DEC1

Gene Summary

Gene:DEC1; deleted in esophageal cancer 1
Aliases: CTS9
Location:9q32
Summary:The function of this gene is not known. This gene is located in a region commonly deleted in esophageal squamous cell carcinomas. Gene expression is reduced or absent in these carcinomas and thus this is a candidate tumor suppressor gene for esophageal squamous cell carcinomas. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:deleted in esophageal cancer 1
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
DEC1 is implicated in:
- negative regulation of cell proliferation
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 07 August 2015 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: DEC1 (cancer-related)

You J, Lin L, Liu Q, et al.
The correlation between the expression of differentiated embryo-chondrocyte expressed gene l and oral squamous cell carcinoma.
Eur J Med Res. 2014; 19:21 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study aims to explore the correlation between expression of differentiated embryo-chondrocyte expressed gene l (DEC1) and oral squamous cell carcinoma (OSCC), which could provide the reference for treatment and prognosis assessment of OSCC.
METHODS: The expression of DEC1 in tissues from 56 primary OSCC patients and 20 normal oral mucosa samples were detected using real-time polymerase chain reaction and immunohistochemical methods, respectively.
RESULTS: The results showed that the positive expression rate of DEC1 in the OSCC group was significantly higher than that in the normal group (P <0.05); further, the expression of DEC1 in different OSCC groups was statistically significant (P <0.05). The expression of DEC1 in the 1-year recurrence OSCC group was significantly higher than other groups. The expression of DEC1 in the 3-years no recurrence OSCC group was the lowest.
CONCLUSIONS: The expression of DEC1 was associated with the incidence of OSCC and there was a negative correlation between the expression of DEC1 and the prognosis of OSCC.

Ma W, Shi X, Lu S, et al.
Hypoxia-induced overexpression of DEC1 is regulated by HIF-1α in hepatocellular carcinoma.
Oncol Rep. 2013; 30(6):2957-62 [PubMed] Related Publications
Hypoxia-inducible factor-1α (HIF-1α) and differentiated embryo-chondrocyte expressed gene 1 (DEC1) are two key factors that protect hepatocellular carcinoma (HCC) cells from a hypoxic microenvironment. However, little is known concerning the effects of hypoxia on the expression of HIF-1α and DEC1 in HCC. In the present study, RT-PCR and western blotting were conducted to assay the mRNA and protein levels of HIF-1α and DEC1 under normoxia and hypoxia induced by exposure to CoCl2 for different time periods (0, 2, 4, 6, 24 and 48 h). In addition, the HIF-1α protein inhibitor, YC-1, was used to analyze the interaction between DEC1 and HIF-1α expression and the related mechanism. Results showed that expression of DEC1 in HCC was significantly upregulated at both the mRNA and protein levels, when compared with that in normal liver cells (P<0.05). Hypoxia induced the upregulation of HIF-1α in a time-dependent manner, which was also observed at the DEC1 mRNA and protein levels (P<0.05). However, hypoxia did not affect the transcription of HIF-1α (P>0.05). A positive correlation was found between HIF-1α and DEC1 expression in both BEL-7402 (r=0.885, P<0.05) and SMMC-7721 cells (r=0.826, P<0.05). Furthermore, inhibition of HIF-1α by YC-1 led to a significant decrease in DEC1 induced by hypoxia (P<0.05). We suggest that hypoxia induced the overexpression of DEC1, the mechanism of which may be related to the upregulation of HIF-1α in HCC. The efficacy of inhibiting HIF-1α and DEC1 expression as a possible treatment for HCC should be assessed in clinical trials.

Jia YF, Xiao DJ, Ma XL, et al.
Differentiated embryonic chondrocyte-expressed gene 1 is associated with hypoxia-inducible factor 1α and Ki67 in human gastric cancer.
Diagn Pathol. 2013; 8:37 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gastric cancer is a leading causes of cancer-related deaths ,but the underlying molecular mechanisms of its progression are largely unknown. Differentiated embryonic chondrocyte-expressed gene 1 (DEC1), is an important transcription factor involved in the progression of tumors and has recently been identified to be strongly inducible by hypoxia. Little is known about the contribution of DEC1 to the intracellular hypoxia and proliferation signaling events in gastric cancer.
METHODS: Immunohistochemistry was used to detect the expression of DEC1, hypoxia-inducible factor 1(HIF-1α) and Ki67 in 173 human gastric cancer samples and adjacent non-tumor tissues samples. The relationship between DEC1, HIF-1α and Ki67 was evaluated.
RESULTS: DEC1 protein was persistently expressed in the nucleus and cytoplasm of gastric cancer tissue. The protein expression of DEC1 and HIF-1α in tumour tissues was 83.8% and 54.3%, respectively, and was significantly higher than that in adjacent normal tissues (83.8% vs 23.7%, P < 0.001; 54.3% vs 12.7%, P < 0.001). The expression of DEC1 and HIF-1α was associated with poor histological differentiation. (P < 0. 01). Furthermore, DEC1 level was positively correlated with HIF-1α (P < 0. 01, r=0.290) and Ki67 expression (P < 0. 01, r=0.249).
CONCLUSION: The upregulation of DEC1 may play an important role in hypoxia regulation and cell proliferation in gastric cancer. The relevant molecular mechanism requires further investigation.

