CDH1

Gene Summary

Gene:CDH1; cadherin 1
Aliases: UVO, CDHE, ECAD, LCAM, Arc-1, CD324
Location:16q22.1
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:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cadherin-1
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
Show (63)
Pathways:What pathways are this gene/protein implicaed in?
Show (5)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 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.

  • Cervical Cancer
  • Down-Regulation
  • Promoter Regions
  • DNA Methylation
  • Breast Cancer
  • Mutation
  • Epithelial-Mesenchymal Transition
  • Case-Control Studies
  • Upper Gastrointestinal Tract
  • Epigenetics
  • alpha Catenin
  • Ovarian Cancer
  • Review Literature as Topic
  • Cell Movement
  • Colorectal Cancer
  • Mutation Rate
  • Lung Cancer
  • DNA Sequence Analysis
  • Cadherins
  • Biomarkers, Tumor
  • Germ-Line Mutation
  • RNA Interference
  • Adenocarcinoma
  • Gene Expression Profiling
  • snail family transcription factors
  • Signal Transduction
  • Therapeutic Irrigation
  • Genetic Predisposition
  • Liver Cancer
  • Pedigree
  • Staging
  • Risk Factors
  • Papillomavirus Infections
  • Chromosome 16
  • Cell Proliferation
  • Cancer Gene Expression Regulation
  • Stomach Cancer
  • Neoplasm Metastasis
  • Protein Interaction Maps
  • CDH1
  • Proportional Hazards Models
  • Bladder Cancer
  • Homeodomain Proteins
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (9)

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)

Zhang L, Jia G, Shi B, et al.
PRSS8 is Downregulated and Suppresses Tumour Growth and Metastases in Hepatocellular Carcinoma.
Cell Physiol Biochem. 2016; 40(3-4):757-769 [PubMed] Related Publications
BACKGROUND: Protease serine 8 (PRSS8), a trypsin-like serine peptidase, has been shown to function as a tumour suppressor in various malignancies. The present study aimed to investigate the expression pattern, prognostic value and the biological role of PRSS8 in human hepatocellular carcinoma (HCC).
METHODS: PRSS8 expression in 106 HCC surgical specimens was examined by Real-time polymerase chain reaction (PCR) and immunohistochemistry, and its clinical significance was analysed. The role of PRSS8 in cell proliferation, apoptosis and invasion were examined in vitro and in vivo.
RESULTS: PRSS8 mRNA and protein expression were decreased in most HCC tumours from that in matched adjacent non-tumour tissues. Low intratumoral PRSS8 expression was significantly correlated with poor overall survival (OS) in patients with HCC (P = 0.001). PRSS8 expression was an independent prognostic factor for OS (hazard ratio [HR] = 1.704, P = 0.009). Furthermore, restoring PRSS8 expression in high metastatic HCCLM3 cells significantly inhibited cell proliferation and invasion. In contrast, silencing PRSS8 expression in non-metastatic HepG2 cells significantly enhanced cell growth and invasion. Moreover, our in vivo data revealed that attenuated PRSS8 expression in HepG2 cells greatly promoted tumour growth, while overexpression of PRSS8 remarkably inhibited tumour growth in an HCCLM3 xenograft model. Enhanced cell growth and invasion ability mediated by the loss of PRSS8 expression was associated with downregulation of PTEN, Bax and E-cadherin and an upregulation in Bcl-2, MMP9 and N-cadherin.
CONCLUSIONS: Our data demonstrate that PRSS8 may serve as a tumour suppressor in HCC progression, and represent a valuable prognostic marker and potential therapeutic target for HCC.

Zhou M, Zhang XY, Yu X
Overexpression of the long non-coding RNA SPRY4-IT1 promotes tumor cell proliferation and invasion by activating EZH2 in hepatocellular carcinoma.
Biomed Pharmacother. 2017; 85:348-354 [PubMed] Related Publications
BACKGROUND: Increasing evidences have demonstrated that the dysregulation of long non-coding RNAs (lncRNAs) may act as an important role in tumor progression. The long non-coding RNA SPRY4 intronic transcript 1 (SPRY4-IT1) has been reported in some cancer including regulating cell growth, differentiation, apoptosis, and cancer progression. However, the expression and function of SPRY4-IT1 in the progression of hepatocellular carcinoma (HCC) remain largely unknown.
METHODS: The lncRNA SPRY4-IT1 was detected by quantitative real time PCR (qRT-PCR) in HCC cell lines, CCK8 cell proliferation and transwell invasion assays were performed to detect the GC cell proliferation and invasion abilities. The protein expression of E-cadherin, Vimentin and Twist1 was analyzed by Western blotting assays. Furthermore, RNA immunoprecipitation (RIP) and Chromatin immunoprecipitation (ChIP) assays were used to analyze potential molecular mechanism of SPRY4-IT1 in HCC cells.
RESULTS: We found that SPRY4-IT1 was up-regulated in HCC cell lines. Further function analysis demonstrated that knockdown of SPRY4-IT1 significantly inhibited HCC cells proliferation and invasion, but over-expression of SPRY4-IT1 had the opposite effects on HCC cells in vitro. Moreover, our results also indicated that SPRY4-IT1 over-expression significantly promoted the epithelial-mesenchymal transition (EMT) by up-regulating the transcription factor Twist1 and EMT marker Vimentin and inhibited the E-cadherin expression in MHCC97L cell. Whereas, knockdown of SPRY4-IT1 suppressed the transcription factor Twist1 and EMT marker Vimentin and increased the E-cadherin expression in MHCC97H cells. Mechanisms investigations showed that SPRY4-IT1 interacted with the EZH2 and epigenetically repressed the E-cadherin expression. In vivo, we also demonstrated that the tumor growth was inhibited in SPRY4-IT1 knockdown group compared with the control group.
CONCLUSIONS: These results suggested that lncRNA SPRY4-IT1 might be considered as a therapeutic target in HCC.

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.

