PTPN13

Gene Summary

Gene:PTPN13; protein tyrosine phosphatase non-receptor type 13
Aliases: PNP1, FAP-1, PTP1E, PTPL1, PTPLE, PTP-BL, hPTP1E, PTP-BAS
Location:4q21.3
Summary:The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP is a large intracellular protein. It has a catalytic PTP domain at its C-terminus and two major structural domains: a region with five PDZ domains and a FERM domain that binds to plasma membrane and cytoskeletal elements. This PTP was found to interact with, and dephosphorylate, Fas receptor and IkappaBalpha through the PDZ domains. This suggests it has a role in Fas mediated programmed cell death. This PTP was also shown to interact with GTPase-activating protein, and thus may function as a regulator of Rho signaling pathways. Four alternatively spliced transcript variants, which encode distinct proteins, have been reported. [provided by RefSeq, Oct 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tyrosine-protein phosphatase non-receptor type 13
Source:NCBIAccessed: 01 September, 2019

Ontology:

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

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • BCL2 protein
  • Transfection
  • DNA Methylation
  • Cell Proliferation
  • Tumor Suppressor Gene
  • Mutation
  • bcl-2-Associated X Protein
  • Transcription Factors
  • Gene Expression Profiling
  • Carrier Proteins
  • Breast Cancer
  • Phosphorylation
  • beta Catenin
  • Biomarkers, Tumor
  • Chromosome 4
  • Protein Tyrosine Phosphatases
  • fas Receptor
  • RTPCR
  • Protein Binding
  • src-Family Kinases
  • Cancer Gene Expression Regulation
  • Promoter Regions
  • Cell Survival
  • Lung Cancer
  • p53 Protein
  • Messenger RNA
  • Squamous Cell Carcinoma
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13
  • Single Nucleotide Polymorphism
  • Colorectal Cancer
  • PTPN13
  • Oligonucleotide Array Sequence Analysis
  • Apoptosis
  • Young Adult
  • Signal Transduction
  • Two-Hybrid System Techniques
  • Protein Phosphatase 1
  • Repressor Proteins
  • Sequence Deletion
  • bcl-X Protein
  • Western Blotting
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: PTPN13 (cancer-related)

Bowler E, Porazinski S, Uzor S, et al.
Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells.
BMC Cancer. 2018; 18(1):355 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mounting evidence suggests that one of the ways that cells adapt to hypoxia is through alternative splicing. The aim of this study was firstly to examine the effect of hypoxia on the alternative splicing of cancer associated genes using the prostate cancer cell line PC3 as a model. Secondly, the effect of hypoxia on the expression of several regulators of splicing was examined.
METHODS: PC3 cells were grown in 1% oxygen in a hypoxic chamber for 48 h, RNA extracted and sent for high throughput PCR analysis at the RNomics platform at the University of Sherbrooke, Canada. Genes whose exon inclusion rate PSI (ψ) changed significantly were identified, and their altered exon inclusion rates verified by RT-PCR in three cell lines. The expression of splice factors and splice factor kinases in response to hypoxia was examined by qPCR and western blotting. The splice factor kinase CLK1 was inhibited with the benzothiazole TG003.
RESULTS: In PC3 cells the exon inclusion rate PSI (ψ) was seen to change by > 25% in 12 cancer-associated genes; MBP, APAF1, PUF60, SYNE2, CDC42BPA, FGFR10P, BTN2A2, UTRN, RAP1GDS1, PTPN13, TTC23 and CASP9 (caspase 9). The expression of the splice factors SRSF1, SRSF2, SRSF3, SAM68, HuR, hnRNPA1, and of the splice factor kinases SRPK1 and CLK1 increased significantly in hypoxia. We also observed that the splice factor kinase CLK3, but not CLK2 and CLK4, was also induced in hypoxic DU145 prostate, HT29 colon and MCF7 breast cancer cell lines. Lastly, we show that the inhibition of CLK1 in PC3 cells with the benzothiazole TG003 increased expression of the anti-apoptotic isoform caspase 9b.
CONCLUSIONS: Significant changes in alternative splicing of cancer associated genes occur in prostate cancer cells in hypoxic conditions. The expression of several splice factors and splice factor kinases increases during hypoxia, in particular the Cdc-like splice factor kinases CLK1 and CLK3. We suggest that in hypoxia the elevated expression of these regulators of splicing helps cells adapt through alternative splicing of key cancer-associated genes. We suggest that the CLK splice factor kinases could be targeted in cancers in which hypoxia contributes to resistance to therapy.

Bruurs LJM, van der Net MC, Zwakenberg S, et al.
The Phosphatase PTPL1 Is Required for PTEN-Mediated Regulation of Apical Membrane Size.
Mol Cell Biol. 2018; 38(12) [PubMed] Free Access to Full Article Related Publications
PTEN is a tumor suppressor that is frequently lost in epithelial malignancies. A part of the tumor-suppressive properties of PTEN is attributed to its function in cell polarization and consequently its role in maintaining epithelial tissue integrity. However, surprisingly little is known about the function and regulation of PTEN during epithelial cell polarization. We used clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated gene disruption to delete PTEN in intestinal epithelial Ls174T:W4 cells, which upon differentiation form a microvillus-covered apical membrane (brush border) on a part of the cell cortex, independent of cell-cell junctions. We show that loss of PTEN results in the formation of a larger brush border that, in a fraction of the cells, even spans the entire plasma membrane, revealing that PTEN functions in the regulation of apical membrane size. Depletion of the phosphatase PTPL1 resulted in a similar defect. PTPL1 interacts with PTEN, and this interaction is necessary for apical membrane enrichment of PTEN. Importantly, phosphatase activity of PTPL1 is not required, indicating that PTPL1 functions as an anchor protein in this process. Our work thus demonstrates a novel function for PTEN during cell polarization in controlling apical membrane size and identifies PTPL1 as a critical apical membrane anchor for PTEN in this process.