Liu Y, Miao Y, Wang J, et al.
DEC1 is positively associated with the malignant phenotype of invasive breast cancers and negatively correlated with the expression of claudin-1.
Int J Mol Med. 2013; 31(4):855-60 [PubMed] Related Publications
Differentiated embryo-chondrocyte expressed gene 1 (DEC1) is a basic helix-loop-helix transcriptional regulator, reportedly involved in cell growth, differentiation, apoptosis and tumorigenesis. In breast cancer, DEC1 expression correlates with increased malignant potential and invasiveness. Nevertheless, the detailed mechanisms by which DEC1 modulates breast cancer progression are still unclear. Claudin-1, an important tight junction protein, functions as a tumor invasion suppressor. In the present study, the relationship between DEC1 and claudin-1 in 147 cases of invasive breast ductal carcinomas was examined by immunohistochemistry. Based on the data, DEC1 expression was elevated in invasive breast ductal carcinomas and DEC1 levels were positively correlated with tumor grade (P=0.023). Moreover, DEC1 expression was negatively correlated with the claudin-1 level (correlation coefficient =-0.245, P=0.003). We further identified that, in MCF-7 and MDA-MB-231 breast cancer cell lines, DEC1 knockdown led to the enhanced expression of claudin-1 at both the mRNA and protein levels, and reduced cell invasive capacity. Collectively, our data suggest that overexpression of DEC1 may promote the invasiveness of breast cancer through downregulation of claudin-1.

Liu Y, Wang L, Lin XY, et al.
The transcription factor DEC1 (BHLHE40/STRA13/SHARP-2) is negatively associated with TNM stage in non-small-cell lung cancer and inhibits the proliferation through cyclin D1 in A549 and BE1 cells.
Tumour Biol. 2013; 34(3):1641-50 [PubMed] Related Publications
The objective of the current study was to investigate the expression pattern and clinicopathological significance of differentiated embryo-chondrocyte-expressed gene 1 (DEC1) in patients with non-small-cell lung cancer (NSCLC). In 118 archived NSCLC tissues, the positive rate of DEC1 was reduced in human lung cancer samples (36/118, 30.5 %) compared with adjacent normal lung tissues (106/118, 89.8 %), as measured by immunohistochemical staining. Loss of DEC1 was correlated with poor differentiation (p=0.005) and high p-TNM stage (p=0.002). Consistently, downregulation of DEC1 by siRNA knockdown promoted the growth and colony formation in the A549 lung cancer cell line, and overexpression of DEC1 inhibited the growth and colony formation in the BE1 lung cancer cell line. In addition, a significant negative correlation was found between DEC1 and cyclin D1 (p=0.014) in 118 cases of NSCLC. Knockdown of DEC1 resulted in the upregulation of cyclin D1, and overexpression of DEC1 led to the downregulation of cyclin D1. Together with the observation that DEC1 bound directly to the promoter region of cyclin D1 in A549 cells, these results indicate that loss of DEC1 may promote tumor progression in NSCLC through upregulation of cyclin D1, and DEC1 might serve as a novel therapeutic target of NSCLC.

Xu Q, Ma P, Hu C, et al.
Overexpression of the DEC1 protein induces senescence in vitro and is related to better survival in esophageal squamous cell carcinoma.
PLoS One. 2012; 7(7):e41862 [PubMed] Free Access to Full Article Related Publications
Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related death in China and has limited effective therapeutic options except for early surgery, since the underlying molecular mechanism driving its precursor lesions towards invasive ESCC is not fully understood. Cellular senescence is the state of the permanent growth arrest of a cell, and is considered as the initial barrier of tumor development. Human differentiated embryo chondrocyte expressed gene 1 (Dec1) is an important transcription factor that related to senescence. In this study, DEC1 immunohistochemical analysis was performed on tissue microarray blocks constructed from ESCC combined with adjacent precursor tissues of 241 patients. Compared with normal epithelia, DEC1 expression was significantly increased in intraepithelial neoplasia and DEC1 expression was significantly decreased in ESCC in comparison with intraepithelial neoplasia. In vitro, DEC1 overexpression induced cellular senescence, and it inhibited cell growth and colony formation in ESCC cell line EC9706. Fresh esophagectomy tissue sections from five ESCC patients were detected by immunohistochemistry of DEC1 and senescence-associated β-galactosidase (SA-β-Gal) activity, and strongly positive expression of DEC1 was correlated to more senescent cells in these fresh tissue sections. Kaplan-Meier method analysis of the 241 patients revealed that DEC1 expression levels were significantly correlated with the survival of ESCC patients after surgery. The expression levels of DEC1 were also correlated with age, tumor embolus, depth of invasion of ESCC, lymph metastasis status and pTNMs. These results suggest that DEC1 overexpression in precursor lesions of ESCC is a protective mechanism by inducing cellular senescence in ESCC initiation, and DEC1 may be a potential prognostic marker of ESCC.

Wu Y, Sato F, Yamada T, et al.
The BHLH transcription factor DEC1 plays an important role in the epithelial-mesenchymal transition of pancreatic cancer.
Int J Oncol. 2012; 41(4):1337-46 [PubMed] Related Publications
DEC1 (BHLHE40/Stra13/Sharp2) is a basic helix-loop-helix (bHLH) transcription factor that is involved in the regulation of apoptosis and cell proliferation and the response to hypoxia. Epithelial-mesenchymal transition (EMT) is an important step leading to invasion and migration of various tumor cells, and TGF-β treatment has been shown to induce cancer cells to undergo EMT. However, the significance of DEC1 in TGF-β-induced EMT remains unknown. We examined the role of DEC1 in EMT of PANC-1 cells, a human pancreatic cancer cell line. As a result, we found that DEC1 was upregulated by TGF-β in PANC-1 cells, and regulated the expression and the levels of nuclear, cytoplasmic or membrane localization of EMT-related factors, including phosphorylated Smad3 (pSmad3), snail, claudin-4 and N-cadherin. In the presence of TGF-β, DEC1 knockdown by siRNA inhibited morphological changes during EMT processes, while TGF-β induced PANC-1 cells to taken on a spindle-shaped morphology. Furthermore, a combination treatment of DEC1 expression with TGF-β was closely linked to the migration and invasion of PANC-1 cells. Immunohistochemically, DEC1 and pSmad3 were detected within pancreatic cancer tissues, whereas claudin-4 expression was weaker in the cancer tissues compared with the adjacent non-cancer pancreatic tissues. These findings suggest that DEC1 plays an important role in the regulation of these EMT-related factors in pancreatic cancer.

