Breast.
Dokl Biochem Biophys. 2019; 484(1):59-62 [PubMed] Related Publications
Biopsy material of patients with malignant and benign breast diseases was examined. HRG mRNA expression was detected in 70% of cases in biopsy material obtained from patients with nonspecific invasive carcinoma and in 66.7% of cases in biopsy material of patients with benign breast diseases. Immunohistochemical analysis revealed expression of collagen II, the beta-1 integrin, and E-cadherin-markers of epithelial-mesenchymal transition. The use of RT-qPCR combined with immunohistochemical study made it possible to identify atypical cells, which can be regarded as precancerous changes, in individual patients.

Hu C, Li M, Guo T, et al.
Anti-metastasis activity of curcumin against breast cancer via the inhibition of stem cell-like properties and EMT.
Phytomedicine. 2019; 58:152740 [PubMed] Related Publications
BACKGROUND: Curcumin is a polyphenolic compound with potent chemopreventive and anti-cancer efficacy.
PURPOSE: To explore the potential anti-metastasis efficacy of curcumin in breast cancer stem-like cells (BCSCs), which are increasingly considered to be the origin of the recurrence and metastasis of breast cancer.
METHODS: A CCK8 assay was performed to evaluate cell viability, and a colony formation assay was conducted to determine cell proliferation in MCF-7 and MDA-MB-231 adherent cells. Transwell and wound healing assays were used to detect the effect of curcumin on cell migration and invasion in MDA-MB-231 cells. Mammospheres were cultured with serum free medium (SFM) for three generations and the BCSC surface marker CD44
RESULTS: Curcumin exhibited anti-proliferative and colony formation inhibiting activities in both the MCF-7 and MDA-MB-231 cell lines. It also suppressed the migration and invasion of MDA-MB-231 cells. The CD44
CONCLUSION: The results of the present study suggest that the inhibitor effects of curcumin on breast cancer cells may be related to resistance to cancer stem-like characters and the EMT process. These data indicate that curcumin could function as a type of anti-metastasis agent for breast cancer.

Oue N, Sentani K, Sakamoto N, et al.
Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells.
Int J Clin Oncol. 2019; 24(7):771-778 [PubMed] Related Publications
Gastric cancer (GC), one of the most common human cancers, is a heterogeneous disease with different phenotypes, prognoses, and responses to treatment. Understanding the pathogenesis of GC at the molecular level is important for prognosis prediction and determining treatments. Microsatellite instability (MSI), silencing of MLH1, MGMT, and CDKN2A genes by DNA hypermethylation, KRAS mutation, APC mutation, and ERBB2 amplification are frequently found in intestinal type GC. Inactivation of CDH1 and RARB by DNA hypermethylation, and amplification of FGFR and MET, are frequently detected in diffuse type GC. In addition, BST2 and PCDHB9 genes are overexpressed in intestinal type GC. Both genes are associated with GC progression. GC can be divided into gastric/intestinal mucin phenotypes according to mucin expression. MSI, alterations of TP73, CDH1 mutation, and DNA methylation of MLH are detected frequently in the gastric mucin phenotype. TP53 mutation, deletion of APC, and DNA methylation of MGMT are detected frequently in the intestinal mucin phenotype. FKTN is overexpressed in the intestinal mucin phenotype, and IQGAP3 is overexpressed in the gastric mucin phenotype. These genes are involved in GC progression. To characterize cancer stem cells, a useful method is spheroid colony formation. KIFC1 and KIF11 genes show more than twofold higher expression in spheroid-forming cells than that in parental cells. Both KIF genes are overexpressed in GC, and knockdown of these genes inhibits spheroid formation. Alterations of these molecules may be useful to understand gastric carcinogenesis. Specific inhibitors of these molecules may also be promising anticancer drugs.

