Gene Summary

Gene:CDH11; cadherin 11
Aliases: OB, ESWS, CAD11, CDHOB, OSF-4
Summary:This gene encodes a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Mature cadherin proteins are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. Expression of this particular cadherin in osteoblastic cell lines, and its upregulation during differentiation, suggests a specific function in bone development and maintenance. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (11)

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.

  • CpG Islands
  • RT-PCR
  • Adolescents
  • Liver Cancer
  • High-Throughput Nucleotide Sequencing
  • FISH
  • Translocation
  • Tissue Array Analysis
  • Retinoblastoma
  • Chromosome 16
  • Childhood Cancer
  • Down-Regulation
  • Mutation
  • Oncogene Proteins
  • Cell Proliferation
  • Breast Cancer
  • MicroRNAs
  • Adenocarcinoma
  • Retinoblastoma-Like Protein p130
  • Tumor Suppressor Proteins
  • DNA Methylation
  • Gene Expression Profiling
  • Cell Movement
  • Proto-Oncogene Proteins
  • Gene Dosage
  • Cancer Gene Expression Regulation
  • Staging
  • Stomach Cancer
  • Biomarkers, Tumor
  • Neoplasm Invasiveness
  • Gene Fusion
  • Bone Cysts, Aneurysmal
  • Promoter Regions
  • Ubiquitin Thiolesterase
  • Messenger RNA
  • Epigenetics
  • Genomics
  • Neoplasm Metastasis
  • Cadherins
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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: CDH11 (cancer-related)

Zhang JX, He WL, Feng ZH, et al.
A positive feedback loop consisting of C12orf59/NF-κB/CDH11 promotes gastric cancer invasion and metastasis.
J Exp Clin Cancer Res. 2019; 38(1):164 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastasis remains the main cause of cancer-related death for gastric cancer (GC) patients, but the mechanisms are poorly understood. Using The Cancer Genome Atlas (TCGA) data base and bioinformatics analyses, we identified C12orf59 might act as a potential oncogenic protein in GC.
METHODS: We investigate the expression pattern and clinical significance of C12orf59 in two independent cohorts of GC samples. In the training cohort, we used the X-tile program software to generate the optimal cutoff value for C12orf59 expression in order to classify patients accurately according to clinical outcome. In the validation cohort, this derived cutoff score was applied to exam the association of C12orf59 expression with survival outcome. A series of in vivo and in vitro assays were then performed to investigate the function of C12orf59 in GC.
RESULTS: C12orf59 was significantly upregulated, and associated with poor survival outcome in two cohorts of GC samples. Gain- and loss of- function studies demonstrated C12orf59 promotes GC cell invasive and metastatic capacity both in vitro and in vivo, and induces epithelial-mesenchymal transition and angiogenesis. Mechanically, C12orf59 exerts oncogenic functions by up-regulating CDH11 expression via NF-κB signaling. Interesting, CDH11 could in turn promote NF-κB bind to C12orf59's promoter and form a positive feedback loop to sustain the metastatic ability of GC cells. Additionally, downregulation of miR-654-5p is another important mechanism for C12orf59 overexpression in GC.
CONCLUSION: Our finding suggested the newly identified C12orf59/NF-κB/CDH11 feedback loop may represent a new strategy for GC treatment.

Di Y, Chen D, Yu W, Yan L
Bladder cancer stage-associated hub genes revealed by WGCNA co-expression network analysis.
Hereditas. 2019; 156:7 [PubMed] Free Access to Full Article Related Publications
Background: Bladder cancer was a malignant disease in patients, our research aimed at discovering the possible biomarkers for the diseases.
Results: The gene chip GSE31684, including 93samples, was downloaded from the GEO datasets and co-expression network was constructed by the data. Molecular complex detection(MCODE) was used to identify hub genes. The most significant cluster including 16 genes:

Šekoranja D, Boštjančič E, Salapura V, et al.
Primary aneurysmal bone cyst with a novel SPARC-USP6 translocation identified by next-generation sequencing.
Cancer Genet. 2018; 228-229:12-16 [PubMed] Related Publications
Aneurysmal bone cyst (ABC) is a benign but locally aggressive, mostly pediatric neoplasm, with characteristic USP6 gene rearrangement that distinguishes it from a secondary ABC and other primary bone tumors. With the advent of next-generation sequencing (NGS) technology, several hitherto unknown USP6 fusion partners have been identified in ABC. Accordingly, we present a case of an 18-year-old male with a solid sub-periosteal primary ABC in the diaphysis of the left femur. Using an NGS-based assay, we identified SPARC-USP6 fusion, which has not previously been described in ABC. Including our case, the list of currently known USP6 fusion partners in primary ABC include: CDH11, CNBP, COL1A1, CTNNB1, EIF1, FOSL2, OMD, PAFAH1B1, RUNX2, SEC31A, SPARC, STAT3 and THRAP3.

Brooks PJ, Chadwick JW, Caminiti M, et al.
Primary aneurysmal bone cyst of the mandibular condyle with USP6-CDH11 fusion.
Pathol Res Pract. 2019; 215(3):607-610 [PubMed] Related Publications
Primary aneurysmal bone cyst (ABC) is a cystic bone neoplasm characterized by disease-defining gene fusions involving the USP6/Tre2 gene. The literature describing gnathic ABC is limited. This case report describes a 27-year-old man presenting with a long-standing left-sided facial asymmetry. Multi-detector computed tomography imaging demonstrated a large expansile lesion positioned within the left condylar head. The lesion was biopsied and resected. The specimen showed a giant cell-rich cystic neoplasm, with fibrous tissue lined by multinucleated giant cells. Next-generation sequencing confirmed the presence of a USP6-CDH11 fusion gene, consistent with classification as a primary ABC, the first reported to be translocation-positive in the head of the mandibular condyle.