Wu Y, Sato F, Bhawal UK, et al.
BHLH transcription factor DEC2 regulates pro-apoptotic factor Bim in human oral cancer HSC-3 cells.
Biomed Res. 2012; 33(2):75-82 [PubMed] Related Publications
DEC1 (BHLHE40/Stra13/Sharp2) and DEC2 (BHLHE41/Sharp1) are basic helix-loop-helix (bHLH) transcription factors that are involved in the regulation of apoptosis, cell proliferation, circadian rhythms and the response to hypoxia. We previously showed the functional effects of DEC1 and DEC2 on apoptosis in human breast cancer MCF-7 cells. However, the roles of DEC1 and DEC2 in oral cancer are poorly understood. We examined whether DEC1 and DEC2 are involved in the regulation of apoptosis in human oral cancer HSC-3 and CA9-22 cells. The expression of DEC2 was upregulated by cis-diamminedichloroplatinum (II) (cisplatin: CDDP) treatment in HSC-3 cells, whereas CDDP treatment had little effects on the expression of DEC2 in CA9-22 cells. We showed that DEC2 overexpression inhibits pro-apoptotic factor Bim and inhibits apoptosis induced by CDDP in HSC-3 cells, whereas it had little effects on apoptosis in CA9-22 cells. DEC1 overexpression had little effects on apoptosis induced by CDDP in these cells. We also found that CDDP upregulated the amounts of DEC2 in the nucleus in HSC-3 cells. These results suggest that DEC2 has anti-apoptotic effects on apoptosis induced by CDDP in HSC-3 cells.

Wei H, Ke HL, Lin J, et al.
MicroRNA target site polymorphisms in the VHL-HIF1α pathway predict renal cell carcinoma risk.
Mol Carcinog. 2014; 53(1):1-7 [PubMed] Free Access to Full Article Related Publications
Renal cell carcinoma (RCC) accounts for ∼4% of all human malignancies and is the 9th leading cause of male cancer death in the United States. The purpose of this study was to determine the effect of variation within microRNA (miRNA)-binding sites of genes in the VHL-HIF1α pathway on RCC risk. We identified 429 miRNA-binding site single-nucleotide polymorphisms (SNPs) in 102 pathway genes and assessed 53 tagging-SNPs for 31 of these genes for risk in a case-control study consisting of 894 RCC cases and 1,516 controls. Results showed that five SNPs were significantly associated with RCC risk. The most significant finding was rs743409 in MAPK1. Under the additive model, the variant was associated with a 10% risk reduction (OR: 0.90, 95% CI, 0.77-0.98). Other significant findings were for SNPs in CDCP1, TFRC, and DEC1. Cumulative effects analysis showed that subjects carrying four or five unfavorable genotypes had a 2.14-fold increase in risk (95% CI, 1.03-4.43, P = 0.04) than those with no unfavorable genotypes. Potential higher-order gene-gene interactions were identified and categorized subjects into different risk groups. The OR of the high-risk group defined by two SNPs: CDCP1:rs6773576 (GG) and DEC1:rs10982724 (GG) was 4.46 times higher than that of low-risk reference group (95% CI, 1.31-15.08). Overall, our study provides the first evidence supporting a connection between miRNA-binding site SNPs within the VHL-HIF1α pathway and RCC risk. These novel genetic risk factors might help identify individuals at high risk to enable detection of tumors at an early, curable stage.

Feige E, Yokoyama S, Levy C, et al.
Hypoxia-induced transcriptional repression of the melanoma-associated oncogene MITF.
Proc Natl Acad Sci U S A. 2011; 108(43):E924-33 [PubMed] Free Access to Full Article Related Publications
Microphthalmia-associated transcription factor (MITF) regulates normal melanocyte development and is also a lineage-selective oncogene implicated in melanoma and clear-cell sarcoma (i.e., melanoma of soft parts). We have observed that MITF expression is potently reduced under hypoxic conditions in primary melanocytes and melanoma and clear cell sarcoma cells through hypoxia inducible factor 1 (HIF1)-mediated induction of the transcriptional repressor differentially expressed in chondrocytes protein 1 (DEC1) (BHLHE40), which subsequently binds and suppresses the promoter of M-MITF (melanocyte-restricted MITF isoform). Correspondingly, hypoxic conditions or HIF1α stabilization achieved by using small-molecule prolyl-hydroxylase inhibitors reduced M-MITF expression, leading to melanoma cell growth arrest that was rescued by ectopic expression of M-MITF in vitro. Prolyl hydroxylase inhibition also potently suppressed melanoma growth in a mouse xenograft model. These studies illuminate a physiologic hypoxia response in pigment cells leading to M-MITF suppression, one that suggests a potential survival advantage mechanism for MITF amplification in metastatic melanoma and offers a small-molecule strategy for suppression of the MITF oncogene in vivo.