Juodzbalys G, Kasradze D, Cicciù M, et al.
Modern molecular biomarkers of head and neck cancer. Part I. Epigenetic diagnostics and prognostics: Systematic review.
Cancer Biomark. 2016; 17(4):487-502 [PubMed] Related Publications
INTRODUCTION: Nearly half of the head and neck cancer cases are diagnosed in late stages. Traditional screening modalities have many disadvantages. The aim of the present article was to review the scientific literature about novel head and neck cancer diagnostics - epigenetic biomarkers.
EVIDENCE ACQUISITION: A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed database. Authors conducted the search of articles in English language published from 2004 to 2015.
EVIDENCE SYNTHESIS: A total of thirty three relevant studies were included in the review. Fifteen of them concerned DNA methylation alterations, nine evaluation of abundancies in histone expressions and nine miRNA expression changes in HNC.
CONCLUSIONS: Considerable number of epigenetic biomarkers have been identified in both tumor tissue and salivary samples. Genes with best diagnostic effectiveness rates and further studying prospects were: TIMP3, DCC, DAPK, CDH1, CCNA1, AIM1, MGMT, HIC1, PAX1, PAX5, ZIC4, p16, EDNRB, KIF1A, MINT31, CD44, RARβ , ECAD. Individual histone and miRNA alterations tend to be hnc specific. Prognostic values of separate biomarkers are ambiguous. No established standards for molecular assay of head and neck cancer was found in order to elude the paradoxical results and discrepancies in separate trials.

Rogers MA, Kalter V, Strowitzki M, et al.
IGF2 knockdown in two colorectal cancer cell lines decreases survival, adhesion and modulates survival-associated genes.
Tumour Biol. 2016; 37(9):12485-12495 [PubMed] Related Publications
Increased expression of insulin-like growth factor 2 (IGF2) is found in tumors of colorectal cancer (CRC) patients exhibiting a gained region on chromosome 11q15 and is implicated in poor patient survival. This study analyzes in vitro phenotypic- and gene expression changes associated with IGF2 shRNA-mediated knockdown. Initially, doxycycline inducible IGF2 knockdown cell lines were generated in the CRC cell lines SW480 and LS174T. The cells were analyzed for changes in proliferation, cell cycle, apoptosis, adhesion, and invasion. Expression profiling analysis was performed, and, for a subset of the identified genes, expression was validated by qRT-PCR and Western blot. IGF2 knockdown inhibited cell proliferation in both cell lines induced G1 cell cycle blockade and decreased adhesion to several extracellular matrix proteins. Knockdown of IGF2 did not alter invasiveness in SW480 cells, while a slight increase in apoptosis was seen only in the LS174T cell line. Knockdown of IGF2 in SW480 deregulated 58 genes, several of which were associated with proliferation and cell-cell/cell-ECM contacts. A subset of these genes, including CDK2, YAP1, and BIRC5 (Survivin), are members of a common network. This study supports the concept of direct autocrine/paracrine tumor cell activation through IGF2 and a shows role of IGF2 in CRC proliferation, adhesion and, to a limited extent, apoptosis.

Zhu H, Qin H, Li DM, et al.
Effect of PPM1H on malignant phenotype of human pancreatic cancer cells.
Oncol Rep. 2016; 36(5):2926-2934 [PubMed] Related Publications
The objective of this study was to investigate the effect of silencing gene protein phosphatase 1H (PPM1H) on malignant phenotype of human pancreatic cancer cell line BxPC-3. In order to explore the function of PPM1H in pancreatic cancer cells, real-time PCR and western blotting were used to detect the expression of PPM1H in different pancreatic cancer cell lines. Human pancreatic cancer cell line BxPC-3 was treated with 10 ng/ml TGF-β1 and 200 ng/ml BMP2 for 72 h, respectively, and the mRNA and protein expression levels of PPM1H and EMT-related markers (E-cadherin, vimentin) were detected by real-time PCR and western blotting, respectively. Using exogenous RNA interference technology to silence the PPM1H gene, the expression of PPM1H and EMT-related markers at mRNA and protein levels were detected by real-time PCR and western blotting. The cell migration and invasion were measured using Transwell assays. Finally, cell counting kit-8 (CCK-8) and flow cytometry were used to determine the effect of PPM1H on cell proliferation and apoptosis of BxPC-3 cells. The expression levels of PPM1H in all of the examined pancreatic cancer cell lines (BxPC-3, MIA-PACA2, PANC-1, SW1990, PANC-03.27) were lower than that of normal pancreatic ductal epithelial cells (HPDE6-C7) at both mRNA and protein levels. Both TGF-β1 and BMP2 treatment induced EMT and downregulation of PPM1H in BxPC-3 cells. By using RNA interference to transiently knock down PPM1H expression in BxPC-3 cells, we found that the expression of E-cadherin was downregulated while vimentin was up-regulated. The data suggested that silencing PPM1H gene can induce EMT in BxPC-3 cells. In addition, Transwell migration assays showed that silencing PPM1H gene can promote the invasion and metastasis of BxPC-3 cells. Cell proliferation and apotosis detection demonstrated that silencing PPM1H gene can promote the proliferation and inhibit apoptosis of BxPC-3 cells. In conclusion, PPM1H is aberrantly expressed in human pancreatic cancer cell lines and can be downregulated when EMT is induced by cytokine stimulation. Silencing PPM1H gene can induce EMT in BxPC-3 cells, and promote the invasion and metastasis of BxPC-3 cells. Moreover, silencing PPM1H gene can promote the proliferation and inhibit apoptosis of BxPC-3 cells. PPM1H may be a new tumor-suppressor factor for pancreatic cancer and provides new insight into molecular targets for gene therapy of pancreatic cancer.

Bustos-Carpinteyro AR, Delgado-Figueroa N, Santiago-Luna E, et al.
Association between the CDH1-472delA and -160C>A polymorphisms and diffuse and intestinal gastric cancer in a Mexican population.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
Gastric cancer (GC), the third leading cause of cancer-related deaths in Mexico and worldwide, can be classified into diffuse (DGC) or intestinal (IGC) types based on its histological characteristics. DGC is characterized by reduced expression of the cell adhesion protein E-cadherin, which is encoded by CDH1. The -472delA (rs5030625) and -160C>A (rs16260) polymorphisms in CDH1 induce a decrease in gene transcription; in fact, these mutated alleles have been associated with GC in some populations, with conflicting results. The aim of this study was to determine the association between the CDH1 -472delA and -160C>A polymorphisms and DGC and IGC in Mexican patients. The study was conducted in 24, 23, 48, and 93 individuals with DGC and IGC, without GC (control), and belonging to the general Mexican population (GMP), respectively. The genotypes were obtained by polymerase chain reaction - restriction fragment length polymorphism and the obtained data analyzed using Arlequin 3.1. The frequencies of the mutated allele (A) of -472delA were 0.326, 0.318, 0.284, and 0.296 in the DGC, IGC, control, and GMP groups, respectively, and those of the -160C>A polymorphism were 0.174, 0.318, 0.313, and 0.280, respectively. The genotype and allele frequencies of the two polymorphisms did not differ significantly (P > 0.05) among DGC, IGC, and control subjects. Therefore, we concluded that the CDH1 -472delA and -160C>A polymorphisms are not associated with DGC or IGC in patients from western Mexico.