Lu Y, Li C, Chen H, Zhong W
Identification of hub genes and analysis of prognostic values in pancreatic ductal adenocarcinoma by integrated bioinformatics methods.
Mol Biol Rep. 2018; 45(6):1799-1807 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the world, and more molecular mechanisms should be illuminated to meet the urgent need of developing novel detection and therapeutic strategies. We analyzed the related microarray data to find the possible hub genes and analyzed their prognostic values using bioinformatics methods. The mRNA microarray datasets GSE62452, GSE15471, GSE102238, GSE16515, and GSE62165 were finally chosen and analyzed using GEO2R. The overlapping genes were found by Venn Diagrams, functional and pathway enrichment analyses were performed using the DAVID database, and the protein-protein interaction (PPI) network was constructed by STRING and Cytoscape. OncoLnc, which was linked to TCGA survival data, was used to investigate the prognostic values. In total, 179 differentially expressed genes (DEGs) were found in PDAC, among which, 130 were up-regulated genes and 49 were down-regulated. DAVID showed that the up-regulated genes were significantly enriched in extracellular matrix and structure organization, collagen catabolic and metabolic process, while the down-regulated genes were mainly involved in proteolysis, reactive oxygen species metabolic process, homeostatic process and cellular response to starvation. From the PPI network, the 21 nodes with the highest degree were screened as hub genes. Based on Molecular Complex Detection (MCODE) plug-in, the top module was formed by ALB, TGM, PLAT, PLAU, EGF, MMP7, MMP1, LAMC2, LAMA3, LAMB3, COLA1, FAP, CDH11, COL3A1, ITGA2, and VCAN. OncoLnc survival analysis showed that, high expression of ITGA2, MMP7, ITGB4, ITGA3, VCAN and PLAU may predict poor survival results in PDAC. The present study identified hub genes and pathways in PDAC, which may be potential targets for its diagnosis, treatment, and prognostic prediction.

Nanchahal J, Ball C, Davidson D, et al.
Anti-Tumour Necrosis Factor Therapy for Dupuytren's Disease: A Randomised Dose Response Proof of Concept Phase 2a Clinical Trial.
EBioMedicine. 2018; 33:282-288 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor.
METHODS: Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with (NCT03180957) and the EudraCT (2015-001780-40).
FINDINGS: We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng/μg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ± 84 pg/μg total protein) compared with placebo (817 ± 78 pg/μg). There were two serious adverse events, both considered unrelated to the study drug.
INTERPRETATION: In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease.
FUNDING: Health Innovation Challenge Fund (Wellcome Trust and Department of Health) and 180 Therapeutics LP.

Sandoval-Bórquez A, Polakovicova I, Carrasco-Véliz N, et al.
MicroRNA-335-5p is a potential suppressor of metastasis and invasion in gastric cancer.
Clin Epigenetics. 2017; 9:114 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiple aberrant microRNA expression has been reported in gastric cancer. Among them, microRNA-335-5p (miR-335), a microRNA regulated by DNA methylation, has been reported to possess both tumor suppressor and tumor promoter activities.
RESULTS: Herein, we show that miR-335 levels are reduced in gastric cancer and significantly associate with lymph node metastasis, depth of tumor invasion, and ultimately poor patient survival in a cohort of Amerindian/Hispanic patients. In two gastric cancer cell lines AGS and, Hs 746T the exogenous miR-335 decreases migration, invasion, viability, and anchorage-independent cell growth capacities. Performing a PCR array on cells transfected with miR-335, 19 (30.6%) out of 62 genes involved in metastasis and tumor invasion showed decreased transcription levels. Network enrichment analysis narrowed these genes to nine (PLAUR, CDH11, COL4A2, CTGF, CTSK, MMP7, PDGFA, TIMP1, and TIMP2). Elevated levels of PLAUR, a validated target gene, and CDH11 were confirmed in tumors with low expression of miR-335. The 3'UTR of CDH11 was identified to be directly targeted by miR-335. Downregulation of miR-335 was also demonstrated in plasma samples from gastric cancer patients and inversely correlated with DNA methylation of promoter region (Z = 1.96,
CONCLUSIONS: Comprehensive evaluation of metastasis and invasion pathway identified a subset of associated genes and confirmed PLAUR and CDH11, both targets of miR-335, to be overexpressed in gastric cancer tissues. DNA methylation of miR-335 may be a promissory strategy for non-invasive approach to gastric cancer.

Visser E, Franken IA, Brosens LAA, et al.
Targeted next-generation sequencing of commonly mutated genes in esophageal adenocarcinoma patients with long-term survival.
Dis Esophagus. 2017; 30(9):1-8 [PubMed] Related Publications
Survival of patients with esophageal adenocarcinoma remains poor and individual differences in prognosis remain unexplained. This study investigated whether gene mutations can explain why patients with high-risk (pT3-4, pN+) esophageal adenocarcinoma survive past 5 years after esophagectomy. Six long-term survivors (LTS) (≥5 years survival without recurrence) and six short-term survivors (STS) (<2 years survival due to recurrence) who underwent resection without neoadjuvant therapy for high-risk esophageal adenocarcinoma were included. Targeted next-generation sequencing of 16 genes related to esophageal adenocarcinoma was performed. Mutations were compared between the LTS and STS and described in comparison with literature. A total of 48 mutations in 10 genes were identified. In the LTS, the median number of mutated genes per sample was 5 (range: 0-5) and the samples together harbored 22 mutations in 8 genes: APC (n = 1), CDH11 (n = 2), CDKN2A (n = 2), FAT4 (n = 5), KRAS (n = 1), PTPRD (n = 1), TLR4 (n = 8), and TP53 (n = 2). The median number of mutated genes per sample in the STS was 4 (range: 1-8) and in total 26 mutations were found in six genes: CDH11 (n = 5), FAT4 (n = 7), SMAD4 (n = 1), SMARCA4 (n = 1), TLR4 (n = 7), and TP53 (n = 5). CDH11, CDKN2A, FAT4, TLR4, and TP53 were mutated in at least 2 LTS or STS, exceeding mutation rates in literature. Mutations across the LTS and STS were found in 10 of the 16 genes. The results warrant future studies to investigate a larger range of genes in a larger sample size. This may result in a panel with prognostic genes, to predict individual prognosis and to select effective individualized therapy for patients with esophageal adenocarcinoma.