Zheng Y, Shi X, Wang M, et al.
The increased expression of DEC1 gene is related to HIF-1α protein in gastric cancer cell lines.
Mol Biol Rep. 2012; 39(4):4229-36 [PubMed] Related Publications
Overexpression of differentiated embryo chondrocyte 1 (DEC1) has been reported to contribute to the cellular differentiation, proliferation, and apoptosis of various cancers. Our previous studies have shown that DEC1 was highly expressed in gastric cancer (GCa) tissues. However, there is no report about the expression of DEC1 in GCa cell lines until now. In this study, We evaluated the mRNA and protein expression of DEC1 and hypoxia-inducible factor 1α (HIF-1α) under normoxic and hypoxic conditions in six GCa cell lines: BGC-823, MGC80-3, MKN1, AGS, FU97 and SGC-7901. An HIF-1α protein inhibitor was used to analyze the association of DEC1 and HIF-1α expression. Under normoxia, the mRNA expression of both HIF-1α and DEC1 was moderate, whereas the protein expression of DEC1 was higher than that of HIF-1α. Hypoxia induced the mRNA expression of DEC1 and the protein expression of HIF-1α and DEC1 in a time-dependent manner but had no effect on the mRNA expression of HIF-1α. Furthermore, inhibition of HIF-1α protein expression resulted in a significant decrease in both the mRNA and protein expression of DEC1. Taken together, DEC1 expression is correlated with HIF-1α protein in GCa cell line, blockage of HIF-1α protein led to reduced DEC1 expression. The efficacy of inhibiting HIF-1α and DEC1 expression should be tested in clinical trials as possible treatment for GCa.

Phadke M, Krynetskaia N, Mishra A, Krynetskiy E
Accelerated cellular senescence phenotype of GAPDH-depleted human lung carcinoma cells.
Biochem Biophys Res Commun. 2011; 411(2):409-15 [PubMed] Free Access to Full Article Related Publications
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a pivotal glycolytic enzyme, and a signaling molecule which acts at the interface between stress factors and the cellular apoptotic machinery. Earlier, we found that knockdown of GAPDH in human carcinoma cell lines resulted in cell proliferation arrest and chemoresistance to S phase-specific cytotoxic agents. To elucidate the mechanism by which GAPDH depletion arrests cell proliferation, we examined the effect of GAPDH knockdown on human carcinoma cells A549. Our results show that GAPDH-depleted cells establish senescence phenotype, as revealed by proliferation arrest, changes in morphology, SA-β-galactosidase staining, and more than 2-fold up-regulation of senescence-associated genes DEC1 and GLB1. Accelerated senescence following GAPDH depletion results from compromised glycolysis and energy crisis leading to the sustained AMPK activation via phosphorylation of α subunit at Thr172. Our findings demonstrate that GAPDH depletion switches human tumor cells to senescent phenotype via AMPK network, in the absence of DNA damage. Rescue experiments using metabolic and genetic models confirmed that GAPDH has important regulatory functions linking the energy metabolism and the cell cycle networks. Induction of senescence in LKB1-deficient non-small cell lung cancer cells via GAPDH depletion suggests a novel strategy to control tumor cell proliferation.

Bhawal UK, Sato F, Arakawa Y, et al.
Basic helix-loop-helix transcription factor DEC1 negatively regulates cyclin D1.
J Pathol. 2011; 224(3):420-9 [PubMed] Related Publications
DEC1 (also known as Stra13/Bhlhb2/Sharp2) and DEC2 (also known as Bhlhb3/Sharp1) are two paralogous basic helix-loop-helix (bHLH) transcriptional regulators which exhibit a robust circadian gene expression pattern in the suprachiasmatic nucleus (SCN) and in peripheral organs. DEC1 has been suggested to play key roles in mammalian cell differentiation, the cell cycle and circadian regulation, hypoxia response, and carcinogenesis. Here we show that DEC1 overexpression exhibits delayed wound healing and reduces cell proliferation, migration, and invasion. DEC1 strongly repressed the promoter activity of cyclin D1. We further identify a possible DEC-response element in the cyclin D1 promoter region, and confirmed the direct binding of DEC1 to that element. Forced expression of DEC1 efficiently repressed the cyclin D1 promoter and expression. Our clinical data provide the first evidence that there is a strong inverse correlation between DEC1 and cyclin D1 expression in oral cancer, and DEC1 expression significantly correlated with clinicopathological parameters. We suggest that radiation-induced DEC1 overexpression and Akt phosphorylation in cancer cells are mediated via PI-3K signalling. Overexpression of DEC1 activates the PI-3K/Akt signalling pathway through reactive oxygen species (ROS).

Wu Y, Sato F, Bhawal UK, et al.
Basic helix-loop-helix transcription factors DEC1 and DEC2 regulate the paclitaxel-induced apoptotic pathway of MCF-7 human breast cancer cells.
Int J Mol Med. 2011; 27(4):491-5 [PubMed] Related Publications
Differentiated embryonic chondrocyte gene (DEC) 1 (BHLHE40/Stra13/Sharp2) and DEC2 (BHLHE41/Sharp1) are basic helix-loop-helix (bHLH) transcription factors that are associated with the regulation of apoptosis, cell proliferation and circadian rhythms, as well as malignancy in various cancers. However, the roles of DEC1 and DEC2 expression in breast cancer are poorly understood. In this study, we sought to examine the roles of DEC1 and DEC2 in MCF-7 human breast cancer cells that had been treated with paclitaxel. The expression of DEC1 and DEC2 was up-regulated in paclitaxel-treated MCF-7 cells. Knockdown of DEC1 by siRNA decreased the amount of cleaved poly (ADP-ribose) polymerase (PARP), after treatment with paclitaxel, whereas DEC2 knockdown increased the amount of cleaved PARP in both the presence and absence of paclitaxel. Immunofluorescent staining revealed that paclitaxel treatment increased the amount of DEC1 in the nucleus, and increased the amount of DEC2 in both the nucleus and cytoplasm. These results indicate that DEC1 has pro-apoptotic effects, whereas DEC2 has anti-apoptotic effects on the paclitaxel-induced apoptosis in human breast cancer MCF-7 cells.