Zhuang L, Shou T, Li K, et al.
MicroRNA-30e-5p promotes cell growth by targeting PTPN13 and indicates poor survival and recurrence in lung adenocarcinoma.
J Cell Mol Med. 2017; 21(11):2852-2862 [PubMed] Free Access to Full Article Related Publications
Aberrant microRNA expression is involved in the regulation of various cellular processes, such as proliferation and metastasis in multiple diseases including cancers. MicroRNA-30e-5p (miR-30e) was previously reported as an oncogenic or tumour suppressing miRNA in some malignancies, but its function in lung adenocarcinoma (LAC) remains largely undefined. In this study, we found that the expression of miR-30e was increased in LAC tissues and cell lines, associated with tumour size and represented an independent prognostic factor for overall survival and recurrence of LAC patients. Further functional experiments showed that knockdown of miR-30e suppressed cell growth while its overexpression promoted growth of LAC cells and xenografts in vitro and in vivo. Mechanistically, PTPN13 was identified as the direct target of miR-30e in LAC, in which PTPN13 expression was down-regulated in LAC tissues and showed the inverse correlation with miR-30e expression. Overexpression of PTPN13 inhibited cell growth and rescued the proliferation-promoting effect of miR-30e through inhibition of the EGFR signalling. Altogether, our findings suggest that miR-30e could function as an oncogene in LAC via targeting PTPN13 and act as a potential therapeutic target for treating LAC.

Laczmanska I, Karpinski P, Gil J, et al.
The PTPN13 Y2081D (T>G) (rs989902) polymorphism is associated with an increased risk of sporadic colorectal cancer.
Colorectal Dis. 2017; 19(7):O272-O278 [PubMed] Related Publications
AIM: Colorectal cancer (CRC) is one of the most common cancers worldwide and, although the majority of cases are sporadic, its development and progression depends on a range of factors: environmental, genetic and epigenetic. A variety of genetic pathways have been described as being crucial in CRC, including protein tyrosine phosphatases (PTPs). PTPN13 (also called FAP-1) is a non-receptor PTP and interacts with a number of important components of growth and apoptosis pathways. It is also involved in the inhibition of Fas-induced apoptosis.
METHOD: The single nucleotide polymorphism genotype at Y2081D (T>G) (rs989902) of PTPN13 exon 39 was determined in DNA extracted from blood samples from 174 sporadic CRC patients and 176 healthy individuals. Also, a meta-analysis was performed based on three articles accessed via the PubMed and ResearchGate databases.
RESULTS: The risk of CRC was 2.087 times greater for patients with the GG genotype than for those with the TT genotype (P = 0.0475). In the meta-analysis, a significantly increased risk of cancer associated with the G allele was observed in the squamous cell carcinoma of the head and neck subgroup (TT vs GG+GT, OR 1.23, 95% CI [1.02, 1.47], P = 0.0258), and a significantly decreased risk in the breast cancer subgroup (TT vs GG+GT, OR 0.63, 95% CI [0.41, 0.96], P = 0.0334) and in the CRC subgroup (GT+TT vs GG, OR 0.51, 95% CI [0.41, 0.95], P = 0.0333).
CONCLUSION: PTPN13 rs989902 is significantly associated with the risk of CRC in the Polish population. Given that this report provides the first evidence of an association of PTPN13 rs989902 with the risk of CRC in a Caucasian population, further large scale studies are necessary to confirm this finding.

Dommering CJ, Henneman L, van der Hout AH, et al.
Uptake of prenatal diagnostic testing for retinoblastoma compared to other hereditary cancer syndromes in the Netherlands.
Fam Cancer. 2017; 16(2):271-277 [PubMed] Free Access to Full Article Related Publications
Since the 1980s the genetic cause of many hereditary tumor syndromes has been elucidated. As a consequence, carriers of a deleterious mutation in these genes may opt for prenatal diagnoses (PND). We studied the uptake of prenatal diagnosis for five hereditary cancer syndromes in the Netherlands. Uptake for retinoblastoma (Rb) was compared with uptake for Von Hippel-Lindau disease (VHL), Li-Fraumeni syndrome (LFS), familial adenomatous polyposis (FAP), and hereditary breast ovarian cancer (HBOC). A questionnaire was completed by all nine DNA-diagnostic laboratories assessing the number of independent mutation-positive families identified from the start of diagnostic testing until May 2013, and the number of PNDs performed for these syndromes within these families. Of 187 families with a known Rb-gene mutation, 22 had performed PND (11.8%), this was significantly higher than uptake for FAP (1.6%) and HBOC (<0.2%). For VHL (6.5%) and LFS (4.9%) the difference was not statistically significant. PND for Rb started 3 years after introduction of diagnostic DNA testing and remained stable over the years. For the other cancer syndromes PND started 10-15 years after the introduction and uptake for PND showed an increase after 2009. We conclude that uptake of PND for Rb was significantly higher than for FAP and HBOC, but not different from VHL and LFS. Early onset, high penetrance, lack of preventive surgery and perceived burden of disease may explain these differences.