Lemma SA, Kuusisto M, Haapasaari KM, et al.
Integrin alpha 10, CD44, PTEN, cadherin-11 and lactoferrin expressions are potential biomarkers for selecting patients in need of central nervous system prophylaxis in diffuse large B-cell lymphoma.
Carcinogenesis. 2017; 38(8):812-820 [PubMed] Free Access to Full Article Related Publications
Central nervous system (CNS) relapse is a devastating complication that occurs in about 5% of diffuse large B-cell lymphoma (DLBCL) patients. Currently, there are no predictive biological markers. We wanted to study potential biomarkers of CNS tropism that play a role in adhesion, migration and/or in the regulation of inflammatory responses. The expression levels of ITGA10, CD44, PTEN, cadherin-11, CDH12, N-cadherin, P-cadherin, lactoferrin and E-cadherin were studied with IHC and IEM. GEP was performed to see whether found expressional changes are regulated at DNA/RNA level. IHC included 96 samples of primary CNS lymphoma (PCNSL), secondary CNS lymphoma (sCNSL) and systemic DLBCL (sDLBCL). IEM included two PCNSL, one sCNSL, one sDLBCL and one reactive lymph node samples. GEP was performed on two DLBCL samples, one with and one without CNS relapse. CNS disease was associated with enhanced expression of cytoplasmic and membranous ITGA10 and nuclear PTEN (P < 0.0005, P = 0.002, P = 0.024, respectively). sCNSL presented decreased membranous CD44 and nuclear and cytoplasmic cadherin-11 expressions (P = 0.001, P = 0.006, P = 0.048, respectively). In PCNSL lactoferrin expression was upregulated (P < 0.0005). IEM results were mainly supportive of the IHC results. In GEP CD44, cadherin-11, lactoferrin and E-cadherin were under-expressed in CNS disease. Our results are in line with previous studies, where gene expressions in extracellular matrix and adhesion-related pathways are altered in CNS lymphoma. This study gives new information on the DLBCL CNS tropism. If further verified, these markers might become useful in predicting CNS relapses.

Warren M, Xu D, Li X
Gene fusions PAFAH1B1-USP6 and RUNX2-USP6 in aneurysmal bone cysts identified by next generation sequencing.
Cancer Genet. 2017; 212-213:13-18 [PubMed] Related Publications
Aneurysmal bone cyst (ABC) is a locally aggressive, expansile, typically multilocular cystic bone tumor. ABC was previously thought to be a non-neoplastic lesion; however, it is now considered to be neoplasm that features recurrent chromosomal translocations resulting in gene fusions between ubiquitin specific peptidase 6 (USP6) and multiple partners, including COL1A1, CDH11, TRAP150, ZNF90 and OMD. Using next generation sequencing (NGS), we uncovered two fusion partners of USP6 in two ABCs: platelet activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1), which is known to contribute to tumorigenesis in lung cancer, and runt-related transcription factor 2 (RUNX2), which is known to regulate osteoblastic differentiation, osteosarcoma tumorigenesis and its metastasis. In our study, the PAFAH1B1-USP6 fusion consisted of the promoter of PAFAH1B1 fused to the 5'-untranslated region (5'-UTR) of USP6 and was discovered in a typical ABC. The RUNX2-USP6 fusion had the promoter and a short coding region of RUNX2 fused to the translation start codon of USP6 and was detected in an unusually aggressive ABC with an osteosarcoma-like soft tissue extension. Our findings not only expanded the repertoire of the partner genes of USP6 in ABC but also can serve as a reference for future studies to better understand the correlation between various gene fusions and the progression of ABC.

Zhu C, Feng X, Ye G, Huang T
Meta-analysis of possible role of cadherin gene methylation in evolution and prognosis of hepatocellular carcinoma with a PRISMA guideline.
Medicine (Baltimore). 2017; 96(16):e6650 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cadherins (CDHs) have been reported to be associated with cancer. However, the clinical significance of CDH gene methylation in hepatocellular carcinoma (HCC) remains unclear.
METHODS: Based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria, available studies were identified from online electronic database. The overall odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated and analyzed.
RESULTS: A total of 29 eligible studies with 2562 HCC samples and 1685 controls were included. E-cadherin (CDH1) hypermethylation was observed to be significantly higher in HCC than in benign, adjacent, or normal samples. Moreover, CDH1 hypermethylation was not associated with gender, tumor grade, clinical stage, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection in HCC patients. H-cadherin (CDH13), protocadherin-10 (PCDH10), P-cadherin (CDH3), and M-cadherin (CDH15) methylation may have an increased risk of HCC in fewer than 4 studies, and methylated cadherin 8, type 2 (CDH8) and OB-cadherin (CDH11) had a similar OR in HCC and adjacent samples. When HCC samples were compared with normal samples, the analysis of sample type revealed a significantly higher OR in normal blood samples than in normal tissues for hypermethylated CDH1 (50.82 vs 4.44).
CONCLUSION: CDH1 hypermethylation may play a key role in the carcinogenesis of HCC. However, CDH1 hypermethylation was not correlated with clinicopathological features. Methylated CDH13, PCDH10, CDH3, and CDH15, but not methylated CDH8 or CDH11, may lead to an increased risk of HCC. Hypermethylated CDH1 may become a noninvasive blood biomarker. Further studies with more data are necessary.