Kunimoto Y, Nakano S, Kataoka H, et al.
Deleted in Esophageal Cancer 1(DEC1) is down-regulated and contributes to migration in head and neck squamous cell carcinoma cell lines.
ORL J Otorhinolaryngol Relat Spec. 2011; 73(1):17-23 [PubMed] Related Publications
BACKGROUND: Previous studies have shown that the expression of Deleted in Esophageal Cancer 1 (DEC1) is significantly reduced in esophageal squamous cell carcinoma. Patients with head and neck squamous cell carcinoma (HNSCC) often develop esophageal carcinomas.
MATERIALS AND METHODS: We analyzed the expression of DEC1 and histone modifications in HNSCC cell lines. The motility and invasive ability of the HNSCC cell lines were also studied.
RESULTS: Of 18 cell lines, 12 (66.7%) showed down-regulation of DEC1. Chromatin immunoprecipitation assays indicated that H3 K27 trimethylation levels in the DEC1-down-regulated cell lines were greater than that in the DEC1-expressed cell lines. Migration assays showed that the DEC1-down-regulated cell lines tended to be more motile than the DEC1-expressed cell lines.
CONCLUSION: DEC1 is down-regulated and tends to contribute to the migration ability of HNSCC cell lines. In addition, H3 K27 trimethylation potentially plays an important role in the regulation of DEC1 expression.

Huang YJ, Niu J, Wei S, et al.
A novel functional DEC1 promoter polymorphism -249T>C reduces risk of squamous cell carcinoma of the head and neck.
Carcinogenesis. 2010; 31(12):2082-90 [PubMed] Free Access to Full Article Related Publications
Human DEC1 (deleted in esophageal cancer 1) gene is located on chromosome 9q, a region frequently deleted in various types of human cancers, including squamous cell carcinoma of the head and neck (SCCHN). However, only one epidemiological study has evaluated the association between DEC1 polymorphisms and cancer risk. In this hospital-based case-control study, four potentially functional single-nucleotide polymorphisms -1628 G>A (rs1591420), -606 T>C [rs4978620, in complete linkage disequilibrium with -249T>C (rs2012775) and -122 G>A(rs2012566)], c.179 C>T p.Ala60Val (rs2269700) and 3' untranslated region-rs3750505 as well as the TP53 tumor suppressor gene codon 72 (Arg72Pro, rs1042522) polymorphism were genotyped in 1111 non-Hispanic Whites SCCHN patients and 1130 age-and sex-matched cancer-free controls. After adjustment for age, sex and smoking and drinking status, the variant -606CC (i.e. -249CC) homozygotes had a significantly reduced SCCHN risk (adjusted odds ratio = 0.71, 95% confidence interval = 0.52-0.99) compared with the -606TT homozygotes. Stratification analyses showed that a reduced risk associated with the -606CC genotype was more pronounced in subgroups of non-smokers, non-drinkers, younger subjects (defined as ≤57 years), carriers of the TP53 Arg/Arg (rs1042522) genotype, patients with oropharyngeal cancer or late-stage SCCHN. Further in silico analysis revealed that the -249 T-to-C change led to a gain of a transcription factor-binding site. Additional functional analysis showed that the -249T-to-C change significantly enhanced transcriptional activity of the DEC1 promoter and the DNA-protein-binding activity. We conclude that the DEC1 promoter -249 T>C (rs2012775) polymorphism is functional, modulating susceptibility to SCCHN among non-Hispanic Whites.

Liu Y, Sato F, Kawamoto T, et al.
Anti-apoptotic effect of the basic helix-loop-helix (bHLH) transcription factor DEC2 in human breast cancer cells.
Genes Cells. 2010; 15(4):315-25 [PubMed] Related Publications
DEC1 (BHLHB2/Stra13/Sharp2) and DEC2 (BHLHB3/Sharp1) are basic helix-loop-helix (bHLH) transcription factors that are involved in circadian rhythms, differentiation and the responses to hypoxia. We examined whether DEC1 and DEC2 are involved in apoptosis regulation, in human breast cancer MCF-7 cells. We found that siRNA-mediated knockdown of DEC2 resulted in marked enhancement of apoptosis compared with that in control cells transfected with nonspecific siRNA. However, knockdown of DEC1 by siRNA did not affect cell survival. Knockdown of DEC2 affected the expression of mRNA or proteins related to apoptosis, such as Fas, c-Myc, caspase-8, poly (ADP-ribose) polymerase (PARP) and Bax. We also showed that tumor necrosis factor-alpha (TNF-alpha) up-regulates the expression of DEC1 and DEC2. DEC2 over-expression caused by the transfection of an expression vector reduced the amounts of cleaved PARP and caspase-8 induced by TNF-alpha treatment, whereas DEC1 over-expression increased it. Finally, we revealed that treatment with double knockdown against both DEC1 and DEC2 decreased the amounts of cleaved PARP and caspase-8 induced by DEC2 siRNA with or without TNF-alpha. These data indicate that DEC2 has an anti-apoptotic effect, whereas DEC1 has a pro-apoptotic effect, which are involved in the balance of survival of human breast cancer MCF-7 cells.