Cao S, Wendl MC, Wyczalkowski MA, et al.
Divergent viral presentation among human tumors and adjacent normal tissues.
Sci Rep. 2016; 6:28294 [PubMed] Free Access to Full Article Related Publications
We applied a newly developed bioinformatics system called VirusScan to investigate the viral basis of 6,813 human tumors and 559 adjacent normal samples across 23 cancer types and identified 505 virus positive samples with distinctive, organ system- and cancer type-specific distributions. We found that herpes viruses (e.g., subtypes HHV4, HHV5, and HHV6) that are highly prevalent across cancers of the digestive tract showed significantly higher abundances in tumor versus adjacent normal samples, supporting their association with these cancers. We also found three HPV16-positive samples in brain lower grade glioma (LGG). Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma. Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer. Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences. These findings provide important new insights into viral roles of tumor initiation and progression and potential new therapeutic targets.

Xu S, Wang T, Yang Z, et al.
miR-26a desensitizes non-small cell lung cancer cells to tyrosine kinase inhibitors by targeting PTPN13.
Oncotarget. 2016; 7(29):45687-45701 [PubMed] Free Access to Full Article Related Publications
Epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) have emerged as first-line drugs for non-small cell lung cancers (NSCLCs). However, the resistance to TKIs represents the key limitation for their therapeutic efficacy. We found that miR-26a was upregulated in gefitinib-refractory NSCLCs; miR-26a is downstream of EGFR signaling and directly targets and silences protein tyrosine phosphatase non-receptor type 13 (PTPN13) to maintain the activation of Src, a dephosphorylation substrate of PTPN13, thus reinforcing EGFR pathway in a regulatory circuit. miR-26a inhibition significantly improved NSCLC responses to gefitinib. These data revealed a novel mechanism of NSCLC resistance to TKI treatment.

Lim B, Kim C, Kim JH, et al.
Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites.
Oncotarget. 2016; 7(7):8055-66 [PubMed] Free Access to Full Article Related Publications
Peritoneal carcinomatosis accompanied by malignant ascites is a major cause of death of advanced gastric cancer (GC). To comprehensively characterize the underlying genomic events involved in GC peritoneal carcinomatosis, we analyzed whole-exome sequences of normal gastric tissues, primary tumors, and malignant ascites from eight GC patients. We identified a unique mutational signature biased toward C-to-A substitutions in malignant ascites. In contrast, the patients who received treatment of adjuvant chemotherapy showed a high rate of C-to-T substitutions along with hypermutation in malignant ascites. Comparative analysis revealed several candidate mutations for GC peritoneal carcinomatosis: recurrent mutations in COL4A6, INTS2, and PTPN13; mutations in druggable genes including TEP1, PRKCD, BRAF, ERBB4, PIK3CA, HDAC9, FYN, FASN, BIRC2, FLT3, ROCK1, CD22, and PIK3C2B; and mutations in metastasis-associated genes including TNFSF12, L1CAM, DIAPH3, ROCK1, TGFBR1, MYO9B, NR4A1, and RHOA. Notably, gene ontology analysis revealed the significant enrichment of mutations in the Rho-ROCK signaling pathway-associated biological processes in malignant ascites. At least four of the eight patients acquired somatic mutations in the Rho-ROCK pathway components, suggesting the possible relevance of this pathway to GC peritoneal carcinomatosis. These results provide a genome-wide molecular understanding of GC peritoneal carcinomatosis and its clinical implications, thereby facilitating the development of effective therapeutics.

Zhan H, Jiang J, Luo C, et al.
Tumour-suppressive role of PTPN13 in hepatocellular carcinoma and its clinical significance.
Tumour Biol. 2016; 37(7):9691-8 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality and carries a dismal prognosis. The present study aimed to identify the tumour-suppressive role and clinical implications of PTPN13 in HCC progression. We tested the effects of PTPN13 expression in proliferation, invasion, epithelial-mesenchymal transition and associated pathways in HCC cell lines in vitro. Furthermore, its clinical relevance was evaluated in a tissue microarray analysis of samples from 282 HCC patients. Various HCC cell lines expressed relatively low PTPN13 protein levels in vitro. PTPN13 overexpression significantly inhibited the progression of HCC cells, possibly by inhibiting epithelial-mesenchymal transition through inactivation of the EGFR/ERK signalling pathway. Tissue microarray analysis revealed that high PTPN13 expression was correlated with a favourable prognosis in postoperative HCC patients. This study demonstrated the tumour suppressor, PTPN13, as an alternative therapeutic target for HCC.

Mullapudi N, Ye B, Suzuki M, et al.
Genome Wide Methylome Alterations in Lung Cancer.
PLoS One. 2015; 10(12):e0143826 [PubMed] Free Access to Full Article Related Publications
Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.

Wang W, Wang J, Li Z, et al.
Promoter hypermethylation of PTPL1, PTPN6, DAPK, p16 and 5-azacitidine inhibits growth in DLBCL.
Oncol Rep. 2016; 35(1):139-46 [PubMed] Related Publications
Aberrant hypermethylation of CpG islands of tumor suppressor is one of the mechanisms for epigenetic loss of gene function. In the present study, the methylation status of the promoter regions of protein tyrosine phosphatase (PTPN) 6, DAPK, and p16 were studied using methylation-specific polymerase chain reaction (MSP) in 26 diffuse large B cell lymphoma (DLBCL) lymphomas. In OCI-LY1 cell line, gene methylation status, expression of PTPL1 and its reactivation by DNA demethylation was determined by PCR and on the protein level by western blotting. ELISA-like reaction was used to detect global DNA methylation measurement. Induction of apoptosis by 5-azacitidine was analyzed by Annexin V/PI staining and flow cytometry. Our results show that hypermethylation of the PTPN6 gene promoter region was found in 15.4% (4/26), the DAPK gene promoter region in 30.8% (8/26), the p16 gene promoter region in 7.7% (2/26). Notably, we identified that PTPL1 was hypermethylated and transcriptionally silenced in OCI-LY1 cell line. The expression of PTPL1 was re-inducible by 5-azacytidine. 5-azacytidine also inhibits the proliferation and decreases the global methylation level of the OCI-LY1 cell line. We can conclude from our study that a higher prevalence of methylation of PTPL1, PTPN6, DAPK and p16 occur in DLBCL. Our data also highlights 5-azacytidine as a potential therapeutic candidate for DLBCL. Further studies are required to substantiate the role of methylation of PTPL1, PTPN6, DAPK and p16 as a marker in diffuse large B cell lymphoma.