Abdullah M, Choo CW, Alias H, et al.
ADAMTSL5 and CDH11: putative epigenetic markers for therapeutic resistance in acute lymphoblastic leukemia.
Hematology. 2017; 22(7):386-391 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: DNA hypermethylation has been linked to poor treatment outcome in childhood acute lymphoblastic leukemia (ALL). Genes differentially methylated in the chemoresponsive pre-B-ALL compared to chemoresistant pre-B-ALL cases provide potential prognostic markers.
METHODS: DNA methylation profiles of five B-ALL childhood patients who achieved morphological complete remission (chemoresponsive) and five B-ALL patients who did not (chemoresistant) after induction treatments as well as four normal controls were compared on 27 000 CpG sites microarray chips. Subsequently, methylation-specific polymerase chain reaction (MSP) on selected hypermethylated genes was conducted on an additional 37 chemoresponsive and 9 chemoresistant B-ALL samples and 2 normal controls.
RESULTS: Both methods were found to be highly correlated. Unsupervised principal component analysis showed that the chemotherapy-responsive and -resistant B-ALL patients could be segregated from one another. Selection of segregated genes at high stringency identified two potential genes (CDH11 and ADAMTSL5). MSP analysis on the larger cohort of samples (42 chemoresponsive, 14 chemoresistant B-ALL samples and 6 normal controls) revealed significantly higher rates of hypermethylation in chemoresistant samples for ADAMTSL5 (93 vs. 38%; p = 0.0001) and CDH11 (79% vs. 40%, p < 0.01). All control cases remained unmethylated.
CONCLUSION: Chemoresistant B-ALL patients are associated with increased methylation in ADAMTSL5 and CDH11. These findings need to be validated in a larger group of patients, and the functional biological and prognostic significance of differential methylation needs to be studied further.

Birtolo C, Pham H, Morvaridi S, et al.
Cadherin-11 Is a Cell Surface Marker Up-Regulated in Activated Pancreatic Stellate Cells and Is Involved in Pancreatic Cancer Cell Migration.
Am J Pathol. 2017; 187(1):146-155 [PubMed] Free Access to Full Article Related Publications
Chronic pancreatitis is a prominent risk factor for the development of pancreatic ductal adenocarcinoma. In both conditions, the activation of myofibroblast-like pancreatic stellate cells (PSCs) plays a predominant role in the formation of desmoplastic reaction through the synthesis of connective tissue and extracellular matrix, inducing local pancreatic fibrosis and an inflammatory response. Yet the signaling events involved in chronic pancreatitis and pancreatic cancer progression and metastasis remain poorly defined. Cadherin-11 (Cad-11, also known as OB cadherin or CDH11) is a cell-to-cell adhesion molecule implicated in many biological functions, including tissue morphogenesis and architecture, extracellular matrix-mediated tissue remodeling, cytoskeletal organization, epithelial-to-mesenchymal transition, and cellular migration. In this study, we show that, in human chronic pancreatitis and pancreatic cancer tissues, Cad-11 expression was significantly increased in PSCs and pancreatic cancer cells. In particular, an increased expression of Cad-11 can be detected on the plasma membrane of activated PSCs isolated from chronic pancreatitis tissues and in pancreatic cancer cells metastasized to the liver. Moreover, knockdown of Cad-11 in cancer cells reduced pancreatic cancer cell migration. Taken together, our data underline the potential role of Cad-11 in PSC activation and pancreatic cancer metastasis.

Kooi IE, van Mil SE, MacPherson D, et al.
Genomic landscape of retinoblastoma in Rb
Genes Chromosomes Cancer. 2017; 56(3):231-242 [PubMed] Related Publications
Several murine retinoblastoma models have been generated by deleting the genes encoding for retinoblastoma susceptibility protein pRb and one of its family members p107 or p130. In Rb

Weng TY, Wang CY, Hung YH, et al.
Differential Expression Pattern of THBS1 and THBS2 in Lung Cancer: Clinical Outcome and a Systematic-Analysis of Microarray Databases.
PLoS One. 2016; 11(8):e0161007 [PubMed] Free Access to Full Article Related Publications
Thrombospondin 1 and thrombospondin 2 (THBS1 and THBS2) share similar multifunctional domains, and are known to be antiangiogenic. However, the expression pattern of THBS1 and THBS2 is different, and the specific role of THBS2 in different subtypes of lung cancer remains largely unclear. To evaluate the significance of THBS1 and THBS2 in the development of lung cancer, the present study performed a microarray-based systematic-analysis to determine the transcript levels of thrombospondins and their relation to the prognosis in lung cancer. THBS1 was in general underexpressed in lung cancer; in contrast, mRNA levels of THBS2 were markedly overexpressed in a number of datasets of non-small cell lung carcinoma (NSCLC), including lung adenocarcinoma (AC) and squamous cell carcinoma. Similar expression pattern of THBS1 and THBS2 was verified in pulmonary AC cell lines with real-time PCR analysis. The survival of lung AC patients with high THBS2 mRNA expression levels was poorer than patients with low levels of expression of THBS2. In a microarray-based analysis, genes coexpressed with THBS1 or THBS2 were determined. Pulmonary AC patients with a high expression level of sevenTSHB1-coexpressed genes (CCL5, CDH11, FYB, GZMK, LA-DQA1, PDE4DIP, and SELL) had better survival rates than those with a low expression level. Patients with a high expression of seven TSHB2-coexpressed genes (CHI3L1, COL5A2, COL11A1, FAP, MXRA5, THY1, and VCAN) had poor survival rates. Downregulation of VCAN and THBS2 with shRNA inhibited the cell proliferation in the A549 cell line. In summary, THBS1 functions as a tumor suppressor in lung adenocarcinoma. However, THBS2 may play a double-edged role in the progression of lung AC, i.e. anti-angiogenic and oncogenic function. Further study on the mechanism underlying the activity of THBS2 is warranted to have further implications for cancer diagnosis and treatment of pulmonary AC.