Zheng Y, Jia Y, Wang Y, et al.
The hypoxia-regulated transcription factor DEC1 (Stra13, SHARP-2) and its expression in gastric cancer.
OMICS. 2009; 13(4):301-6 [PubMed] Related Publications
Differentiated embryo-chondrocyte expressed gene 1 (DEC1), as a bHLH transcriptional factor, plays important roles in cell differentiation, proliferation, and apoptosis. The expression of DEC1 and its role in human gastric cancer are unknown. This study was designed to characterize the DEC1 gene profiling of human gastric cancer tissues. The expression of DEC1 in gastric cancer tissues was analyzed by cDNA microarray, reverse-transcriptase polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical studies. Microarray assay demonstrated that DEC1 was one of the upregulated genes in gastric cancer when compared with normal tissues. The expression of DEC1 mRNA was increased in gastric cancer as determined by RT-PCR. An increased DEC1 protein expression in gastric cancer was verified by Western blot analysis. Immunohistochemical studies showed that the 83.02% gastric cancer tissues (44/53) were stained positive for DEC1. The DEC1 expression was increased during the tumor progression from well differentiated (50%, 4/8) to moderately differentiated (76%, 13/17), and poorly differentiated (96%, 27/28) tumor tissues. In contrast, a weak staining for DEC1 (low expression) was observed in 10 % normal tissues (1/10). Statistical analysis found a significant correlation between increased DEC1 expression and poorly differentiated cancer tissues. These data characterized DEC1 expression in gastric cancer and identified a correlation between upregulation of DEC1 expression and differentiation of gastric cancer, suggesting that DEC1 may play an important role in the differentiation and progression of gastric cancer.

Pedersen M, Löfstedt T, Sun J, et al.
Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells.
Biochem Biophys Res Commun. 2008; 377(1):98-103 [PubMed] Related Publications
Signaling by the receptor for stem cell factor (SCF), c-Kit, is of major importance for hematopoiesis, melanogenesis and reproduction, and the biological responses are commonly proliferation and cell survival. Thus, constitutive activation due to c-Kit mutations is involved in the pathogenesis of several forms of cancer, e.g. leukemias, gastrointestinal stromal tumors and testicular tumors. Tumor survival requires oxygen supply through induced neovascularization, a process largely mediated by the vascular endothelial growth factor (VEGF), a prominent target of the transcription factors hypoxia-inducible factor-1 (HIF-1) and HIF-2. Using Affymetrix microarrays we have identified genes that are upregulated following SCF stimulation. Interestingly, many of the genes induced were found to be related to a hypoxic response. These findings were corroborated by our observation that SCF stimulation of the hematopoietic cell lines M-07e induces HIF-1alpha and HIF-2alpha protein accumulation at normoxia. In addition, SCF-induced HIF-1alpha was transcriptionally active, and transcribed HIF-1 target genes such as VEGF, BNIP3, GLUT1 and DEC1, an effect that could be reversed by siRNA against HIF-1alpha. We also show that SCF-induced accumulation of HIF-1alpha is dependent on both the PI-3-kinase and Ras/MEK/Erk pathways. Our data suggest a novel mechanism of SCF/c-Kit signaling in angiogenesis and tumor progression.

Qian Y, Chen X
ID1, inhibitor of differentiation/DNA binding, is an effector of the p53-dependent DNA damage response pathway.
J Biol Chem. 2008; 283(33):22410-6 [PubMed] Free Access to Full Article Related Publications
ID1, inhibitor of differentiation/DNA binding, plays an important role in cell proliferation, differentiation, and tumorigenesis. It has been shown that ID1 is de-regulated in multiple cancers and up-regulation of ID1 is correlated with high grades and poor prognosis of human cancers. In contrast, the p53 tumor suppressor was found to be mutated or inactivated in most human cancers and loss of p53 results in early onset of multiple cancers. Although the biological functions of the ID1 oncogene and the p53 tumor suppressor have been intensively investigated, little is known about the upstream regulators of ID1 and the cross-talk between ID1 and p53. Here, we showed that ID1 is down-regulated in cells treated with various DNA damage agents in a p53-dependent manner. Interestingly, we found that DEC1, which was recently identified as a p53 target and mediates p53-dependent cell cycle arrest and senescence, is capable of inhibiting ID1 expression. Conversely, we found that knockdown of DEC1 attenuates DNA damage-induced ID1 repression. In addition, we identified several potential DEC1 responsive elements in the proximal promoter region of the ID1 gene. Moreover, we showed that overexpression of ID1 or ID1', an isoform of ID1, promotes cell proliferation potentially through inhibition of p21 expression. Finally, we found that the extent of DNA damage-induced premature senescence was substantially decreased by overexpression of ID1 or ID1'. Taken together, our study suggests that p53 trans-repressional activity can be mediated by its own target DEC1 and ID1 is an effector of the p53-dependent DNA damage response pathway.

Sato F, Bhawal UK, Kawamoto T, et al.
Basic-helix-loop-helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression.
Genes Cells. 2008; 13(2):131-44 [PubMed] Related Publications
DEC1 (BHLHB2/Sharp2/Stra13) and DEC2 (BHLHB3/Sharp1) are basic-helix-loop-helix (bHLH) transcription factors, involved in cellular differentiation, responses to hypoxia and circadian rhythms. We recently showed that the expression of DEC1 and DEC2 was up-regulated by hypoxia; however, the functions of these two factors under hypoxic conditions have not been elucidated in detail. It is well established that the expression of vascular endothelial growth factor (VEGF) is up-regulated by hypoxia, and the expression of VEGF in response to hypoxia depends on transcriptional activation by a heterodimer comprising hypoxia-inducible factor 1alpha (HIF-1alpha) and arylhydrocarbon receptor nuclear translocator 1 (ARNT1). In the present study, we showed that DEC2, but not DEC1, suppressed VEGF gene expression under hypoxic conditions. DEC2 protein was co-immunoprecipitated with HIF-1alpha but not with ARNT1. The binding of HIF-1alpha to the hypoxia response element (HRE) in the VEGF promoter was decreased by DEC2 over-expression, and increased by DEC2 knockdown. We also showed that the circadian expression of VEGF showed a reciprocal pattern to that of DEC2 in cartilage. DEC2 had a circadian oscillation in implanted Sarcoma 180 cells. We conclude that DEC2 negatively regulates VEGF expression and plays an important role in the pathological conditions in which VEGF is involved.