Wang W, Wang J, Li M, et al.
5-Azacitidine induces demethylation of PTPL1 and inhibits growth in non-Hodgkin lymphoma.
Int J Mol Med. 2015; 36(3):698-704 [PubMed] Free Access to Full Article Related Publications
Non-Hodgkin lymphoma (NHL) consists of various lymphoid malignancies with a diverse clinical pathology and biological characteristics. Methylation of cytosine residues by DNA methyltransferases at CpG dinucleotides in the promoter region of the genes is a major epigenetic modification in mammalian genomes that can have profound effects on gene expression. The PTPL1 methylation pattern was screened by methylation‑specific polymerase chain reaction (MSP) in 7 lymphoma‑derived cell lines and in 47 samples of diffuse large B cell lymphoma (DLBCL). The PTPL1 gene was hypermethylated in the CA46, Raji, Jurkat and DB cell lines; however, it was unmethylated in the Hut78, Maver and Z138 cell lines. The expression of PTPL1 mRNA was re‑inducible by 5‑azacytidine (5‑Aza), an agent of DNA demethylation. The methylations were detected in 59.6% of DLBCL versus 6.3% in reactive lymph node proliferation. Therefore, the present data showed that PTPL1 was epigenetically regulated in NHL suggesting an involvement of the PTPL1 tumor‑suppressor genes in NHL, and highlights 5-Aza as a potential therapeutic candidate for NHL.

Yan C, Yang F, Zhou C, et al.
MCT1 promotes the cisplatin-resistance by antagonizing Fas in epithelial ovarian cancer.
Int J Clin Exp Pathol. 2015; 8(3):2710-8 [PubMed] Free Access to Full Article Related Publications
This study was designed to investigate the role of MCT1 in the development of cisplatin-resistant ovarian cancer and its possible relationship with Fas. We found the expression of MCT1 was obviously increased both in cisplatin-resistant ovarian cancer tissue and A2780/CP cells compared with sensitive ovarian cancer tissue and cell lines A2780. And in A2780 cells treated with Cisplatin, the expression of MCT1 increased in a concentration-dependent manner, MCT1 knockdown attenuates cisplatin-induced cell viability. In A2780 and A2780/CP cells transfected with MCT1 siRNA, the activation of several downstream targets of Fas, including FasL and FAP-1 were largely prevented, whereas the expression of Caspase-3 was increased, accompanying with increased abundance of Fas. Coimmunoprecipitation and immunofluorescence showed that there is interaction between endogenous MCT1 with Fas in vivo and in vitro. In vivo, depletion of MCT1 by shRNA reverses cisplatin-resistance and the expression of Fas. This study showed that down regulation of MCT1 promote the sensibility to Cisplatin in ovarian cancer cell line. And this effect appeared to be mediated via antagonizing the effect of Fas.

Yu D, Son W, Lim J, Xiao G
Statistical completion of a partially identified graph with applications for the estimation of gene regulatory networks.
Biostatistics. 2015; 16(4):670-85 [PubMed] Free Access to Full Article Related Publications
We study the estimation of a Gaussian graphical model whose dependent structures are partially identified. In a Gaussian graphical model, an off-diagonal zero entry in the concentration matrix (the inverse covariance matrix) implies the conditional independence of two corresponding variables, given all other variables. A number of methods have been proposed to estimate a sparse large-scale Gaussian graphical model or, equivalently, a sparse large-scale concentration matrix. In practice, the graph structure to be estimated is often partially identified by other sources or a pre-screening. In this paper, we propose a simple modification of existing methods to take into account this information in the estimation. We show that the partially identified dependent structure reduces the error in estimating the dependent structure. We apply the proposed method to estimating the gene regulatory network from lung cancer data, where protein-protein interactions are partially identified from the human protein reference database. The application shows that proposed method identified many important cancer genes as hub genes in the constructed lung cancer network. In addition, we validated the prognostic importance of a newly identified cancer gene, PTPN13, in four independent lung cancer datasets. The results indicate that the proposed method could facilitate studying underlying lung cancer mechanisms and identifying reliable biomarkers for lung cancer prognosis.

Pavicic W, Nieminen TT, Gylling A, et al.
Promoter-specific alterations of APC are a rare cause for mutation-negative familial adenomatous polyposis.
Genes Chromosomes Cancer. 2014; 53(10):857-64 [PubMed] Related Publications
n familial adenomatous polyposis (FAP), 20% of classical and 70% of attenuated/atypical (AFAP) cases remain mutation-negative after routine testing; yet, allelic expression imbalance may suggest an APC alteration. Our aim was to determine the proportion of families attributable to genetic or epigenetic changes in the APC promoter region. We studied 51 unrelated families/cases (26 with classical FAP and 25 with AFAP) with no point mutations in the exons and exon/intron borders and no rearrangements by multiplex ligation-dependent probe amplification (MLPA, P043-B1). Promoter-specific events of APC were addressed by targeted resequencing, MLPA (P043-C1), methylation-specific MLPA, and Sanger sequencing of promoter regions. A novel 132-kb deletion encompassing the APC promoter 1B and upstream sequence occurred in a classical FAP family with allele-specific APC expression. No promoter-specific point mutations or hypermethylation were present in any family. In conclusion, promoter-specific alterations are a rare cause for mutation-negative FAP (1/51, 2%). The frequency and clinical correlations of promoter 1B deletions are poorly defined. This investigation provides frequencies of 1/26 (4%) for classical FAP, 0/25 (0%) for AFAP, and 1/7 (14%) for families with allele-specific expression of APC. Clinically, promoter 1B deletions may associate with classical FAP without extracolonic manifestations.