Feng ZM, Guo SM
Tim-3 facilitates osteosarcoma proliferation and metastasis through the NF-κB pathway and epithelial-mesenchymal transition.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
The aim of this study was to investigate the expression of T-cell immunoglobulin mucin domain molecule-3 (Tim-3) in osteosarcoma tissues, and analyze its effect on cell proliferation and metastasis in an osteosarcoma cell line. Tim-3 mRNA and protein expression in osteosarcoma tissue was detected by reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. Additionally, the cell viability, apoptosis rate, and invasive ability of the osteosarcoma cell line MG-63 were tested using the methyl thiazolyl tetrazolium assay, Annexin V-propidium iodide flow cytometry, and a Transwell assay, respectively, following Tim-3 interference using small interfering RNA (siRNA). We also analyzed the expression of Snail, E-cadherin, vimentin, and nuclear factor (NF)-kB in the cells by western blot. We observed that Tim-3 mRNA and protein was significantly overexpressed in osteosarcoma tissues, compared to the adjacent normal tissue (P < 0.01). Moreover, MG-63 cells transfected with the Tim-3 siRNA presented lower cell viability, a greater number of apoptotic cells, and decreased invasive ability (P < 0.01), compared to control cells. Additionally, we observed a decrease in Snail and vimentin expression, an increase in the E-cadherin level, and an increase in NF-kB p65 phosphorylation (P < 0.01) in Tim-3 siRNA-transfected MG-63 cells. Based on these results, we concluded that Tim-3 is highly expressed in osteosarcoma tissue. Moreover, we speculated that interfering in Tim-3 expression could significantly suppress osteosarcoma cell (MG-63) proliferation and metastasis via the NF-kB/Snail signaling pathway and epithelial-mesenchymal transition.

Li A, Zhang W, Xia H, et al.
Overexpression of CASS4 promotes invasion in non-small cell lung cancer by activating the AKT signaling pathway and inhibiting E-cadherin expression.
Tumour Biol. 2016; 37(11):15157-15164 [PubMed] Related Publications
The role of Crk-associated substrate (CAS) family members in regulating invasion and metastasis has been described in several cancers. As the fourth member of the CAS family, CASS4 is also related with positive lymph node metastasis and poor prognosis in lung cancer. However, the underlying mechanisms and downstream effectors of CASS4 in the development and progression of non-small cell lung cancer (NSCLC) remain unclear. In this study, CASS4 overexpression inhibited E-cadherin expression and enhanced invasion in NSCLC cell line transfected with CASS4 plasmid, while CASS4 depletion upregulated E-cadherin expression and inhibited invasion in NSCLC cell line transfected with CASS4 siRNA. The effect of CASS4 overexpression in facilitating invasion of NSCLC cells was reversed by restoring E-cadherin expression, which indicates that CASS4 may promote invasion by inhibiting E-cadherin expression. Subsequent immunohistochemistry results confirmed that CASS4 overexpression correlated with loss of E-cadherin expression. We next investigated the phosphorylation levels of focal adhesion kinase (FAK), p38, extracellular signal-related kinase (ERK), and AKT after CASS4 plasmid or CASS4 siRNA transfection. CASS4 facilitated AKT (Ser473) phosphorylation. Treatment with an AKT phosphorylation inhibitor reversed the increased invasive capacity and downregulation of E-cadherin protein induced by CASS4 overexpression. Taken together, the present results indicate that CASS4 may promote NSCLC invasion by activating the AKT signaling pathway, thereby inhibiting E-cadherin expression.

Pećina-Šlaus N, Kafka A, Vladušić T, et al.
AXIN1 Expression and Localization in Meningiomas and Association to Changes of APC and E-cadherin.
Anticancer Res. 2016; 36(9):4583-94 [PubMed] Related Publications
BACKGROUND/AIM: Tumor suppressor gene AXIN1 is an inhibitor of Wnt signaling pathway. It down-regulates the pathway's main signaling effector molecule, beta-catenin, in an AXIN-based destruction complex. In the present study we investigated the involvement of AXIN1 in intracranial meningioma.
MATERIALS AND METHODS: Loss of heterozygosity and microsatellite instability analyses were performed. The consequences of genetic changes on protein expression levels were studied in the same patients by immunohistochemistry.
RESULTS: Allelic deletions of AXIN1 gene were found in 21.1% of meningiomas. Microsatellite instability was also observed in 5.3% of cases. Weak or lack of AXIN1 expression was found in 21.9% of meningiomas. We found strong statistical correlations between cytoplasmic localization of AXIN1 and its weak expression and also between the simultaneous cytoplasmic and nuclear localizations and moderate and strong expression levels (p<0.000). The findings on AXIN1 were compared to concomitant expression of APC, beta-catenin and E-cadherin in the same patients by Chi-Square tests and Pearson's correlations. Analysis revealed that AXIN1 genetic changes were significantly associated to lack of the expression of APC and presence of mutant APC proteins (p<0.018). Moderate and strong cytoplasmic and nuclear AXIN1 expressions were positively correlated to strong expression of E-cadherin (p<0.05).
CONCLUSION: Our findings on genetic changes and expression levels of AXIN1 bring novel data on its involvement in meningeal brain tumors and reveal AXIN1's relation to specific Wnt molecules.