Hsieh SL, Hsieh S, Lai PY, et al.
Carnosine Suppresses Human Colorectal Cell Migration and Intravasation by Regulating EMT and MMP Expression.
Am J Chin Med. 2019; 47(2):477-494 [PubMed] Related Publications
Carnosine is an endogenous dipeptide found in the vertebrate skeletal muscles that is usually obtained through the diet. To investigate the mechanism by which carnosine regulates the migration and intravasation of human colorectal cancer (CRC) cells, we used cultured HCT-116 cells as an experimental model in this study. We examined HCT-116 cell migratory and intravasive abilities and expression of epithelial-mesenchymal transition (EMT)-associated molecules and matrix metalloproteinases (MMPs) after carnosine treatment. The results showed that both migration and invasion were inhibited in cells treated with carnosine. We found significant decreases in Twist-1 protein levels and increases in E-cadherin protein levels in HCT-116 cells after carnosine exposure. Although plasminogen activator (uPA) and MMP-9 mRNA and protein levels were decreased, TIMP-1 mRNA and protein levels were increased. Furthermore, the cytosolic levels of phosphorylated I

Xu LH, Zhao F, Yang WW, et al.
MYB promotes the growth and metastasis of salivary adenoid cystic carcinoma.
Int J Oncol. 2019; 54(5):1579-1590 [PubMed] Free Access to Full Article Related Publications
The incidence of recurrent t(6;9) translocation of the MYB proto‑oncogene to NFIB (the gene that encodes nuclear factor 1 B‑type) in adenoid cystic carcinoma (ACC) tumour tissues is high. However, MYB [the gene that encodes transcriptional activator Myb (MYB)] overexpression is more common, indicating that MYB serves a key role in ACC. The current study aimed to investigate the role of MYB in salivary (S)ACC growth and metastasis. A total of 50 fresh‑frozen SACC tissues and 41 fresh‑frozen normal submandibular gland (SMG) tissues were collected to measure MYB mRNA expression, and to analyse the associations between MYB and epithelial‑mesenchymal transition (EMT) markers. Compared with normal SMG tissue, SACC tissues demonstrated significantly increased MYB expression, with a high expression rate of 90%. Interestingly, MYB tended to be negatively correlated with CDH1 [the gene that encodes cadherin‑1 (E‑cadherin)] and positively correlated with VIM (the gene that encodes vimentin), suggesting that MYB is associated with SACC metastasis. To explore the role of MYB in SACC, the authors stably overexpressed and knocked down MYB in SACC cells. The authors of the current study demonstrated that MYB overexpression promoted SACC cell proliferation, migration and invasion, whereas its knockdown inhibited these activities. Additionally, when MYB was overexpressed, CDH1 expression was downregulated, and CDH2 (the gene that encodes cadherin‑2), VIM and ACTA2 (the gene that encodes actin, aortic smooth muscle) expression was upregulated. Then, the effect of MYB on lung tumour metastasis was investigated in vivo in non‑obese diabetic/severe combined immunodeficiency mice. MYB overexpressing and control cells were injected into the mice through the tail vein. The results revealed that MYB promoted SACC lung metastasis. Collectively, these results demonstrated that MYB is aberrantly overexpressed in SACC tissues, and promotes SACC cell proliferation and metastasis, indicating that MYB may be a novel therapeutic target for SACC.

Salvagno C, Ciampricotti M, Tuit S, et al.
Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response.
Nat Cell Biol. 2019; 21(4):511-521 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
Recent studies have revealed a role for macrophages and neutrophils in limiting chemotherapy efficacy; however, the mechanisms underlying the therapeutic benefit of myeloid-targeting agents in combination with chemotherapy are incompletely understood. Here, we show that targeting tumour-associated macrophages by colony-stimulating factor-1 receptor (CSF-1R) blockade in the K14cre;Cdh1