Porta-Pardo E, Godzik A
Mutation Drivers of Immunological Responses to Cancer.
Cancer Immunol Res. 2016; 4(9):789-98 [PubMed] Free Access to Full Article Related Publications
In cancer immunology, somatic missense mutations have been mostly studied with regard to their role in the generation of neoantigens. However, growing evidence suggests that mutations in certain genes, such as CASP8 or TP53, influence the immune response against a tumor by other mechanisms. Identifying these genes and mechanisms is important because, just as the identification of cancer driver genes led to the development of personalized cancer therapies, a comprehensive catalog of such cancer immunity drivers will aid in the development of therapies aimed at restoring antitumor immunity. Here, we present an algorithm, domainXplorer, that can be used to identify potential cancer immunity drivers. To demonstrate its potential, we used it to analyze a dataset of 5,164 tumor samples from The Cancer Genome Atlas (TCGA) and to identify protein domains in which mutation status correlates with the presence of immune cells in cancer tissue (immune infiltrate). We identified 122 such protein regions, including several that belong to proteins with known roles in immune response, such as C2, CD163L1, or FCγR2A. In several cases, we show that mutations within the same protein can be associated with more or less immune cell infiltration, depending on the specific domain mutated. These results expand the catalog of potential cancer immunity drivers and highlight the importance of taking into account the structural context of somatic mutations when analyzing their potential association with immune phenotypes. Cancer Immunol Res; 4(9); 789-98. ©2016 AACR.

Ferrer-Torres D, Nancarrow DJ, Kuick R, et al.
Genomic similarity between gastroesophageal junction and esophageal Barrett's adenocarcinomas.
Oncotarget. 2016; 7(34):54867-54882 [PubMed] Free Access to Full Article Related Publications
The current high mortality rate of esophageal adenocarcinoma (EAC) reflects frequent presentation at an advanced stage. Recent efforts utilizing fluorescent peptides have identified overexpressed cell surface targets for endoscopic detection of early stage Barrett's-derived EAC. Unfortunately, 30% of EAC patients present with gastroesophageal junction adenocarcinomas (GEJAC) and lack premalignant Barrett's metaplasia, limiting this early detection strategy. We compared mRNA profiles from 52 EACs (tubular EAC; tEAC) collected above the gastroesophageal junction with 70 GEJACs, 8 normal esophageal and 5 normal gastric mucosa samples. We also analyzed our previously published whole-exome sequencing data in a large cohort of these tumors. Principal component analysis, hierarchical clustering and survival-based analyses demonstrated that GEJAC and tEAC were highly similar, with only modest differences in expression and mutation profiles. The combined expression cohort allowed identification of 49 genes coding cell surface targets overexpressed in both GEJAC and tEAC. We confirmed that three of these candidates (CDH11, ICAM1 and CLDN3) were overexpressed in tumors when compared to normal esophagus, normal gastric and non-dysplastic Barrett's, and localized to the surface of tumor cells. Molecular profiling of tEAC and GEJAC tumors indicated extensive similarity and related molecular processes. Identified genes that encode cell surface proteins overexpressed in both Barrett's-derived EAC and those that arise without Barrett's metaplasia will allow simultaneous detection strategies.

Carter JM, Wang X, Dong J, et al.
USP6 genetic rearrangements in cellular fibroma of tendon sheath.
Mod Pathol. 2016; 29(8):865-9 [PubMed] Related Publications
Fibroma of tendon sheath is a benign (myo)fibroblastic neoplasm of the tenosynovial soft tissues, typically affecting the distal extremities. It is classically described as a paucicellular, densely collagenized tumor; however, cellular variants have been described. A subset of cellular fibromas of tendon sheath shares similar histological features with nodular fasciitis. As nodular fasciitis very frequently harbors rearrangement of ubiquitin-specific peptidase 6 (USP6), we hypothesized that cellular fibromas of tendon sheath with nodular fasciitis-like features may also contain USP6 rearrangements. Cases of fibroma of tendon sheath (n=19), including cellular (n=9) and classic (n=10) variants, were evaluated for USP6 rearrangement by fluorescence in situ hybridization studies. A subset of cases was tested for MYH9 rearrangements and MYH9-USP6 and CDH11-USP6 fusion products. Classic fibroma of tendon sheath occurred in 5 males and 5 females (median age 67 years, range 23-77 years) as soft tissue masses of the hand (n=4), finger (n=3), forearm (n=1) and foot (n=2). Cellular fibroma of tendon sheath occurred in 5 males and 4 females in a younger age group (median age 32 years, range 12-46 years) as small soft tissue masses of the finger (n=5), hand (n=3) and wrist (n=1). USP6 rearrangements were detected in 6/9 cellular fibromas of tendon sheath. Among cellular fibromas of tendon sheath with USP6 rearrangements, no MYH9 rearrangements were detected. By RT-PCR, neither the MYH9-USP6 or the CDH11-USP6 fusion products were detected in any case. Neither USP6 nor MYH9 rearrangement were detected in any classic fibroma of tendon sheath. We report for the first time the presence of USP6 rearrangements in a subset of cellular fibroma of tendon sheath. Based on the similar morphological and molecular genetic features, we suspect that a subset of cellular fibromas of tendon sheath are under-recognized examples of tenosynovial nodular fasciitis, driven by alternate USP6 fusion genes. Further investigation will delineate how these lesions should best be classified.