Machackova T, Mlcochova H, Stanik M, et al.
MiR-429 is linked to metastasis and poor prognosis in renal cell carcinoma by affecting epithelial-mesenchymal transition.
Tumour Biol. 2016; 37(11):14653-14658 [PubMed] Related Publications
MicroRNAs (miRNAs) have been proven to be important oncogenes and tumor suppressors in wide range of cancers, including renal cell carcinoma (RCC). In our study, we evaluated miRNA-429 as potential diagnostic/prognostic biomarker in 172 clear cell RCC patients and as a potential regulator of epithelial-mesenchymal transition (EMT) in vitro. We demonstrated that miR-429 is down-regulated in tumor tissue samples (P < 0.0001) and is significantly associated with cancer metastasis (P < 0.0001), shorter disease-free (P = 0.0105), and overall survival (P = 0.0020). In addition, ectopic expression of miR-429 in 786-0 RCC cells followed by TGF-β treatment led to increase in the levels of E-cadherin expression (P < 0.0001) and suppression of cellular migration (P < 0.0001) in comparison to TGF-β-treated controls. Taken together, our findings suggest that miR-429 may serve as promising diagnostic and prognostic biomarker in RCC patients. We further suggest that miR-429 has a capacity to inhibit loss of E-cadherin in RCC cells undergoing EMT and consequently attenuate their motility.

Zhang Z, Bu X, Chen H, et al.
Bmi-1 promotes the invasion and migration of colon cancer stem cells through the downregulation of E-cadherin.
Int J Mol Med. 2016; 38(4):1199-207 [PubMed] Free Access to Full Article Related Publications
Metastasis and recurrence are the challenges of cancer therapy. Recently, mounting evidence has suggested that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) are critical factors in tumor metastasis and recurrence. The oncogene, Bmi-1, promotes the development of hematologic malignancies and many solid tumors. The aim of the present study was to elucidate the mechanisms through which Bmi-1 promotes the invasion and migration of colon CSCs (CCSCs) using the HCT116 colon cancer cell line. Sphere formation medium and magnetic‑activated cell sorting were used to enrich and screen the CCSCs. CD133 and CD44 were regarded as markers of CCSCs and they were found to be co-expressed in the HCT116 colon cancer cell line. Colony formation assay, cell proliferation assay and viability assay using the Cell Counting Kit-8, and transplantation assay using nude mice injected with CCSCs were used to examine the CCSCs. The CD133+CD44+ HCT116 cells exhibited greater cloning efficiency, an enhanced proliferative ability, increased cell viability and stronger tumorigenicity; these cells were used as the CCSCs for subsequent experiments. In addition, the invasive and migratory abilities of the CD133+CD44+ HCT116 cells were markedly decreased when Bmi-1 was silenced by small interfering RNA (siRNA). The results of RT-qPCR and western blot analysis suggested that Bmi-1 had a negative effect on E-cadherin expression. On the whole, our findings suggest that Bmi-1 promotes the invasion and migration of CCSCs through the downregulation of E-cadherin, possibly by inducing EMT. Our findings thus indicate that Bmi-1 may be a novel therapeutic target for the treatment of colon cancer.

Kondratyeva LG, Sveshnikova AA, Grankina EV, et al.
Downregulation of expression of mater genes SOX9, FOXA2, and GATA4 in pancreatic cancer cells stimulated with TGFβ1 epithelial-mesenchymal transition.
Dokl Biochem Biophys. 2016; 469(1):257-9 [PubMed] Related Publications
We show characteristic morphological changes corresponding to epithelial-mesenchymal transition (EMT) program fulfillment in PANC1 cell line stimulated with TGFβ1. Our results support downregulation of E-cadherin protein. We show 5- and 28-fold increase in SNAI1 and SNAI2 expression levels and 25- and 15-fold decrease in CDH1 and KRT8 expression levels, respectively, which confirms the EMT-program fulfillment. We demonstrate downregulation of expression of pancreatic master genes SOX9, FOXA2, and GATA4 (2-, 5-, and 4-fold, respectively) and absence of significant changes in HES1, NR5A2, and GATA6 expression levels in the cells stimulated with TGFβ1. Our results indicate the absence of induction of expression of PTF1A, PDX1, HNF1b, NEUROG3, RPBJL, NKX6.1, and ONECUT1 genes, which are inactive in PANC1 cell line after the EMT stimulated by TGFβ1.

van der Post RS, Gullo I, Oliveira C, et al.
Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future.
Adv Exp Med Biol. 2016; 908:371-91 [PubMed] Related Publications
Familial clustering is seen in 10 % of gastric cancer cases and approximately 1-3 % of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis. Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.Immunohistochemical profile of early and advanced HDGC is often characterized by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as "dotted" or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an "indolent" phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT > 1) display an "aggressive" phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.

Caspar A, Mostertz J, Leymann M, et al.
In Vitro Cultivation of Primary Prostate Cancer Cells Alters the Molecular Biomarker Pattern.
In Vivo. 2016 09-10; 30(5):573-9 [PubMed] Related Publications
BACKGROUND/AIM: The high variability of primary cells propagated in vitro led us to study the expression patterns of 11 most commonly accepted and widely used biomarkers specific for prostate cancer (PC) cells in primary cell models.
MATERIALS AND METHODS: Primary PC cells from five PC patients were partially subjected to RNA preparation immediately and remaining cells were propagated up to 84 days followed by RNA preparation. Subsequently, biomarker mRNA quantification was performed by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and biomarker transcript concentrations before and after cultivation of primary PC cells were compared.
RESULTS: Evaluation of androgen receptor, prostate-specific antigen, acid phosphatase, prostate-specific membrane antigen, fatty acid synthase, cytokeratin types 5/8/19, E-cadherin, epithelial cell adhesion molecule and fibroblast-specific protein 1 demonstrated temporal changes, as well as individual differences in expression, during primary PC cell propagation.
CONCLUSION: Experimental design, as well as data evaluation, may need to take under consideration the high variability of biomarker expression in primary PC cells.