Sun Z, Wang L, Eckloff BW, et al.
Conserved recurrent gene mutations correlate with pathway deregulation and clinical outcomes of lung adenocarcinoma in never-smokers.
BMC Med Genomics. 2014; 7:32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Novel and targetable mutations are needed for improved understanding and treatment of lung cancer in never-smokers.
METHODS: Twenty-seven lung adenocarcinomas from never-smokers were sequenced by both exome and mRNA-seq with respective normal tissues. Somatic mutations were detected and compared with pathway deregulation, tumor phenotypes and clinical outcomes.
RESULTS: Although somatic mutations in DNA or mRNA ranged from hundreds to thousands in each tumor, the overlap mutations between the two were only a few to a couple of hundreds. The number of somatic mutations from either DNA or mRNA was not significantly associated with clinical variables; however, the number of overlap mutations was associated with cancer subtype. These overlap mutants were preferentially expressed in mRNA with consistently higher allele frequency in mRNA than in DNA. Ten genes (EGFR, TP53, KRAS, RPS6KB2, ATXN2, DHX9, PTPN13, SP1, SPTAN1 and MYOF) had recurrent mutations and these mutations were highly correlated with pathway deregulation and patient survival.
CONCLUSIONS: The recurrent mutations present in both DNA and RNA are likely the driver for tumor biology, pathway deregulation and clinical outcomes. The information may be used for patient stratification and therapeutic target development.

Augoff K, Hryniewicz-Jankowska A, Tabola R, et al.
Upregulated expression and activation of membrane‑associated proteases in esophageal squamous cell carcinoma.
Oncol Rep. 2014; 31(6):2820-6 [PubMed] Related Publications
To better understand the role of membrane-associated proteolytic systems in the development of esophageal cancer, we studied the expression of two serine proteases, fibroblast activation protein-α (FAP-α) and dipeptidyl peptidase IV (DPPIV) and three metalloproteinases, matrix metalloproteinase (MMP)-2, MMP-9 and MT1-MMP in 24 primary esophageal squamous cell carcinoma (ESCC) tissues and paired non-cancer tissues. Using reverse-transcription PCR, western blotting and zymography, we showed that both serine proteases and all three metalloproteinases were highly altered in ESCC. A positive correlation between the expression of FAP-α and DPPIV and the activity of both gelatinases was found. This may indicate that these proteolytic systems are tightly linked to each other and collectively are involved in the process of ECM degradation that facilitates cancer cell invasion and metastasis.

Wei W, Jiang M, Luo L, et al.
Colorectal cancer susceptibility variants alter risk of breast cancer in a Chinese Han population.
Genet Mol Res. 2013; 12(4):6268-74 [PubMed] Related Publications
Recent genome wide association studies (GWAS) and candidate gene studies have revealed many novel loci associated with colorectal cancer susceptibility. We evaluated the effect of these colorectal cancer-associated variants on the risk of breast cancer in a Chinese Han population. Seven single nucleotide polymorphisms (SNPs) (rs3856806 in PPARG, rs7014346 in POU5F1P1, rs989902 in PTPN13, rs1801278 in IRS1, rs7003146 in TCF7L2, rs1503185 in PTPRJ, and rs63750447 in MLH1) were genotyped in Han Chinese subjects, including 216 patients with breast cancer and 216 matched controls, using the Sequenom MassARRAY platform. The association of genotypes with susceptibility to breast cancer was analyzed using the odds ratio (OR), with 95% confidence interval (CI) and logistic regression. Three SNPs (rs7014346, rs989902, and rs7003146) were found to be significantly associated with the susceptibility of breast cancer. The GA and AA genotypes of rs7003146 in TCF7L2, and the CA and CC genotype of rs989902 in PTPN13 were associated with reduced breast cancer risk in the Chinese Han population based on the best-fit dominant model. The GG genotype of rs7014346 in POU5F1P1 was also significantly associated with decreased breast cancer risk under the best-fit additive model. Our results confirmed the association of rs7014346 in POU5F1P1, rs989902 in PTPN13, and rs7003146 in TCF7L2 with variations in the risk of breast cancer in a Chinese Han population.