Singh V, Singh AP, Sharma I, et al.
Epigenetic deregulations of Wnt/β-catenin and transforming growth factor beta-Smad pathways in esophageal cancer: Outcome of DNA methylation.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):192-203 [PubMed] Related Publications
Background: Promoter methylation of tumor suppressor genes (TSGs) is a well-reported portent in carcinogenesis; hence, it is worthy to investigate this in high-risk Northeast population of India. The study was designed to investigate methylation status of 94 TSGs in esophageal squamous cell carcinoma (ESCC). Further, the effect of OPCML promoter methylation on gene expression was analyzed by immunohistochemistry. Moreover, in silico protein-protein interactions were examined among 8 TSGs identified in the present study and 23 epigenetically regulated genes reported previously by our group in ESCC.
Materials and Methods: Methylation profiling was carried out by polymerase chain reaction array and OPCML protein expression was examined by tissue microarray-based immunohistochemistry.
Results: OPCML, NEUROG1, TERT, and WT1 genes were found hypermethylated and SCGB3A1, CDH1, THBS1, and VEGFA were hypomethylated in Grade 2 tumor. No significant change in OPCML expression was observed among control, Grade 1, and Grade 2 tumor. Conclusively, hypermethylation of the studied OPCML promoter in Grade 2 tumor produced no effect on expression. Unexpectedly, OPCML expression was downregulated in Grade 3 tumor in comparison to other groups signifying that downregulation of OPCML expression may lead to higher grade of tumor formation at the time of diagnosis of ESCC in patients. Significant interactions at protein level were found as VEGFA:PTK2, CTNNB1:CDH1, CTNNB1:VEGFA, CTNNB1:NEUROG1, CTNND2:CDH1, and CTNNB1:TERT. These interactions are pertinent to Wnt/β-catenin and TGF-β-Smad pathways.
Conclusions: Deranged OPCML expression may lead to high-grade ESCC as well as epigenetically regulated genes, that is, CDH1, CTNNB1, CTNND2, THBS1, PTK2, WT1, OPCML, TGFB1, and SMAD4 may alter the Wnt/β-catenin and TGF-β-Smad pathways in ESCC. Further study of these genes could be useful to understand the molecular pathology of ESCC with respect to epithelial-mesenchymal transition (EMT) mediated by Wnt/β-catenin and TGF-β signaling pathways.

Bahadir A, Eral G, Budak M, et al.
Association of clinicopathological features with E-cadherin (CDH1) gene-160 C>A promoter polymorphism in Turkish colorectal cancer patients.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):26-31 [PubMed] Related Publications
Background and Aim of Study: The role of E-cadherin (CDH1) gene-160 C>A (rs16260) promoter polymorphism in colorectal cancer (CRC) still remains inconclusive. The aim of this study is to investigate the associations between the CDH1-160 C>A polymorphism with the susceptibility and clinicopathological development of CRC in the Turkish patients. To our knowledge, this is the first report examining the role of CDH1 polymorphism in Turkish CRC patients.
Materials and Methods: A total of 92 colorectal carcinoma cases (including 62 colon and 30 rectal cancer patients) and the corresponding adjacent normal tissues as controls were studied. The polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis. Clinicopathological features including patient's age, gender, tumor stage, and tumor location (colon/rectum) were compared statistically with the polymorphism status.
Results: There was no significant difference in both genotype and allele frequencies of the CDH1 polymorphism between colorectal tumor cases and normal samples (P = 0.472 and 0.508, respectively). Furthermore, no significant associations were observed between the CDH1 polymorphism status and age, gender, tumor stage, and tumor location of the colorectal tumor cases (all P > 0.05).
Conclusions: These results indicate that CDH1-160 C>A polymorphism does not contribute to the genetic susceptibility of CRC and the polymorphism may not be a direct effect on the progression of the disease in Turkish CRC patients.

Imtiaz H, Afroz S, Hossain MA, et al.
Genetic polymorphisms in CDH1 and Exo1 genes elevate the prostate cancer risk in Bangladeshi population.
Tumour Biol. 2019; 41(3):1010428319830837 [PubMed] Related Publications
The polymorphisms of invasion suppressor gene CDH1 and DNA mismatch repair gene Exo1 have been reported to play critical role in the development, tumorigenesis, and progression of several kinds of cancers including prostate cancer. This study was designed to analyze the contribution of single-nucleotide polymorphisms of the CDH1 (-160C/A) and Exo1 (K589E) to prostate cancer susceptibility in Bangladeshi population. The study included 100 prostate cancer cases and age-matched 100 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to determine the genetic polymorphisms. A significant association was found between CDH1 -160C/A (rs16260) and Exo1 (rs1047840, K589E) polymorphisms and prostate cancer risk. In case of CDH1 -160C/A polymorphism, the frequencies of the three genotypes C/C,C/A, and A/A were 45%, 48%, and 7% in cases and 63%, 32%, and 5% in controls, respectively. The heterozygote C/A genotype and combined C/A + A/A genotypes showed 2.10-fold (odds ratio = 2.1000, 95% confidence interval = 1.2956-4.0905, p = 0.013) and 2.08-fold (odds ratio = 2.0811, 95% confidence interval = 1.1820-3.6641, p = 0.011) increased risk of prostate cancer, respectively, when compared with homozygous C/C genotypes. The variant A allele also was associated with increased risk of prostate cancer (odds ratio = 1.6901, 95% confidence interval = 1.0740-2.6597, p = 0.0233). In case of Exo1 (K589E) polymorphism, G/A heterozygote, A/A homozygote, and combined G/A + A/A genotypes were found to be associated with 2.30-, 4.85-, and 3.04-fold higher risk of prostate cancer, respectively (odds ratio = 2.3021, 95% confidence interval = 2.956-4.0905, p = 0.0031; odds ratio = 4.8462, 95% confidence interval = 1.0198-23.0284, p = 0.0291; OR = 3.0362, 95% confidence interval = 1.7054-5.4053, p = 0.0001, respectively). The "A" allele showed significant association with increased susceptibility (2.29-fold) to prostate cancer (odds ratio = 2.2955, 95% confidence interval = 1.4529-3.6270, p = 0.0004). Our results suggest that CDH1 -160C/A and Exo1 K589E polymorphisms are associated with increased susceptibility to prostate cancer in Bangladeshi population.