Li W, Wu D, Niu Z, et al.
5-Azacytidine suppresses EC9706 cell proliferation and metastasis by upregulating the expression of SOX17 and CDH1.
Int J Mol Med. 2016; 38(4):1047-54 [PubMed] Free Access to Full Article Related Publications
5-Azacytidine is a well-known anticancer drug that is clinically used in the treatment of breast cancer, melanoma and colon cancer. It has been reported that 5-azacytidine suppresses the biological behavior of esophageal cancer cells. However, corresponding mechanisms remain unclear. In this study, using Transwell invasion and cell proliferation assays, we demonstrated that 5-azacytidine significantly inhibited the metastasis and proliferation of EC9706 cells, and upregulated the expression of cadherin 1 (CDH1) and SRY-box containing gene 17 (SOX17). Moreover, the inhibition of the metastasis of the 5-azacytidine-treated EC9706 cells was impaired following transfection with siRNA targeting CDH1 (CDH1 siRNA), and the inhibition of cell proliferation was attenuated following the downregulation of SOX17 by siRNA targeting SOX17 (SOX17 siRNA). Furthermore, 5-azacytidine remarkably reduced the CDH1 and SOX17 promoter methylation levels, suggesting that 5-azacytidine upregulates the expression of SOX17 and CDH1 by inhibiting the methylation of the SOX17 and CDH1 promoter. The findings of our study confirm that 5-azacytidine suppresses the proliferation and metastasis of EC9706 esophageal cancer cells by upregulating the expression of CDH1 and SOX17. The expression levels of CDH1 and SOX17 negatively correlate with the promoter methylation levels. CDH1 and SOX17 are potential indicators of the clinical application of 5-azacytidine.

Isaeva AV, Zima AP, Saprina TV, et al.
Comparative Evaluation of β-Catenin and E-Cadherin Expression in Liquid Aspiration Biopsy Specimens of Thyroid Nodules.
Bull Exp Biol Med. 2016; 161(2):288-91 [PubMed] Related Publications
We compared the results of gene molecular and immunocytochemical studies of β-catenin and E-cadherin in different variants of nodular thyroid disease (nodular colloid goiter, follicular thyroid adenocarcinoma, papillary thyroid cancer) and revealed changes of the function of the E-cadherin/β-catenin complex leading to switching from adhesion function of β-catenin in nodular colloid goiter to predominantly transcriptional activity in papillary carcinoma. The results confirm the important role of disturbances in E-cadherin-β-catenin interactions in the mechanisms of malignant transformation of follicular epithelium.

Rashid H, Alam K, Afroze D, et al.
Hypermethylation Status of E-Cadherin Gene in Gastric Cancer Patients in a High Incidence Area.
Asian Pac J Cancer Prev. 2016; 17(6):2757-60 [PubMed] Related Publications
Gastric cancer (GC) is the fourth most prevalant cancer and the second leading cause of cancer-related mortality worldwide. As in other cancers gastric carcinogenesis is multifactorial involving environmental, genetic and epigenetic components. Epigenetic silencing due to hypermethylation of tumour suppressor genes is one of the key events in gastric carcinogenesis. This study was aimed to analyse the hypermethylation status of the E-Cadherin (CDH1) gene promoter in GCs in the ethnic Kashmiri population. In this study a total of 80 GC patients were recruited. Hypermethylation in tumour tissue was detected by methylation specific PCR (MS-PCR). Hypermethylation of CDH1 promoter was observed in 52 (65%) of gastric carcinoma cases which was significantly much higher than adjacent normal tissue [p≤0.0001]. Further the frequency of CDH1 promoter methylation was significantly different with intestinal and diffuse types of gastric cancer [55.7% vs 82.1%; <0.05]. Moreover females and cases with lymph node invasion had higher frequencies of CDH1 hypermethylation [P≤0.05]. Thus the current data indicate a vital role of epigenetic alteration of CDH1 in the causation and development of gastric cancer, particularly of diffuse type, in our population.

Wang Y, Lin G
TP53INP1 3'-UTR functions as a ceRNA in repressing the metastasis of glioma cells by regulating miRNA activity.
Biotechnol Lett. 2016; 38(10):1699-707 [PubMed] Related Publications
OBJECTIVES: To explore the effects of the competitive endogenous RNA (ceRNA) network between TP53INP1 and E-cadherin on the invasion and migration of glioma.
RESULTS: TP53INP1 and E-cadherin mRNA and protein were significantly overexpressed in normal brain tissues compared with glioma tissue specimens and correlated with the grades of glioma negatively. The expression of TP53INP1 and E-cadherin were correlated positively. Patients with higher TP53INP1 or E-cadherin expression had longer overall survival. Moreover, TP53INP1 3'-UTR inhibited glioma cell proliferation, invasion and proliferation; Furthermore, the 3'-UTRs of TP53INP1 and E-cadherin harboured seven identical miRNAs binding sites, and TP53INP1 3'-UTR could increase the expression of E-cadherin and decrease the expression of vimentin thus repressing the epithelial-mesenchymal transition (EMT). However, the coding sequence of TP53INP1 could not increase the expression of E-cadherin and the inhibitory effect on EMT of TP53INP1 3'-UTR was reversed by the siRNA against Dicer.
CONCLUSIONS: TP53INP1 3'-UTR could inhibit the EMT, thus hindering the migration and invasion of glioma via acting as a ceRNA for E-cadherin.

Zhang TJ, Zhou JD, Ma JC, et al.
CDH1 (E-cadherin) expression independently affects clinical outcome in acute myeloid leukemia with normal cytogenetics.
Clin Chem Lab Med. 2017; 55(1):123-131 [PubMed] Related Publications
BACKGROUND: Epithelial-mesenchymal transition (EMT) is a critical process which involves in tumor metastasis. As an important EMT marker gene, CDH1 (E-cadherin) expression and its clinical implication in acute myeloid leukemia (AML) remain largely elusive.
METHODS: Real-time quantitative PCR (RQ-PCR) was carried out to examine CDH1 transcript level in 123 de novo AML patients and 34 controls.
RESULTS: Compared with controls, CDH1 was significantly downregulated in AML (p<0.001). The median level of CDH1 expression divided total AML patients into CDH1 low-expressed (CDH11ow) and CDH1 high-expressed (CDH1high) groups. There were no significant differences between the two groups in age, peripheral blood cell counts, complete remission (CR) rate, and the distribution of FAB/WHO subtypes as well as karyotypes/karyotypic classifications (p>0.05). However, CDH11ow group tended to have a higher bone marrow (BM) blasts (p=0.093). The spearman correlation analysis further illustrated a trend towards a negative correlation between CDH1 expression level and BM blasts (r=-0.214, p=0.052). CDH1low group had a tendency towards a lower frequency of N/K-RAS mutations (p=0.094). Furthermore, CDH1low patients had markedly shorter overall survival (OS) time in cytogenetic normal AML (CN-AML) (p=0.019). Both univariate and multivariate analyses confirmed the prognostic value of CDH1 expression in CN-AML patients (p=0.027 and 0.033, respectively).
CONCLUSIONS: CDH1 downregulation acted as an independent prognostic biomarker in CN-AML patients.