Choi M, Lee S, Choi T, Lee C
Roles of the PDZ domain-binding motif of the human papillomavirus type 16 E6 on the immortalization and differentiation of primary human foreskin keratinocytes.
Virus Genes. 2014; 48(2):224-32 [PubMed] Related Publications
A number of PDZ domain-containing proteins have been identified as binding partners for the oncoprotein E6 of the high-risk type human papillomaviruses (HPVs). These include hDlg, hScrib, MAGI1, MAGI2, and MAGI3, MUPP1, 14-3-3zeta, Na/H exchange regulatory factor 1, PTPN13, TIP-2/GIPC, Tip-1, and PATJ. The PDZ domain-binding motif (-X-T-X-V) at the carboxy terminus of E6 is essential for targeting PDZ proteins for proteasomal degradation. However, contribution of degradation of PDZ proteins by E6 to HPV-induced oncogenesis is still controversial. In order to clarify potential roles of molecular interactions between high-risk HPV E6 and one of best characterized PDZ proteins, hDlg in HPV-induced transformation, we used a retroviral infection system to overexpress HPV16 E7 gene alone or together with either HPV16 E6 wild type or E6 mutant gene lacking the PDZ domain-binding motif and investigated the effect of mutating the PDZ domain-binding motif of E6 on the immortalization and differentiation of human foreskin keratinocytes (HFKs) by the high-risk type HPV E6 and E7. Although the PDZ domain-binding motif of E6 was found to be required for the efficient growth of HFKs, it was not necessary for the E6 and E7-induced immortalization of HFKs. Furthermore, the overexpression of E6 and E7 neither induced degradation nor altered cellular localization of hDlg in undifferentiated or differentiated HFKs. These data indicate that the PDZ domain-binding motif of E6 contributes to the efficient cellular growth through mechanisms other than degradation and changes in the subcellular localizations of hDlg.

Han XJ, Xue L, Gong L, et al.
Stat3 inhibits PTPN13 expression in squamous cell lung carcinoma through recruitment of HDAC5.
Biomed Res Int. 2013; 2013:468963 [PubMed] Free Access to Full Article Related Publications
Proteins of the protein tyrosine phosphatase (PTP) family are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, and apoptosis. PTPN13 (also known as FAP1, PTPL1, PTPLE, PTPBAS, and PTP1E), a putative tumor suppressor, is frequently inactivated in lung carcinoma through the loss of either mRNA or protein expression. However, the molecular mechanisms underlying its dysregulation have not been fully explored. Interleukin-6 (IL-6) mediated Stat3 activation is viewed as crucial for multiple tumor growth and progression. Here, we demonstrate that PTPN13 is a direct transcriptional target of Stat3 in the squamous cell lung carcinoma. Our data show that IL-6 administration or transfection of a constitutively activated Stat3 in HCC-1588 and SK-MES-1 cells inhibits PTPN13 mRNA transcription. Using luciferase reporter and ChIP assays, we show that Stat3 binds to the promoter region of PTPN13 and promotes its activity through recruiting HDAC5. Thus, our results suggest a previously unknown Stat3-PTPN13 molecular network controlling squamous cell lung carcinoma development.

Han X, Xue L, Zhou L, et al.
The role of PTPN13 in invasion and metastasis of lung squamous cell carcinoma.
Exp Mol Pathol. 2013; 95(3):270-5 [PubMed] Related Publications
OBJECTIVES: PTPN13 is a new candidate tumor-suppressing gene. To investigate the PTPN13 expression and its potential function in the invasion and metastasis of lung squamous cell carcinoma (LSCC), we performed this study in 91 primary LSCC tissues and the adjacent non-cancerous tissues.
METHODS: The mRNA expression of PTPN13 and FAK was quantitated by reverse transcription polymerase chain reaction. The protein expression of PTPN13, focal adhesion kinase (FAK) and phosphorylated FAK (P-FAK) was evaluated using immunohistochemical staining and western blotting. The association among PTPN13 expression, FAK expression and the clinicopathological parameters were analyzed.
RESULTS: PTPN13 expression was down-regulated in LSCC, and was negatively correlated with the cancer grade and stage. FAK mRNA, as well as FAK protein level was elevated in LSCC tissues. P-FAK level, also found increased, had no association with FAK mRNA and FAK protein expression, but had a negative correlation with the PTPN13 expression. P-FAK level had a significant positive correlation with the TNM classification.
CONCLUSION: The over-expression of FAK and increased FAK phosphorylation plays an important role in the invasion and metastasis of LSCC.

Castilla C, Chinchón D, Medina R, et al.
PTPL1 and PKCδ contribute to proapoptotic signalling in prostate cancer cells.
Cell Death Dis. 2013; 4:e576 [PubMed] Free Access to Full Article Related Publications
PTPL1 is a non-receptor protein tyrosine phosphatase involved in apoptosis regulation, although controversial findings have been reported in different cancer types. We report here a proapoptotic role for PTPL1 in PC3 and LNCaP prostate cancer cells, as its absence induces apoptosis resistance upon treatment with different drugs. In PC3 cells, PTPL1 silencing by small interfering RNA influences the expression levels of Bcl-xL and Mcl-1(S) proteins as well as final events in the apoptotic process such as activation of caspases and caspase-mediated cleavage of proteins like Mcl-1 or poly (ADP-ribose) polymerase. We have identified PKCδ as an intermediary of PTPL1-mediated apoptotic signalling and that phosphorylation status of NF-κB and IκBα is influenced by PTPL1 and PKCδ. Furthermore, the loss of PTPL1 and PKCδ expression in poorly differentiated, more aggressive human prostate cancers also indicate that their absence could be related to apoptosis resistance and tumour progression.

Huang W, Bei L, Eklund EA
Fas-associated phosphatase 1 (Fap1) influences βcatenin activity in myeloid progenitor cells expressing the Bcr-abl oncogene.
J Biol Chem. 2013; 288(18):12766-76 [PubMed] Free Access to Full Article Related Publications
Increased βcatenin activity correlates with leukemia stem cell expansion and disease progression in chronic myeloid leukemia (CML). We found previously that expression of the CML-related Bcr-abl oncoprotein in myeloid progenitor cells increases expression of Fas-associated phosphatase 1 (Fap1). This resulted in Fap1-dependent resistance to Fas-induced apoptosis in these cells. Fap1 also interacts with the adenomatous polyposis coli (Apc) protein, but the functional significance of this interaction is unknown. Apc participates in a complex that includes glycogen synthase kinase β (Gsk3β) and βcatenin. Assembly of this complex results in phosphorylation of βcatenin by Gsk3β, which facilitates βcatenin ubiquitination and degradation by the proteasome. In this study, we found increased association of Fap1 with the Apc complex in Bcr-abl(+) myeloid progenitor cells. We also found Fap1-dependent inactivation of Gsk3β and consequent stabilization of βcatenin in these cells. Consistent with this, Bcr-abl(+) cells exhibited a Fap1-dependent increase in βcatenin activity. Our studies identified Fap1-dependent Gsk3β inactivation as a molecular mechanism for increased βcatenin activity in CML.