Zhao X, Sun Q, Dou C, et al.
BMP4 inhibits glioblastoma invasion by promoting E-cadherin and claudin expression.
Front Biosci (Landmark Ed). 2019; 24:1060-1070 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is a brain tumor that deeply infiltrates adjacent tissues and causes significant mortality. Thus, understanding the mechanisms that derive the invasion of brain tissue by GBM might help the treatment of this cancer. To this end, we examined the impact of BMP4 on invasion of GBM. In this study, Human GBM samples, GBM cells and human orthotopic GBM-xenografted animal model, quantitative PCR, immunostaining, immunoblotting, Scratch wound and transwell assays were used to detect the effect and the mechanism of BMP4 in GBM cells. BMP4 expression was found to positively correlate with E-cadherin and claudin expression in human GBM samples. Elevation or suppression of BMP4 expression resulted in a respective increase or decrease in E-cadherin and claudin levels, both

Ma X, Li B, Liu J, et al.
Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E.
J Exp Clin Cancer Res. 2019; 38(1):66 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
BACKGROUND: Pancreatic cancer is one of the most malignant cancers. The overall 5-year survival rate of its patients is 8%, the lowest among major cancer types. It is very urgent to study the development mechanisms of this cancer and provide potential targets for therapeutics design. Glucose, one of the most essential nutrients, is highly exploited for aerobic glycolysis in tumor cells to provide building blocks. However, the glucose consumption manner in pancreatic cancer cells is unclear. And the mechanism of the substantial metabolic pathway promoting pancreatic cancer development is also unrevealed.

Khodaei R, Ahmady A, Khoshfetrat SM, et al.
Voltammetric immunosensor for E-cadherin promoter DNA methylation using a Fe
Mikrochim Acta. 2019; 186(3):170 [PubMed] Related Publications
Silencing of tumor suppressor genes (E-cadherin) by promoter DNA methylation may lead to the development of invasive phenotypes in epithelial tissues. The authors describe an electrochemical nanobiosensor for early detection and screening of circulating methylated DNA as a biomarker for cancers. First, the antibody against 5-methylcytosine was physically immobilized onto modified with reduced graphene oxide and polyvinylalcohol. In the next step, methylated target DNA in samples was hybridized with ssDNA probe conjugated to Fe