Sahami-Fard MH, Yazd EF, Khazaei Z, Neamatzadeh H
Lack of Association between the CDH1 -160C>A Polymorphism and Risk of Gastrointestinal Cancer - a Meta-Analysis.
Asian Pac J Cancer Prev. 2016; 17(5):2415-21 [PubMed] Related Publications
E-cadherin (CDH1) genetic variations alter gene transcriptional activity of epithelial cells in vitro and may cause susceptibility to various cancers. Associations of CDH1 -160C>A polymorphism with various cancers have been widely reported. However, the results are controversial and inconsistent. To derive a more accurate estimation of the relationship, a meta-analysis was performed with regard to gastrointestinal (GI) cancer risk. Eligible studies were identified through a search of PubMed database until December 2015. Associations between the CDH1 -160C>A polymorphism and GI cancer risk was considered by odds ratios (ORs) together with their 95% confidence intervals (CIs). A total of 31 studies including 11,606 cases and 12,655 controls were involved in this meta-analysis. Overall, this meta-analysis showed no association between CDH1 -160C>A polymorphism and GI cancer risk (A vs. C: OR = 1.08, 95%CI = 0.98-1.18, P = 0.086;CA vs. CC: OR = 1.09, 95%CI = 0.97- 1.22, P = 0.118; AA vs. CC: OR = 1.10, 95%CI = 0.89-1.35, P = 0.356; AA vs. CC + CA: OR = 1.06, 95%CI = 0.96-1.18, P = 0.207; CA+AA vs. CC: OR = 1.01, 95%CI = 0.84-1.22, P = 0.89). In subgroup analysis, similar results were found. In conclusion, this meta-analysis has demonstrated that there is a lack of association of the CDH1-160C>A polymorphism with GI cancer susceptibility.

Sugimoto M, Kohashi K, Itsumi M, et al.
Epithelial to Mesenchymal Transition in Clear Cell Renal Cell Carcinoma with Rhabdoid Features.
Pathobiology. 2016; 83(6):277-86 [PubMed] Related Publications
AIMS: The aims of this study were to investigate the association of renal cell carcinoma (RCC) displaying rhabdoid features and morphologically mesenchymal characteristics with epithelial to mesenchymal transition (EMT), and to clarify the expression of EMT markers.
METHODS: We investigated the expression of EMT markers (E-cadherin, vimentin, Snail, Slug, ZEB1, ZEB2 and Twist1) using immunohistochemistry, Western blotting and real-time polymerase chain reaction in 18 cases of clear cell RCC (ccRCC) with rhabdoid features and 74 ccRCC cases with Fuhrman grade 1-3 (G1 to G3).
RESULTS: In ccRCCs with rhabdoid features, low E-cadherin and high vimentin expression were found. In G1 to G3 ccRCCs, low E-cadherin expression and high expression of vimentin, ZEB1 and ZEB2 were found. There was no significant difference in the immunoexpression of E-cadherin and vimentin between the two ccRCC groups.
CONCLUSIONS: The rhabdoid features may histologically and biologically be associated with EMT in ccRCC. There is a possibility that in G1 to G3 ccRCCs showing epithelial structures, other cell-cell adhesion mechanisms apart from E-cadherin adhesion may continue to work, and that ccRCC with rhabdoid features may be caused by an inactivation or loss of these mechanisms.

Lin SH, Wang BY, Lin CH, et al.
Chidamide alleviates TGF-β-induced epithelial-mesenchymal transition in lung cancer cell lines.
Mol Biol Rep. 2016; 43(7):687-95 [PubMed] Related Publications
Transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition is a critical process in the initiation of metastasis of various types of cancer. Chidamide is a class I histone deacetylase inhibitor with anti-tumor activity. This study investigated the effects of chidamide on TGF-β-mediated suppression of E-cadherin expression in adenocarcinomic lung epithelial cells and the molecular mechanisms involved in these effects. Western blot analysis, confocal microscopy, Quantitative methyl-specific PCR and bisulfite sequencing were used to evaluate the effects of different treatments on chidamide ameliorating TGF-β induced-E-cadherin loss. H3 acetylation binding to the promoter of E-cadherin was detected by chromatin immunoprecipitations (CHIP). We found that chidamide reduced the level of lung cancer cell migration observed using a Boyden chamber assay (as an indicator of metastatic potential). Chidamide inhibited TGF-β-induced SMAD2 phosphorylation and attenuated TGF-β-induced loss of E-cadherin expression in lung cancer cells by Western blotting and confocal microscopy, respectively. Quantitative methyl-specific PCR and bisulfite sequencing revealed that TGF-β-enhanced E-cadherin promoter methylation was ameliorated in cells treated with chidamide. We demonstrated that histone H3 deacetylation within the E-cadherin promoter was required for TGF-β-induced E-cadherin loss; cell treatment with chidamide increased the H3 acetylation detected by CHIP. Taken together, our results demonstrate that TGF-β suppressed E-cadherin expression by regulating promoter methylation and histone H3 acetylation. Chidamide significantly enhanced E-cadherin expression in TGF-β-treated cells and inhibited lung cancer cell migration. These findings indicate that chidamide has a potential therapeutic use due to its capacity to prevent cancer cell metastasis.