Hagemann N, Ackermann N, Christmann J, et al.
The serologically defined colon cancer antigen-3 interacts with the protein tyrosine phosphatase PTPN13 and is involved in the regulation of cytokinesis.
Oncogene. 2013; 32(39):4602-13 [PubMed] Related Publications
Cytokinesis is the final step of cell division. Increasing evidence suggests failure of cytokinesis might contribute to the development of cancer. Here, we demonstrate that the serologically defined colon cancer antigen-3 (SDCCAG3) forms a complex with PTPN13, a protein tyrosine phosphatase known to be involved in the regulation of cytokinesis, carcinogenesis and tumor aggressiveness. We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. SDCCAG3 undergoes dynamic localization during cell division with strong accumulation at the midbody during cytokinesis. Overexpression as well as downregulation correlates with the generation of multinucleate cells. Furthermore, we show interaction of SDCCAG3 with the Arf GTPase activating protein GIT1 (G protein-coupled receptor kinase interactor-1). Overexpression of an ArfGAP-negative version of GIT1 also results in an increased number of multinucleate cells suggesting regulation of Arf-mediated vesicular trafficking or signaling via SDCCAG3. Finally, we demonstrate that SDCCAG3 expression levels are elevated in colon cancers. In summary, we have established SDCCAG3 as a novel endosomal protein, which is involved in the regulation of cytokinesis.

Wieking BG, Vermeer DW, Spanos WC, et al.
A non-oncogenic HPV 16 E6/E7 vaccine enhances treatment of HPV expressing tumors.
Cancer Gene Ther. 2012; 19(10):667-74 [PubMed] Free Access to Full Article Related Publications
Human papillomaviruses (HPVs) are the causative factor for >90% of cervical cancers and 25% of head and neck cancers. The incidence of HPV positive (+) head and neck squamous cell carcinomas has greatly increased in the last 30 years. E6 and E7 are the two key viral oncoproteins that induce and propagate cellular transformation. An immune response generated during cisplatin/radiation therapy improves tumor clearance of HPV(+) cancers. Augmenting this induced response during therapy with an adenoviral HPV16 E6/E7 vaccine improves long-term survival in pre-clinical models. Here, we describe the generation of an HPV16 E6/E7 construct, which contains mutations that render E6/E7 non-oncogenic, while preserving antigenicity. These mutations do not allow E6/E7 to degrade p53, pRb, PTPN13, or activate telomerase. Non-oncogenic E6/E7 (E6(Δ)/E7(Δ)) expressed as a stable integrant, or in the [E1-, E2b-] adenovirus, lacks the ability to transform human cells while retaining the ability to induce an HPV-specific immune response. Moreover, E6(Δ)/E7(Δ) plus chemotherapy/radiation statistically enhances clearance of established HPV(+) cancer in vivo.

Chaudhry P, Srinivasan R, Patel FD
Differential expression of Fas family members and Bcl-2 family members in benign versus malignant epithelial ovarian cancer (EOC) in North Indian population.
Mol Cell Biochem. 2012; 368(1-2):119-26 [PubMed] Related Publications
Epithelial ovarian cancer (EOC) represents the most challenging of gynecological malignancies. Defective apoptosis is a major causative factor in the development and progression of cancer. The two important pathways of apoptosis are extrinsic death receptor pathway (Fas family) and intrinsic mitochondrial pathway (Bcl-2 family). In this study, differential protein expression of the major Fas family members (Fas, FasL, and FAP-1) and Bcl-2 family members (Bax, Bcl-2, and Bcl-X(L)) in benign versus malignant surface epithelial ovarian tumors was evaluated at the protein level by immunohistochemistry. The expression of these molecules was compared in 30 benign versus 35 malignant surface epithelial ovarian tumors. The findings of the present study showed that there was no significant difference in the expression of the Fas family members in benign and malignant ovarian tumors. However, benign tumors showed higher levels of anti-apoptotic Bcl-2 protein levels (p < 0.009), whereas malignant tumors showed higher levels of pro-apoptotic Bax (p < 0.001). In general, there was no significant difference in Bcl-X(L) protein levels. The observations made in the present study suggest that alterations in expression of the Fas family and the Bcl-2 family members occur and play a key role in the deregulated growth of epithelial ovarian cancer.