Weigand A, Boos AM, Tasbihi K, et al.
Selective isolation and characterization of primary cells from normal breast and tumors reveal plasticity of adipose derived stem cells.
Breast Cancer Res. 2016; 18(1):32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There is a need to establish more cell lines from breast tumors in contrast to immortalized cell lines from metastatic effusions in order to represent the primary tumor and not principally metastatic biology of breast cancer. This investigation describes the simultaneous isolation, characterization, growth and function of primary mammary epithelial cells (MEC), mesenchymal cells (MES) and adipose derived stem cells (ADSC) from four normal breasts, one inflammatory and one triple-negative ductal breast tumors.
METHODS: A total of 17 cell lines were established and gene expression was analyzed for MEC and MES (n = 42) and ADSC (n = 48) and MUC1, pan-KRT, CD90 and GATA-3 by immunofluorescence. DNA fingerprinting to track cell line identity was performed between original primary tissues and isolates. Functional studies included ADSC differentiation, tumor MES and MEC invasion co-cultured with ADSC-conditioned media (CM) and MES adhesion and growth on 3D-printed scaffolds.
RESULTS: Comparative analysis showed higher gene expression of EPCAM, CD49f, CDH1 and KRTs for normal MEC lines; MES lines e.g. Vimentin, CD10, ACTA2 and MMP9; and ADSC lines e.g. CD105, CD90, CDH2 and CDH11. Compared to the mean of all four normal breast cell lines, both breast tumor cell lines demonstrated significantly lower ADSC marker gene expression, but higher expression of mesenchymal and invasion gene markers like SNAI1 and MMP2. When compared with four normal ADSC differentiated lineages, both tumor ADSC showed impaired osteogenic and chondrogenic but enhanced adipogenic differentiation and endothelial-like structures, possibly due to high PDGFRB and CD34. Addressing a functional role for overproduction of adipocytes, we initiated 3D-invasion studies including different cell types from the same patient. CM from ADSC differentiating into adipocytes induced tumor MEC 3D-invasion via EMT and amoeboid phenotypes. Normal MES breast cells adhered and proliferated on 3D-printed scaffolds containing 20 fibers, but not on 2.5D-printed scaffolds with single fiber layers, important for tissue engineering.
CONCLUSION: Expression analyses confirmed successful simultaneous cell isolations of three different phenotypes from normal and tumor primary breast tissues. Our cell culture studies support that breast-tumor environment differentially regulates tumor ADSC plasticity as well as cell invasion and demonstrates applications for regenerative medicine.

Sepulveda JL, Gutierrez-Pajares JL, Luna A, et al.
High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing.
Mod Pathol. 2016; 29(2):182-93 [PubMed] Related Publications
Gastric cancers are the most frequent gastric malignancy and usually arise in the sequence of Helicobacter pylori-associated chronic gastritis. CpG methylation is a central mechanism of epigenetic gene regulation affecting cancer-related genes, and occurs early in gastric carcinogenesis. DNA samples from non-metaplastic gastric mucosa with variable levels of gastritis (non-metaplastic mucosa), intestinal metaplasia, or gastric cancer were screened with methylation arrays for CpG methylation of cancer-related genes and 30 gene targets were further characterized by high-definition bisulfite next-generation sequencing. In addition, data from The Cancer Genome Atlas were analyzed for correlation of methylation with gene expression. Overall, 13 genes had significantly increased CpG methylation in gastric cancer vs non-metaplastic mucosa (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, and SNRPN). Further, most of these genes had corresponding reduced expression levels in gastric cancer compared with intestinal metaplasia, including novel hypermethylated genes in gastric cancer (FLI1, GALR1, SGCE, and SNRPN), suggesting that they may regulate neoplastic transformation from non-malignant intestinal metaplasia to cancer. Our data suggest a tumor-suppressor role for FLI1 in gastric cancer, consistent with recently reported data in breast cancer. For the genes with strongest methylation/expression correlation, namely FLI1, the expression was lowest in microsatellite-unstable tumors compared with other gastric cancer molecular subtypes. Importantly, reduced expression of hypermethylated BRINP1 and SGCE was significantly associated with favorable survival in gastric cancer. In summary, we report novel methylation gene targets that may have functional roles in discrete stages of gastric carcinogenesis and may serve as biomarkers for diagnosis and prognosis of gastric cancer.

Yao J, Deng B, Zheng L, et al.
miR-27b is upregulated in cervical carcinogenesis and promotes cell growth and invasion by regulating CDH11 and epithelial-mesenchymal transition.
Oncol Rep. 2016; 35(3):1645-51 [PubMed] Related Publications
Dysregulation of microRNAs (miRNAs) occurs frequently in cervical carcinogenesis. miRNAs function as tumor-suppressors or oncogenes and are involved in tumor behavior. However, the expression and function of miR-27b in cervical carcinogenesis remain unknown. In the present study, we observed that miR-27b was significantly increased in cervical cancer cells and tissues, and upregulation of miR-27b was negatively associated with its direct target, cadherin 11 (CDH11). Upregulation of miR-27b significantly accelerated the proliferation, cell cycle transition from G1 to S phase, migration and invasion of C33A cells, while downregulation of miR-27b suppressed the proliferation and invasion of HeLa cells. Moreover, CDH11 cDNA transfection impaired the oncogenic effect of miR-27b on cancer cells. Knockdown of CDH11 attenuated the suppressive effect of an miR-27b inhibitor on cervical cancer cells. In addition, we found that CDH11 was involved in miR-27b-induced epithelial-mesenchymal transition (EMT) by regulating expression of E-cadherin, vimentin and N-cadherin. Our results for the first time indicate that miR-27b acting as an oncogene may play an important role in the progression of cervical cancer by modulating CDH11 and EMT.