Gu JJ, Zhang JH, Chen HJ, Wang SS
MicroRNA-130b promotes cell proliferation and invasion by inhibiting peroxisome proliferator-activated receptor-γ in human glioma cells.
Int J Mol Med. 2016; 37(6):1587-93 [PubMed] Free Access to Full Article Related Publications
MicroRNA-130b (miR-130b) is a novel tumor-related miRNA that has been found to be involved in several biological processes. However, there is limited evidence regarding the role of miR-130b in the tumorigenesis of human gliomas. In the present study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays were used to quantify miR-130b expression levels in human glioma tissues and glioma cell lines (U251, U87, SNB19 and LN229). The expression level of miR-130b was found to be markedly higher in human glioma tissues than in non‑neoplastic brain specimens. Specifically, higher expression levels of miR‑130b were observed in the glioma cell lines, compared with those in normal human astrocytes (NHA). We also confirmed that miR‑130b interacted with the 3'-untranslated region of peroxisome proliferator‑activated receptor-γ (PPAR‑γ), which negatively affected the protein levels of E-cadherin. Furthermore, its effects on cell proliferation and invasion were examined using CCK8, colony formation, cell cycle and Transwell assays. We found that the upregulation of miR-130b induced cell proliferation, decreased the percentage of cells in the G0/G1 phase and enhanced the invasiveness of U251 glioma cells whereas the downregulation of miR-130b exerted opposing effects. Moreover, it was demonstrated that the downregulation of miR‑130b in U251 glioma cells restored the expression of PPAR-γ and E-cadherin, and inhibited the expression of β-catenin. Notably, PPAR-γ knockdown abolished the inhibitory effect of miR-130b inhibitor on the proliferation and invasivness of U251 cells. Taken together, these findings suggest that miR‑130b promotes the proliferation and invasion of U251 glioma cells by inhibiting PPAR-γ.

Xu CY, Qin MB, Tan L, et al.
NIBP impacts on the expression of E-cadherin, CD44 and vimentin in colon cancer via the NF-κB pathway.
Mol Med Rep. 2016; 13(6):5379-85 [PubMed] Related Publications
NIBP, a novel nuclear factor-κB (NF-κB)-inducing kinase (NIK) and IκB kinase β (IKKβ) binding protein, directly interacts with NIK and IKKβ, and acts as the 'bridge' of the NF‑κB classical and alternative signaling pathways. However, its influence on epithelial‑mesenchymal transition markers in colon cancer remains to be fully elucidated. The aim of the present study was to investigate the roles of NIBP impacting on the expression of E‑cadherin, CD44 and vimentin. In the present study, the associations between NIBP and E‑cadherin, CD44 and vimentin in clinical samples were analyzed by making pairwise comparisons between normal colon tissue, non‑metastatic colon cancer tissue and metastatic colon cancer tissue. In in vitro experiments, after changing the expression of NIBP in cells, the protein expression levels of CD44, vimentin, E‑cadherin were analyzed by western blot analysis. The results revealed that the protein expression levels of NIBP, CD44 and vimentin were markedly increased, and E‑cadherin was markedly decreased, in metastatic colon cancer tissue compared with normal colon tissue and non‑metastatic colon cancer tissue. Upregulation of NIBP expression decreased the levels of E‑cadherin, whereas the downregulation of NIBP increased E‑cadherin levels, while no significant differences were observed in the levels of CD44 and vimentin. In addition, cells that were treated with the NF‑κB inhibitor, pyrrolidine dithiocarbamate (PDTC), also tended to exhibit increased levels of CD44 and vimentin expression in the NIBP upregulated expression group (29‑NIBP group) compared with the mock group, whereas the expression levels of E‑cadherin, CD44 and vimentin were similar in the NIBP downregulated expression group (116‑NIBPmir group) and the HCT116 blank control group (116‑mock group) on treatment of the cells with tumor necrosis factor‑α. These findings indicated that NIBP, E‑cadherin, CD44 and vimentin are possibly associated with metastasis in colon cancer. When the NF‑κB pathway is not subjected to any interventions, NIBP may predominantly regulate the NF‑κB classical pathway, rather than the alternative pathway. When the classical pathway was completely inhibited, NIBP was able to activate the NF‑κB alternative pathway. NIBP is therefore necessary for the interaction between the NF‑κB classical and alternative pathways. In conclusion, NIBP impacts on the expression levels of E‑cadherin, CD44 and vimentin via the NF‑κB classical and alternative pathways. Therapeutic regimens for patients with colorectal cancer may comprise NIBP inhibitors in the future.

Kim CW, Go RE, Lee HM, et al.
Cigarette smoke extracts induced the colon cancer migration via regulating epithelial mesenchymal transition and metastatic genes in human colon cancer cells.
Environ Toxicol. 2017; 32(2):690-704 [PubMed] Related Publications
There was considerable evidence that exposure to cigarette smoke is associated with an increased risk for colon cancer. Nevertheless, the mechanism underlying the relationship between cigarette smoking and colon cancer remains unclear. Moreover, there were only a few studies on effects of complexing substance contained in cigarette smoke on colon cancer. Thus, we further investigated whether cigarette smoke extract (CSE) affects the cell cycle, apoptosis and migration of human metastatic colon cancer cells, SW-620. MTT assay revealed that SW-620 cell proliferation was significantly inhibited following treatments with all CSEs, 3R4F, and two-domestic cigarettes, for 9 days in a concentration-dependent manner. Moreover, CSE treatments decreased cyclin D1 and E1, and increased p21 and p27 proteins by Western blot analysis in SW-620 cells. Additionally, the treatment of the cells with CSE contributed to these effects expressing by apoptosis-related proteins. An increased migration or invasion ability of SW-620 cells following CSE treatment was also confirmed by a scratch or fibronectin invasion assay in vitro. In addition, the protein levels of E-cadherin as an epithelial maker were down-regulated, while the mesenchymal markers, N-cadherin, snail, and slug, were up-regulated in a time-dependent manner. A metastatic marker, cathepsin D, was also down-regulated by CSE treatment. Taken together, these results indicate that CSE exposure in colon cancer cells may deregulate the cell growth by altering the expression of cell cycle-related proteins and pro-apoptotic protein, and stimulate cell metastatic ability by altering epithelial-mesenchymal transition (EMT) markers and cathepsin D expression. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 690-704, 2017.