Frau M, Simile MM, Tomasi ML, et al.
An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis.
Cell Oncol (Dordr). 2012; 35(3):163-73 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND AIMS: Hepatocarcinogenesis is under polygenic control. We analyzed gene expression patterns of dysplastic liver nodules (DNs) and hepatocellular carcinomas (HCCs) chemically-induced in F344 and BN rats, respectively susceptible and resistant to hepatocarcinogenesis.
METHODS: Expression profiles were performed by microarray and validated by quantitative RT-PCR and Western blot.
RESULTS: Cluster analysis revealed two distinctive gene expression patterns, the first of which included normal liver of both strains and BN nodules, and the second one F344 nodules and HCC of both strains. We identified a signature predicting DN and HCC progression, characterized by highest expression of oncosuppressors Csmd1, Dmbt1, Dusp1, and Gnmt, in DNs, and Bhmt, Dmbt1, Dusp1, Gadd45g, Gnmt, Napsa, Pp2ca, and Ptpn13 in HCCs of resistant rats. Integrated gene expression data revealed highest expression of proliferation-related CTGF, c-MYC, and PCNA, and lowest expression of BHMT, DMBT1, DUSP1, GADD45g, and GNMT, in more aggressive rat and human HCC. BHMT, DUSP1, and GADD45g expression predicted patients' survival.
CONCLUSIONS: Our results disclose, for the first time, a major role of oncosuppressor genes as effectors of genetic resistance to hepatocarcinogenesis. Comparative functional genomic analysis allowed discovering an evolutionarily conserved gene expression signature discriminating HCC with different propensity to progression in rat and human.

Winterhoff BJ, Arlt A, Duttmann A, et al.
Characterisation of FAP-1 expression and CD95 mediated apoptosis in the A818-6 pancreatic adenocarcinoma differentiation system.
Differentiation. 2012; 83(3):148-57 [PubMed] Related Publications
The present study investigated the expression and localisation of FAP-1 (Fas associated phosphatase-1) and CD95 in a 3D differentiation model in comparison to 2D monolayers of the pancreatic adenocarcinoma cell line A818-6. Under non-adherent growth conditions, A818-6 cells differentiate into 3D highly organised polarised epithelial hollow spheres, resembling duct-like structures. A818-6 cells showed a differentiation-dependent FAP-1 localisation. Cells grown as 2D monolayers revealed FAP-1 staining in a juxtanuclear cisternal position, as well as localisation in the nucleus. After differentiation into hollow spheres, FAP-1 was relocated towards the actin cytoskeleton beneath the outer plasma membrane of polarised cells and no further nuclear localisation was observed. CD95 surface staining was found only in a subset of A818-6 monolayer cells, while differentiated hollow spheres appeared to express CD95 in all cells of a given sphere. We rarely observed co-localisation of CD95 and FAP-1 in A818-6 monolayer cells, but strong co-localisation beneath the outer plasma membrane in polarised cells. Analysis of surface expression by flow cytometry revealed that only a subset (36%) of monolayer cells showed CD95 surface expression, and after induction of hollow spheres, CD95 presentation at the outer plasma membrane was reduced to 13% of hollow spheres. Induction of apoptosis by stimulation with agonistic anti-CD95 antibodies, resulted in increased caspase activity in both, monolayer cells and hollow spheres. Knock down of FAP-1 mRNA in A818-6 monolayer cells did not alter resposiveness to CD95 agonistic antibodies. These data suggested that CD95 signal transduction was not affected by FAP-1 expression in A818-6 monolayer cells. In differentiated 3D hollow spheres, we found a polarisation-induced co-localisation of CD95 and FAP-1. A tight control of receptor surface representation and signalling induced apoptosis ensures controlled removal of individual cells instead of a "snowball effect" of apoptotic events.

Vermeer PD, Bell M, Lee K, et al.
ErbB2, EphrinB1, Src kinase and PTPN13 signaling complex regulates MAP kinase signaling in human cancers.
PLoS One. 2012; 7(1):e30447 [PubMed] Free Access to Full Article Related Publications
In non-cancerous cells, phosphorylated proteins exist transiently, becoming de-phosphorylated by specific phosphatases that terminate propagation of signaling pathways. In cancers, compromised phosphatase activity and/or expression occur and contribute to tumor phenotype. The non-receptor phosphatase, PTPN13, has recently been dubbed a putative tumor suppressor. It decreased expression in breast cancer correlates with decreased overall survival. Here we show that PTPN13 regulates a new signaling complex in breast cancer consisting of ErbB2, Src, and EphrinB1. To our knowledge, this signaling complex has not been previously described. Co-immunoprecipitation and localization studies demonstrate that EphrinB1, a PTPN13 substrate, interacts with ErbB2. In addition, the oncogenic V660E ErbB2 mutation enhances this interaction, while Src kinase mediates EphrinB1 phosphorylation and subsequent MAP Kinase signaling. Decreased PTPN13 function further enhances signaling. The association of oncogene kinases (ErbB2, Src), a signaling transmembrane ligand (EphrinB1) and a phosphatase tumor suppressor (PTPN13) suggest that EphrinB1 may be a relevant therapeutic target in breast cancers harboring ErbB2-activating mutations and decreased PTPN13 expression.

Castilla C, Flores ML, Conde JM, et al.
Downregulation of protein tyrosine phosphatase PTPL1 alters cell cycle and upregulates invasion-related genes in prostate cancer cells.
Clin Exp Metastasis. 2012; 29(4):349-58 [PubMed] Related Publications
PTPL1, a non-receptor type protein tyrosine phosphatase, has been involved in the regulation of apoptosis and invasiveness of various tumour cell types, but its role in prostate cancer remained to be investigated. We report here that downregulation of PTPL1 by small interfering RNA in PC3 cells decreases cell proliferation and concomitantly reduces the expression of cell cycle-related proteins such as cyclins E and B1, PCNA, PTTG1 and phospho-histone H3. PTPL1 downregulation also increases the invasion ability of PC3 cells through Matrigel coated membranes. cDNA array of PTPL1-silenced PC3 cells versus control cells showed an upregulation of invasion-related genes such as uPA, uPAR, tPA, PAI-1, integrin α6 and osteopontin. This increased expression was also confirmed in PTPL1-silenced DU145 prostate cancer cells by quantitative real time PCR and western blot. These findings suggest that PTPL1 is an important mediator of central cellular processes such as proliferation and invasion.

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