You YN, Borras E, Chang K, et al.
Detection of Pathogenic Germline Variants Among Patients With Advanced Colorectal Cancer Undergoing Tumor Genomic Profiling for Precision Medicine.
Dis Colon Rectum. 2019; 62(4):429-437 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Genomic profiling of colorectal cancer aims to identify actionable somatic mutations but can also discover incidental germline findings.
OBJECTIVE: The purpose of this study was to report the detection of pathogenic germline variants that confer heritable cancer predisposition.
DESIGN: This was a retrospective study.
SETTINGS: The study was conducted at a tertiary-referral institution.
PATIENTS: Between 2012 and 2015, 1000 patients with advanced cancer underwent targeted exome sequencing of a 202-gene panel. The subgroup of 151 patients with advanced colorectal cancer who underwent matched tumor-normal (blood) sequencing formed our study cohort.
INTERVENTIONS: Germline variants in 46 genes associated with hereditary cancer predisposition were classified according to a defined algorithm based on in silico predictions of pathogenicity. Patients with presumed pathogenic variants were examined for type of mutation, as well as clinical, pedigree, and clinical genetic testing data.
MAIN OUTCOME MEASURES: We measured detection of pathogenic germline variants.
RESULTS: A total of 1910 distinct germline variants were observed in 151 patients. After filtering, 15 pathogenic germline variants (9.9%) were found in 15 patients, arising from 9 genes of varying penetrance for colorectal cancer (APC (n = 2; 13%), ATM (n = 1; 6%), BRCA1 (n = 2; 13%), CDH1 (n = 2; 13%), CHEK2 (n = 4; 27%), MSH2 (n = 1; 7%), MSH6 (n = 1; 7%), NF2 (n = 1; 7%), and TP53 (n = 1; 7%)). Patients with pathogenic variants were diagnosed at a younger age than those without (median, 45 vs 52 y; p = 0.03). Of the 15 patients, 7 patients (46.7%) with variants in low/moderate- penetrant genes for colorectal cancer would likely have not been tested based on clinical and pedigree criteria, where 2 harbored clinically actionable variants (CDH1 and NF2, 28.5% of 7).
LIMITATIONS: This study was limited by its small sample size and advanced-stage patients.
CONCLUSIONS: Tumor-normal sequencing can incidentally discover clinically unsuspected germline variants that confer cancer predisposition in 9.9% of patients with advanced colorectal cancer. Precision medicine should integrate clinical cancer genetics to inform and interpret the actionability of germline variants and to provide follow-up care to mutation carriers. See Video Abstract at

Pereira CV, Duarte M, Silva P, et al.
Polymethoxylated Flavones Target Cancer Stemness and Improve the Antiproliferative Effect of 5-Fluorouracil in a 3D Cell Model of Colorectal Cancer.
Nutrients. 2019; 11(2) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Polymethoxylated flavones (PMFs) from citrus fruits are reported to present anticancer potential. However, there is a lack of information regarding their effect on cancer stem cell (CSC) populations, which has been recognized as responsible for tumor initiation, relapse, and chemoresistance. In this study, we evaluated the effect of an orange peel extract (OPE) and its main PMFs, namely, nobiletin, sinensetin, tangeretin, and scutellarein tetramethylether in targeting cell proliferation and stemness using a 3D cell model of colorectal cancer composed of HT29 cell spheroids cultured for 7 days in stirred conditions. Soft agar assay, ALDH1 activity, and relative quantitative gene expression analysis of specific biomarkers were carried out to characterize the stemness, self-renewal, and mesenchymal features of HT29 cell spheroids. Then, the impact of OPE and PMFs in reducing cell proliferation and modulating cancer stemness and self-renewal was assessed. Results showed that, when compared with monolayer cultures, HT29 cell spheroids presented higher ALDH1 activity (81.97% ± 5.27% compared to 63.55% ± 17.49% for 2D), upregulation of

Lopez G, Costanza J, Colleoni M, et al.
Molecular Insights into the Classification of Luminal Breast Cancers: The Genomic Heterogeneity of Progesterone-Negative Tumors.
Int J Mol Sci. 2019; 20(3) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Estrogen receptor (ER)-positive progesterone receptor (PR)-negative breast cancers are infrequent but clinically challenging. Despite the volume of genomic data available on these tumors, their biology remains poorly understood. Here, we aimed to identify clinically relevant subclasses of ER+/PR- breast cancers based on their mutational landscape. The Cancer Genomics Data Server was interrogated for mutational and clinical data of all ER+ breast cancers with information on PR status from The Cancer Genome Atlas (TCGA), Memorial Sloan Kettering (MSK), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) projects. Clustering analysis was performed using gplots, ggplot2, and ComplexHeatmap packages. Comparisons between groups were performed using the Student's t-test and the test of Equal or Given Proportions. Survival curves were built according to the Kaplan⁻Meier method; differences in survival were assessed with the log-rank test. A total of 3570 ER+ breast cancers (PR- n = 959, 27%; PR+ n = 2611, 73%) were analyzed. Mutations in well-known cancer genes such as TP53, GATA3, CDH1, HER2, CDH1, and BRAF were private to or enriched for in PR- tumors. Mutual exclusivity analysis revealed the presence of four molecular clusters with significantly different prognosis on the basis of PIK3CA and TP53 status. ER+/PR- breast cancers are genetically heterogeneous and encompass a variety of distinct entities in terms of prognostic and predictive information.