Norton N, Advani PP, Serie DJ, et al.
Assessment of Tumor Heterogeneity, as Evidenced by Gene Expression Profiles, Pathway Activation, and Gene Copy Number, in Patients with Multifocal Invasive Lobular Breast Tumors.
PLoS One. 2016; 11(4):e0153411 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Invasive lobular carcinoma (ILC) comprises approximately ~10-20% of breast cancers. In general, multifocal/multicentric (MF/MC) breast cancer has been associated with an increased rate of regional lymph node metastases. Tumor heterogeneity between foci represents a largely unstudied source of genomic variation in those rare patients with MF/MC ILC.
METHODS: We characterized gene expression and copy number in 2 or more foci from 11 patients with MF/MC ILC (all ER+, HER2-) and adjacent normal tissue. RNA and DNA were extracted from 3x1.5 mm cores from all foci. Gene expression (730 genes) and copy number (80 genes) were measured using Nanostring PanCancer and Cancer CNV panels. Linear mixed models were employed to compare expression in tumor versus normal samples from the same patient, and to assess heterogeneity (variability) in expression among multiple ILC within an individual.
RESULTS: 35 and 34 genes were upregulated (FC>2) and down-regulated (FC<0.5) respectively in ILC tumor relative to adjacent normal tissue, q<0.05. 9/34 down-regulated genes (FIGF, RELN, PROM1, SFRP1, MMP7, NTRK2, LAMB3, SPRY2, KIT) had changes larger than CDH1, a hallmark of ILC. Copy number changes in these patients were relatively few but consistent across foci within each patient. Amplification of three genes (CCND1, FADD, ORAOV1) at 11q13.3 was present in 2/11 patients in both foci. We observed significant evidence of within-patient between-foci variability (heterogeneity) in gene expression for 466 genes (p<0.05 with FDR 8%), including CDH1, FIGF, RELN, SFRP1, MMP7, NTRK2, LAMB3, SPRY2 and KIT.
CONCLUSIONS: There was substantial variation in gene expression between ILC foci within patients, including known markers of ILC, suggesting an additional level of complexity that should be addressed.

Zhou J, Jain S, Azad AK, et al.
Notch and TGFβ form a positive regulatory loop and regulate EMT in epithelial ovarian cancer cells.
Cell Signal. 2016; 28(8):838-49 [PubMed] Related Publications
Epithelial-mesenchymal transition (EMT) plays a critical role in the progression of epithelial ovarian cancer (EOC). However, the mechanisms that regulate EMT in EOC are not fully understood. Here, we report that activation of Notch1 induces EMT in EOC cells as evidenced by downregulation of E-cadherin and cytokeratins, upregulation of Slug and Snail, as well as morphological changes. Interestingly, activation of Notch1 increases TGFβ/Smad signaling by upregulating the expression of TGFβ and TGFβ type 1 receptor. Time course experiments demonstrate that inhibition of Notch by DAPT (a γ-secretase inhibitor) decreases TGFβ-induced phosphorylation of receptor Smads at late, but not at early, timepoints. These results suggest that Notch activation plays a role in sustaining TGFβ/Smad signaling in EOC cells. Furthermore, inhibition of Notch by DAPT decreases TGFβ induction of Slug and repression of E-cadherin and knockdown of Notch1 decreases TGFβ-induced repression of E-cadherin, indicating that Notch is required, at least in part, for TGFβ-induced EMT in EOC cells. On the other hand, TGFβ treatment increases the expression of Notch ligand Jagged1 and Notch target gene HES1 in EOC cells. Functionally, the combination of Notch1 activation and TGFβ treatment is more potent in promoting motility and migration of EOC cells than either stimulation alone. Taken together, our results indicate that Notch and TGFβ form a reciprocal positive regulatory loop and cooperatively regulate EMT and promote EOC cell motility and migration.

Monahan KJ, Hopkins L
Diagnosis and Management of Hereditary Gastric Cancer.
Recent Results Cancer Res. 2016; 205:45-60 [PubMed] Related Publications
A positive family history is consistently reported as a risk factor for gastric cancer (GC), but the molecular basis for the familial aggregation is largely unknown. The risk associated with having one first-degree relative (FDR) with GC is approximately 1.3-3.5 fold increased. Hereditary cancer syndromes have been relatively well characterised, but their rarity largely precludes the development of trials of surveillance. In hereditary diffuse gastric cancer (HDGC), patients have a CDH1 mutation that results in a high penetrance of GC meaning that prophylactic gastrectomy is recommended, although this treatment results in significant psychosocial issues. The management of HDGC patients includes endoscopic surveillance, surgery and histological interpretation which require a high degree of selective expertise. Much of the remaining heritable risk of GC may be accounted for by low- and intermediate-penetrant genetic factors, i.e. common and rare variants, respectively. The advent of new methods such as next-generation sequencing has revealed a number of new candidate gene loci.

Wang Q, Wang B, Zhang YM, Wang W
The association between CDH1 promoter methylation and patients with ovarian cancer: a systematic meta-analysis.
J Ovarian Res. 2016; 9:23 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The down-regulation of E-cadherin gene (CDH1) expression has been regarded as an important event in cancer invasion and metastasis. However, the association between CDH1 promoter methylation and ovarian cancer remains unclear. A meta-analysis was conducted to evaluate the potential role of CDH1 promoter methylation in ovarian cancer.
METHODS: Relevant articles were identified by searches of PubMed, EMBASE, Cochrane Library, CNKI and Wanfang databases. The pooled odds ratio (OR) and corresponding 95 % confidence interval (CI) were calculated to assess the strength of association.
RESULTS: Nine studies were performed using the fixed-effects model in this study, including 485 cancer tissues and 255 nonmalignant tissues. The findings showed that CDH1 promoter methylation had an increased risk of ovarian cancer in cancer tissues (OR = 8.71, P < 0.001) in comparison with nonmalignant tissues. Subgroup analysis of the ethnicity showed that the OR value of CDH1 methylation in Asian population subgroup (OR = 13.20, P < 0.001) was higher than that in Caucasian population subgroup (OR = 3.84, P = 0.005). No significant association was found between ovarian cancer and low malignant potential (LMP) tumor (P = 0.096) among 2 studies, and between CDH1 promoter methylation and tumor stage and tumor histology (all P > 0.05). There was not any evidence of publication bias by Egger's test (all P > 0.05).
CONCLUSIONS: CDH1 promoter methylation can be a potential biomarker in ovarian cancer risk prediction, especially Asians can be more susceptible to CDH1 methylation. However, more studies are still done in the future.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. CDH1, Cancer Genetics Web: http://www.cancer-genetics.org/CDH1.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 11 March, 2017     Cancer Genetics Web, Established 1999