Satcher RL, Pan T, Bilen MA, et al.
Cadherin-11 endocytosis through binding to clathrin promotes cadherin-11-mediated migration in prostate cancer cells.
J Cell Sci. 2015; 128(24):4629-41 [PubMed] Free Access to Full Article Related Publications
Cadherin-11 (Cad11) cell adhesion molecule plays a role in prostate cancer cell migration. Because disassembly of adhesion complexes through endocytosis of adhesion proteins has been shown to play a role in cell migration, we examined whether Cad11 endocytosis plays a role in Cad11-mediated migration. The mechanism by which Cad11 is internalized is unknown. Using a GST pulldown assay, we found that clathrin binds to the Cad11 cytoplasmic domain but not to that of E-cadherin. Using deletion analysis, we identified a unique sequence motif, VFEEE, in the Cad11 membrane proximal region (amino acid residues 11-15) that binds to clathrin. Endocytosis assays using K(+)-depletion buffer showed that Cad11 internalization is clathrin dependent. Proximity ligation assays showed that Cad11 colocalizes with clathrin, and immunofluorescence assays showed that Cad11 localizes in vesicles that stain for the early endosomal marker Rab5. Deletion of the VFEEE sequence from the Cad11 cytoplasmic domain (Cad11-cla-Δ5) leads to inhibition of Cad11 internalization and reduces Cad11-mediated cell migration in C4-2B and PC3-mm2 prostate cancer cells. These observations suggest that clathrin-mediated internalization of Cad11 regulates surface trafficking of Cad11 and that dynamic turnover of Cad11 regulates the migratory function of Cad11 in prostate cancer cells.

Bringuier PP, Schalken JA, Hervieu V, Giroldi LA
Involvement of orphan nuclear receptor COUP-TFII in cadherin-6 and cadherin-11 regulation: implications in development and cancer.
Mech Dev. 2015; 136:64-72 [PubMed] Related Publications
Changes in cadherin expression are instrumental both in embryonic development and disease, underlining the importance of understanding how cadherin expression is controlled. Kidney development is characterized by a mesenchymal-epithelial transition underlain by a cadherin-11 to cadherin-6 switch, the regulation mechanisms of which are presently unexplained. Using transfection and RNA-interference we demonstrate that COUP-TFII (NR2F2) induces down-regulation of cadherin-6 and up-regulation of cadherin-11 in cultured cell lines. Double immunolabeling of mouse embryos provides indirect evidence that COUP-TFII negatively controls the cadherin-11 to cadherin-6 switch underlying the kidney developmental mesenchymal-epithelial transition. Furthermore, we found high expression of COUP-TFII in some gastric and oesophageal adenocarcinomas, correlating with abnormal cadherin-11 expression and suggesting reactivation of embryonic pathways linked to COUP-TFII in these tumors. Altogether, our data shed new light upon the role of COUP-TFII in development and in cancer.

Ortiz A, Lee YC, Yu G, et al.
Angiomotin is a novel component of cadherin-11/β-catenin/p120 complex and is critical for cadherin-11-mediated cell migration.
FASEB J. 2015; 29(3):1080-91 [PubMed] Free Access to Full Article Related Publications
Loss of E-cadherin and up-regulation of mesenchymal cadherins, a hallmark of the epithelial-mesenchymal transition, contributes to migration and dissemination of cancer cells. Expression of human cadherin-11 (Cad11), also known as osteoblast cadherin, in prostate cancer increases the migration of prostate cancer cells. How Cad11 mediates cell migration is unknown. Using the human Cad11 cytoplasmic domain in pulldown assays, we identified human angiomotin (Amot), known to be involved in cell polarity, migration, and Hippo pathway, as a component of the Cad11 protein complex. Deletion analysis showed that the last C-terminal 10 amino acids in Cad11 cytoplasmic domain are required for Amot binding. Further, Cad11 preferentially interacts with Amot-p80 than Amot-p130 isoform and binds directly to the middle domain of Amot-p80. Cad11-Amot interaction affects Cad11-mediated cell migration, but not homophilic adhesion, as deletion of Amot binding motif of Cad11 (Cad11-ΔAmot) did not abolish Cad11-mediated cell-cell adhesion of mouse L cells, but significantly reduced Cad11-mediated cell migration of human C4-2B4 and PC3-mm2 prostate cancer cells and human HEK293T cells. Together, our studies identified Amot-p80 as a novel component of the Cad11 complex and demonstrated that Amot-p80 is critical for Cad11-mediated cell migration.

Wang J, Dong L, Xu L, et al.
B cell CLL/lymphoma 6 member B inhibits hepatocellular carcinoma metastases in vitro and in mice.
Cancer Lett. 2014; 355(2):192-200 [PubMed] Related Publications
B cell CLL/lymphoma 6 member B (BCL6B) is a novel tumor suppressor silenced in human cancer. In this study, we investigated the functional role and underlying mechanisms of BCL6B in hepatocellular carcinoma (HCC). BCL6B was expressed in normal HCC tissues, but its expression was suppressed in 6 out of 9 HCC cell lines. Loss of BCL6B expression was associated with promoter hypermethylation. Ectopic expression of BCL6B in HepG2 and Huh7 cell lines inhibited colony formation (P <0.05), cell viability (P <0.01), and tumorigenicity in nude mice (P <0.05). BCL6B expression also induced apoptosis (P <0.05), an effect associated with activation of the caspase cascade and cleavage of PARP. Stable expression of BCL6B in MHCC97L cells suppressed cell migration (P <0.05) and invasion (P <0.05), and significantly reduced the incidence and severity of lung metastasis in an orthotopic HCC mouse model. The anti-metastatic effect of BCL6B was mediated by up-regulation of cell adhesion gene E-cadherin, OB-cadherin, HIV-1 Tat interactive protein 2, and transient receptor potential cation channel, subfamily M, member 1; and down-regulation of angiogenesis gene VEGFA. BCL6B functions as a tumor suppressor that inhibits HCC metastases in vitro and in vivo.