Li X, Lin H, Jiang F, et al.
Knock-Down of HOXB8 Prohibits Proliferation and Migration of Colorectal Cancer Cells via Wnt/β-Catenin Signaling Pathway.
Med Sci Monit. 2019; 25:711-720 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND There has been no research on the mechanism of HOXB8 action on colorectal cancer so far. This study was designed to investigate the mechanism of HOXB8 regulating colorectal cancer cell proliferation and invasion in vivo and in vitro. MATERIAL AND METHODS HOXB8 shRNA, HOXB8 overexpression, and negative control vector were designed and stably transfected into HCT116 cells. MTT assays were performed to detect cell proliferation. Western blot was utilized to detect HOXB8 expression level in HCT116 stable cells. The invasive and migration abilities were detected by Transwell assay and wound-healing assay. RESULTS HOXB8 knockdown inhibited cell proliferation. The invasiveness of HCT116 cells was significantly reduced following HOXB8 depletion compared with that in the shRNA control group, whereby the rates were reduced by 67% in HOXB8 knockdown group. The wound-healing rate of HOXB8 over-expression cells was significantly increased comparing with that of cells in the blank control group (P<0.05). HOXB8 knockdown promotes apoptosis of HCT116 cells. The expression of E-cadherin was restrained in the HOXB8 over-expression group and increased in the HOXB8 knockdown group. CONCLUSIONS Knock-down of HOXB8 prohibits the proliferation and migration of colorectal cancer cells via the Wnt/β-catenin signaling pathway and the downregulation of various factors, such as MMP2, c-Myc, CyclinD1,and vimentin. Our data suggested that HOXB8 has great potential to be developed as a novel therapeutic agent for the treatment of human colorectal cancer.

Tang L, Zhao P, Kong D
Muscleblind‑like 1 destabilizes Snail mRNA and suppresses the metastasis of colorectal cancer cells via the Snail/E‑cadherin axis.
Int J Oncol. 2019; 54(3):955-965 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
RNA‑binding proteins (RBPs) play a fundamental role in the recurrence and metastasis of colorectal cancer (CRC). In this study, we identified muscleblind‑like 1 (MBNL1), an RBP implicated in developmental control, as a robust suppressor of CRC cell metastasis in vitro. By using a scratch assay coupled with time‑lapse live cell imaging, our findings revealed that the knockdown of MBNL1 induced epithelial‑to‑mesenchymal transition (EMT)‑like morphological changes in the HCT‑116 cells, accompanied by an enhanced cell motility, and by the downregulation of E‑cadherin and the upregulation of Snail expression. By contrast, the ectopic overexpression of MBNL1 suppressed EMT, characterized by the upregulation of E‑cadherin and the downregulation of Snail expression. Mechanistically, Snail rather than E‑cadherin, was identified as a direct downstream target gene of MBNL1. The ectopic the overexpression of MBNL1 markedly enhanced the recruitment of Snail transcripts to processing bodies (P‑bodies), leading to the increased degradation of Snail mRNA and consequent translational silencing. Furthermore, the effect of MBNL1 on CRC cell migration was confirmed in additional CRC cell lines. SW480 and HT‑29 cells exhibited similar changes in migratory capacity and the expression of Snail/E‑cadherin to those observed in HCT‑116 cells. On the whole, this study demonstrates that MBNL1 destabilizes Snail transcripts and, in turn, suppresses the EMT of CRC cells through the Snail/E‑cadherin axis in vitro. Therefore, this EMT‑related MBNL1/Snail/E‑cadherin axis may prove to be a novel therapeutic target for CRC metastasis.