Leung AC, Wong VC, Yang LC, et al.
Frequent decreased expression of candidate tumor suppressor gene, DEC1, and its anchorage-independent growth properties and impact on global gene expression in esophageal carcinoma.
Int J Cancer. 2008; 122(3):587-94 [PubMed] Related Publications
Previous studies showed that expression of the novel candidate tumor suppressor gene, DEC1 (Deleted in Esophageal Cancer 1), is reduced in esophageal carcinoma and suppresses cancer cell growth in vitro and tumor growth in vivo in nude mice. This study shows that DEC1 gene expression was downregulated in 100% of 16 esophageal squamous cell carcinoma (ESCC) cell lines and 52 and 45%, respectively, of esophageal tumor specimens from Hong Kong and a high-risk ESCC region of Henan, China. Using epitope tagging, the DEC1 protein was localized to both the cytoplasm and nucleus of the cell. In 3D Matrigel culture, no significant difference in colony numbers formed was observed for DEC1 stable transfectants, as compared to vector-alone transfectant controls. However, significantly smaller colony sizes were observed for the DEC1 transfectants. In in vitro cell migration, invasion and soft agar assays of DEC1 transfectants, only the soft agar assay showed statistically significant differences in colony numbers with the vector-alone controls, indicating that DEC1 may be involved in anchorage-independent cell growth. In addition, the global gene expression affected by DEC1 in tumor-suppressive stable transfectants was investigated using cDNA oligonucleotide microarray hybridization. Three candidate genes, TFPI-2, GDF15 and DUSP6, were identified through this approach; they are downregulated in tumor segregants of DEC1 stable transfectants, ESCC cell lines and esophageal tumors and have a potential role in tumor growth and progression. These studies show that DEC1 is involved in esophageal cancer development and help elucidate its functional role in tumor development.

Zhang L, Li QQ
Embryo-chondrocyte expressed gene 1, downregulating hypoxia-inducible factor 1alpha, is another marker of lung tumor hypoxia.
Acta Pharmacol Sin. 2007; 28(4):549-58 [PubMed] Related Publications
AIM: To explore the mechanism of differentiated embryo-chondrocyte expressed gene 1 (DEC1) in the lung adenocarcinoma A549 cell line and its relationship with hypoxia-inducible factor 1alpha(HIF-1alpha).
METHODS: DEC1 and HIF-1alpha protein levels were detected in lung adenocarcinoma tissues by immunohistochemistry. A549 cells were cultured at hypoxia. MTT assay was used to determine the effect of cell viability. The apoptotic analysis was determined by flow cytometry. RT-PCR and immunocytochemistry were carried out to observe the DEC1 and HIF-1alpha mRNA and protein expression. HIF-1alpha mRNA and protein levels were detected in the stably transfected pcDNA-DEC1+/- A549 cells by RT-PCR and Western blotting. DEC1 mRNA and protein levels were detected in the stably transfected pcDNA-DEC1+/- A549 cells with or without HIF-1alpha antisense oligonucleotide treatment by RT-PCR and Western blotting.
RESULTS: DEC1 was specifically located in 40 (48.8%) lung adenocarcinoma tissues. The results of the MTT test showed the growth of the stably transfected pcDNA-DEC+ A549 cells was higher than those of A549 cells and the stably transfected pcDNA-DEC- A549 cells. Hypoxia also induced the apoptosis of A549 cells and the stably transfected pcDNA-DEC+/- A549 cells. Hypoxia increased the mRNA and protein levels of DEC1 and HIF-1alpha. Both HIF-1alpha mRNA and protein levels decreased in the stably transfected pcDNA-DEC+ cells, but HIF-1alpha antisense oligonucleotide had no effect on DEC1 in the stably transfected pcDNA-DEC+/- A549 cells.
CONCLUSION: DEC1 is a marker of tumor hypoxia. DEC1 downregulates the HIF-1alpha at both mRNA and protein levels at hypoxia in lung adenocarcinoma A549 cells.

Yunokawa M, Tanimoto K, Nakamura H, et al.
Differential regulation of DEC2 among hypoxia-inducible genes in endometrial carcinomas.
Oncol Rep. 2007; 17(4):871-8 [PubMed] Related Publications
In this study, we demonstrate an important role of activation of the hypoxia-inducible factor-1 (HIF-1) pathway in endometrial carcinogenesis and tumor phenotype development of endometrial carcinoma, and suggest a unique role of the HIF-1-target gene, differentiated embryo chondrocyte 2 (DEC2), in carcinogenesis. Hypoxia caused an increase in HIF-1alpha protein expression in 4 endometrial carcinoma cell lines. The expressions of its 5 target genes - DEC1, DEC2, carbonic anhydrase-9 (CA9), vascular endothelial growth factor (VEGF), and solute carrier family 2, member 1 (SLC2A1) - also reactively increased in most of the cell lines, except for DEC2 in the SNG-M cells. The expression levels of DEC2, CA9, and SLC2A1 were significantly higher in the 4 atypical hyperplasia tissues and 82 endometrial carcinomas compared with those in the 21 normal endometria. Clinicopathological analyses of carcinoma patients revealed a significant correlation of the VEGF and SLC2A1 expression with the status of lymph-vascular involvement and lymph node metastasis. The expression levels of CA9 and VEGF were significantly higher in the tumors of post- as opposed to pre-menopausal patients. The SLC2A1 expression was also related to the FIGO stage, but the DEC2 expression was inversely related to the FIGO grade. The activation of the HIF-1 pathway could be related to endometrial carcinogenesis, and the component, DEC2, could have different expression-regulatory mechanisms and unique roles in carcinogenesis.