Marino N, Collins JW, Shen C, et al.
Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines.
Clin Exp Metastasis. 2014; 31(7):771-86 [PubMed] Free Access to Full Article Related Publications
Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.

Gao L, van den Hurk K, Moerkerk PTM, et al.
Promoter CpG island hypermethylation in dysplastic nevus and melanoma: CLDN11 as an epigenetic biomarker for malignancy.
J Invest Dermatol. 2014; 134(12):2957-2966 [PubMed] Related Publications
Dysplastic nevi are melanocytic lesions that represent an intermediate stage between common nevus and melanoma. Histopathological distinction of dysplastic nevus from melanoma can be challenging and there is a requirement for molecular diagnostic markers. In this study, we examined promoter CpG island methylation of a selected panel of genes, identified in a genome-wide methylation screen, across a spectrum of 405 melanocytic neoplasms. Promoter methylation analysis in common nevi, dysplastic nevi, primary melanomas, and metastatic melanomas demonstrated progressive epigenetic deregulation. Dysplastic nevi were affected by promoter methylation of genes that are frequently methylated in melanoma but not in common nevi. We assessed the diagnostic value of the methylation status of five genes in distinguishing primary melanoma from dysplastic nevus. In particular, CLDN11 promoter methylation was specific for melanoma, as it occurred in 50% of primary melanomas but in only 3% of dysplastic nevi. A diagnostic algorithm that incorporates methylation of the CLDN11, CDH11, PPP1R3C, MAPK13, and GNMT genes was validated in an independent sample set and helped distinguish melanoma from dysplastic nevus (area under the curve 0.81). Melanoma-specific methylation of these genes supports the utility as epigenetic biomarkers and could point to their significance in melanoma development.

Li Y, Chao F, Huang B, et al.
HOXC8 promotes breast tumorigenesis by transcriptionally facilitating cadherin-11 expression.
Oncotarget. 2014; 5(9):2596-607 [PubMed] Free Access to Full Article Related Publications
Cell-cell adhesion molecule cadherin-11(CDH11) is preferentially expressed in basal-like breast cancer cells and facilitates breast cancer cell migration by promoting small GTPase Rac activity. However, how the expression of CDH11 is regulated in breast cancer cells is not understood. Here, we show that CDH11 is transcriptionally controlled by homeobox C8 (HOXC8) in human breast cancer cells. HOXC8 serves as a CDH11-specific transcription factor and binds to the site of nucleotides -196 to -191 in the CDH11 promoter. Depletion of HOXC8 leads to the decrease in anchorage-independent cell growth, cell migration/invasion and spontaneous metastasis of breast cancer cells; however, suppressed tumorigenic events were fully rescued by ectopic CDH11 expression in HOXC8-knockdown cells. These results indicate that HOXC8 impacts breast tumorigenesis through CDH11. The analysis of publically available human breast tumor microarray gene expression database demonstrates a strong positive linear association between HOXC8 and CDH11 expression ( = 0.801, p < 0.001). Survival analysis (Kaplan-Meier method, log-rank test) show that both high HOXC8 and CDH11 expression correlate with poor recurrence-free survival rate of patients. Together, our study suggests that HOXC8 promotes breast tumorigenesis by maintaining high level of CDH11 expression in breast cancer cells.

Golubkov VS, Strongin AY
Downstream signaling and genome-wide regulatory effects of PTK7 pseudokinase and its proteolytic fragments in cancer cells.
Cell Commun Signal. 2014; 12:15 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The full-length membrane protein tyrosine kinase 7 (PTK7) pseudokinase, an important component of the planar cell polarity and the Wnt canonical and non-canonical pathways, is a subject of step-wise proteolysis in cells and tissues. The proteolysis of PTK7 involves membrane type-matrix metalloproteinase (MT1-MMP), members of the Disintegrin Domain and Metalloproteinase (ADAM) family, and γ-secretase. This multi-step proteolysis results in the generation of the digest fragments of PTK7. These fragments may be either liberated into the extracellular milieu or retained on the plasma membrane or released into the cytoplasm and then transported into the nucleus.
RESULTS: We employed the genome-wide transcriptional and kinome array analyses to determine the role of the full-length membrane PTK7 and its proteolytic fragments in the downstream regulatory mechanisms, with an emphasis on the cell migration-related genes and proteins. Using fibrosarcoma HT1080 cells stably expressing PTK7 and its mutant and truncated species, the structure of which corresponded to the major PTK7 digest fragments, we demonstrated that the full-length membrane 1-1070 PTK7, the N-terminal 1-694 soluble ectodomain fragment, and the C-terminal 622-1070 and 726-1070 fragments differentially regulate multiple genes and signaling pathways in our highly invasive cancer cell model. Immunoblotting of the selected proteins were used to validate the results of our high throughput assays.
CONCLUSIONS: Our results suggest that PTK7 levels need to be tightly controlled to enable migration and that the anti-migratory effect of the full-length membrane PTK7 is linked to the down-regulation of multiple migration-related genes and to the activation of the Akt and c-Jun pathway. In turn, the C-terminal fragments of PTK7 act predominantly via the RAS-ERK and CREB/ATF1 pathway and through the up-regulation of cadherin-11. In general, our data correlate well with the distinct functionality of the full-length receptor tyrosine kinases and their respective intracellular domain (ICD) proteolytic fragments.

Sobolik T, Su YJ, Wells S, et al.
CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways.
Mol Biol Cell. 2014; 25(5):566-82 [PubMed] Free Access to Full Article Related Publications
Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4ΔCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two-dimensional cultures of MCF-7 CXCR4ΔCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box-binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte-macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4-expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis.

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