Bustos-Carpinteyro AR, Oliveira C, Sousa A, et al.
CDH1 somatic alterations in Mexican patients with diffuse and mixed sporadic gastric cancer.
BMC Cancer. 2019; 19(1):69 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Diffuse gastric cancer (DGC) is associated with the reduction or absence of the expression of the cell adhesion protein E-cadherin (encoded by the CDH1 gene). Molecular characteristics are less well described for mixed gastric cancer (MGC). The main somatic alterations that have been described in the CDH1 gene are mutations, loss of heterozygosity (LOH) and promoter methylation. The aim was to analyze CDH1 somatic alterations in Mexican patients with diffuse and mixed gastric cancer.
METHODS: We searched for mutations in the CDH1 gene in tumor DNA from DGC (n = 13) and MGC (n = 7) patients by next generation sequencing (NGS). Validation of findings was performed using Sanger sequencing. LOH was analyzed using dinucleotide repeat markers surrounding the CDH1 gene, and methylation was investigated by DNA bisulfite conversion and sequencing. E-cadherin protein deficiency was analyzed by immunohistochemistry.
RESULTS: Seventeen point variants were identified by NGS, 13 of them were validated by Sanger sequencing. Only 1/13 had not been previously reported (c.-137C > A), and 12/13 were already reported as polymorphisms. Two DGC cases presented LOH at the locus 16q22.1 (13.3%). CDH1 promoter methylation was positive in (7/11) 63.6% and (4/6) 66.6% of the cases with DGC and MGC, respectively. E-cadherin protein deficiency was observed in 58.3% of DGC cases while 100% in MGC cases.
CONCLUSIONS: While no pathogenic somatic mutations were found that could explain the diffuse histology of gastric cancer in DGC and MGC, methylation was the most common somatic inactivation event of the CDH1 gene, and LOH was rare. The previously unreported c.-137C > A variant modify the CDH1 gene expression since it alters the binding sites for transcription factors.

Chen L, He Q, Liu Y, et al.
PPP3CB Inhibits Migration of G401 Cells via Regulating Epithelial-to-Mesenchymal Transition and Promotes G401 Cells Growth.
Int J Mol Sci. 2019; 20(2) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
PPP3CB belongs to the phosphoprotein phosphatases (PPPs) group. Although the majority of the PPP family play important roles in the epithelial-to-mesenchymal transition (EMT) of tumor cells, little is known about the function of PPP3CB in the EMT process. Here, we found PPP3CB had high expression in kidney mesenchymal-like cells compared with kidney epithelial-like cells. Knock-down of PPP3CB downregulated epithelial marker E-cadherin and upregulated mesenchymal marker Vimentin, promoting the transition of cell states from epithelial to mesenchymal and reorganizing the actin cytoskeleton which contributed to cell migration. Conversely, overexpression of PPP3CB reversed EMT and inhibited migration of tumor cells. Besides, in vitro and in vivo experiments indicated that the loss of PPP3CB suppressed the tumor growth. However, the deletion of the phosphatase domain of PPP3CB showed no effect on the expression of E-cadherin, migration, and G401 cell proliferation. Together, we demonstrate that PPP3CB inhibits G401 cell migration through regulating EMT and promotes cell proliferation, which are both associated with the phosphatase activity of PPP3CB.

Wang Y, Yang B, Zhao J, et al.
Epithelial‑mesenchymal transition induced by bone morphogenetic protein 9 hinders cisplatin efficacy in ovarian cancer cells.
Mol Med Rep. 2019; 19(3):1501-1508 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Bone morphogenetic protein 9 (BMP9) belongs to the transforming growth factor‑β (TGF‑β) superfamily, and has been reported to promote cancer cell proliferation and epithelial‑mesenchymal transition (EMT). Cisplatin (DDP) is the first line treatment for ovarian cancer. However, initiation of EMT confers insensitivity to chemotherapy. The present study aimed to verify and examine the mechanisms underlying the effects of BMP9 on treatment with DDP for ovarian cancer. Prior to treatment with DDP, ovarian cancer cells were exposed to BMP9 for 3 days. Following this, cell viability, apoptosis rate and the extent of DNA damage were evaluated to compare the effects of DDP on BMP9‑pretreated and non‑pretreated ovarian cancer cells. In addition, EMT marker expression was evaluated by western blotting and immunofluorescence. The results demonstrated that BMP9 pretreatment inhibited the cytotoxicity of DDP on ovarian cancer cells. Additionally, BMP9‑pretreated ovarian cancer cells had downregulated expression of the epithelial marker E‑cadherin, which was accompanied by an upregulation of the mesenchymal markers N‑cadherin, Snail, Slug, and Twist. Taken together, the findings of the present study indicated that BMP9 conferred resistance to DDP in ovarian cancer cells by inducing EMT. The present study provided valuable insight into the mechanisms of chemotherapy in ovarian cancer and highlighted the potential of BMP9 as a novel therapeutic target for improving cisplatin chemosensitivity.

Li Y, Zhang T, Qin S, et al.
Effects of UPF1 expression on EMT process by targeting E‑cadherin, N‑cadherin, Vimentin and Twist in a hepatocellular carcinoma cell line.
Mol Med Rep. 2019; 19(3):2137-2143 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. It has been reported that HCC has a poor prognosis. In the majority of cases, once metastatic, HCC is incurable. To identify an effective treatment for HCC, it is important to understand the underlying molecular mechanisms of HCC‑associated occurrence, proliferation, metastasis and carcinogenesis. In the present study, the role of Up‑frameshift 1 (UPF1), a potential tumor suppressor, was investigated in the HCC cell lines. The expression levels of UPF1 in an HCC cell line were examined by reverse transcription‑quantitative polymerase chain reaction. The expression levels of 19 key proteins in numerous signaling pathways were detected via protein array analysis in the presence of UPF1 overexpression. The present study further investigated the effects of UPF1 expression levels on the epithelial‑mesenchymal transition (EMT) process by targeting E‑cadherin, N‑cadherin, Vimentin and Twist‑related protein 1 (Twist). The results of the present study revealed that UPF1 was significantly downregulated in an HCC cell line. The majority of the proteins exhibited upregulated expression levels in the presence of UPF1 overexpression in the HCC cell line, Huh‑7. Key proteins, including cluster of differentiation (CD)31 (platelet endothelial cell adhesion molecule‑1), Vimentin, CD44, PCNA, Ki‑67, N‑Cadherin, Survivin, P53, Met and retinoblastoma exhibited a significant association with UPF1. Furthermore, western blotting indicated that the expression levels of N‑cadherin, Vimentin and Twist were notably upregulated while UPF1 was overexpressed; however, E‑cadherin was downregulated and opposing observations were reported with protein array analysis. In summary, E‑cadherin expression levels were regulated by the manifold, and UPF1, a potential tumor suppressor, may promote the EMT process in Huh‑7 HCC cells. The findings of the present study suggested that UPF1 expression levels affected the EMT process by targeting E‑cadherin, N‑cadherin, Vimentin and Twist.

Funamizu N, Lacy CR, Kamada M, et al.
MicroRNA-200b and -301 are associated with gemcitabine response as biomarkers in pancreatic carcinoma cells.
Int J Oncol. 2019; 54(3):991-1000 [PubMed] Related Publications
Chemotherapy resistance (congenital or acquired) is one of the principal challenges for the treatment of pancreatic carcinoma. Recent evidence has demonstrated that epithelial to mesenchymal transition (EMT) is associated with chemoresistance in pancreatic carcinoma cells. However, the molecular mechanism underlying the development of chemoresistance remains unknown, and limited therapeutic options are available. Therefore, to anticipate individual chemosensitivity or acquired chemoresistance for patients with pancreatic carcinoma, predictive biomarkers are urgently required. Extensive evidence suggests that microRNAs (miRNAs) serve a crucial role in regulating EMT. The aim of this study was to examine the potential role of miRNA (miR)‑200b and miR‑301 in predicting the chemo‑responses to treatment for pancreatic carcinoma. The present results demonstrate that miR‑200b expression predicted chemo‑sensitivity and may have potential as a biomarker. In six different pancreatic carcinoma cell lines (Capan‑1, Capan‑2, Panc‑1, MIAPaCa‑2, BxPC‑3 and PL45 cells), the expression of miR‑200b correlated positively with chemosensitivity. Moreover, the enhanced expression of miR‑200b increased chemosensitivity and induced mesenchymal to epithelial transition. Conversely, miR‑301 modulated gemcitabine resistance and induced EMT through the downregulation of cadherin 1 expression. In addition, gemcitabine‑resistant cells (Capan‑2 and Panc‑1) exhibited upregulated miR‑301 expression and downregulated gemcitabine‑induced apoptosis. In summary, these two miRNAs may serve roles as biomarkers in pancreatic carcinoma, miR‑200b expression may predict chemosensitivity, and elevated miR‑301 expression may have potential applications in the prediction of acquired gemcitabine resistance.

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