Koukourakis MI, Giatromanolaki A, Polychronidis A, et al.
Endogenous markers of hypoxia/anaerobic metabolism and anemia in primary colorectal cancer.
Cancer Sci. 2006; 97(7):582-8 [PubMed] Related Publications
Anemia has been implicated in the decreased oxygen tension noted within the tumor environment. In a series of 79 colorectal adenocarcinomas we investigated the role of anemia in activating molecular pathways regulated by hypoxia. Preoperative Hb levels were correlated with the immunohistochemical expression of HIF1alpha and HIF2alpha, LDH5, GLUT1, VEGF, DEC1 and BNIP3, and with angiogenesis and the cancer cell proliferation index. Upregulation of HIF1alpha and HIF2alpha proteins, found in 43% and 44.3% of cases, respectively, was not related to anemia (Hb < 10 g%). This is in agreement with other studies suggesting that HIF activation occurs for various reasons, such as poor or irregular vascularity, or oncogene activation. Nevertheless, low Hb levels (<10 g%) were linked to activated anaerobic metabolism (LDH5 overexpression) in a subset of tumors not expressing HIF1alpha (P < 0.01). Overexpression of HIFs, whether linked to anemia or not, was associated with a number of factors related to tumor aggressiveness (assessed as local invasion and nodal metastasis), anaerobic metabolism and intratumoral acidosis (LDH5, GLUT1; increased glucose metabolism to lactate), activation of genes related to necrosis (BNIP3) and angiogenesis (VEGF). Expression of BNIP3 emerged as the strongest independent factor related to transmural invasion and metastasis to lymph nodes. Identification of specific patterns of the hypoxia molecular cascade activated in cancer cells might help in developing specific therapeutic policies.

Pogue-Geile KL, Lyons-Weiler J, Whitcomb DC
Molecular overlap of fly circadian rhythms and human pancreatic cancer.
Cancer Lett. 2006; 243(1):55-7 [PubMed] Related Publications
Circumstantial evidence demonstrating a role for circadian rhythms in cancer has been presented but there is little direct molecular evidence to support this idea in human cancer. Herein, we report a significant similarity between fly genes with strong circadian rhythms and human genes under expressed in pancreatic cancer. The list of genes includes both circadian regulator genes, such as period 1 and DEC1, and downstream effectors, such as ubiquitin specific protease 30. This observation may indicate that the pancreas peripheral clock is disrupted in pancreatic cancer and are consistent with the recent proposals that circadian genes act as tumor suppressors.

Preusser M, Birner P, Ambros IM, et al.
DEC1 expression in 1p-aberrant oligodendroglial neoplasms.
Histol Histopathol. 2005; 20(4):1173-7 [PubMed] Related Publications
BACKGROUND: Expression of hypoxia-related tissue factors in 1p-aberrant oligodendroglial neoplasms diminishes patient outcome. Differentiated embryo-chondrocyte expressed gene 1 (DEC1) has been described as novel hypoxia-related tissue factor. In our study, we assessed the expression of DEC1 in 1p aberrant oligodendroglial neoplasms and its association with necrosis and expression of hypoxia-inducible factor 1alpha (HIF-1alpha), carbonic anhydrase-9 (CA9), and vascular endothelial growth factor-mRNA (VEGF).
MATERIALS AND METHODS: 44 primary and 16 recurrent oligodendroglial neoplasms with 1p-aberrations were investigated immunohistochemically for the expression of DEC1, HIF-1alpha, and CA9. Expression of VEGF was investigated using in situ hybridization. DEC1 expression was correlated with necrosis and with expression of HIF-1alpha, CA9, and VEGF.
RESULTS: DEC1 was expressed in tumor cell nuclei, and occasionally in nuclei of endothelial cells, and glial and neuronal cells of surrounding brain tissue. High expression (>10% of tumor cells immunolabeled) of DEC1 was found in 56 cases, low expression (<10% of tumor cells immunolabeled) was found in 3 cases. In 1 case no expression of DEC1 was evident. DEC1 expression showed no topographical association with necrosis or expression of HIF-1alpha, CA9, or VEGF.
CONCLUSION: DEC1 expression is found in the majority of 1p-aberrant oligodendroglial neoplasms and does not correlate with necrosis or expression of HIF-1alpha, CA9, VEGF. Thus, immunohistochemical analysis of DEC1 expression is in our hands not suitable for detection of tissue hypoxia in this type of primary brain tumor.

Yang L, Leung AC, Ko JM, et al.
Tumor suppressive role of a 2.4 Mb 9q33-q34 critical region and DEC1 in esophageal squamous cell carcinoma.
Oncogene. 2005; 24(4):697-705 [PubMed] Related Publications
The key genes involved in the development of esophageal squamous cell carcinoma (ESCC) remain to be elucidated. Previous studies indicate extensive genomic alterations occur on chromosome 9 in ESCC. Using a monochromosome transfer approach, this study provides functional evidence and narrows down the critical region (CR) responsible for chromosome 9 tumor suppressing activity to a 2.4 Mb region mapping to 9q33-q34 between markers D9S1798 and D9S61. Interestingly, a high prevalence of allelic loss in this CR is also observed in primary ESCC tumors by microsatellite typing. Allelic loss is found in 30/34 (88%) tumors and the loss of heterozygosity (LOH) frequency ranges from 67 to 86%. Absent to low expression of a 9q32 candidate tumor suppressor gene (TSG), DEC1 (deleted in esophageal cancer 1), is detected in four Asian ESCC cell lines. Stably expressing DEC1 transfectants provide functional evidence for inhibition of tumor growth in nude mice and DEC1 expression is decreased in tumor segregants arising after long-term selection in vivo. There is 74% LOH in the DEC1 region of ESCC primary tumors. This study provides the first functional evidence for the presence of critical tumor suppressive regions on 9q33-q34. DEC1 is a candidate TSG that may be involved in ESCC development.

Chakrabarti J, Turley H, Campo L, et al.
The transcription factor DEC1 (stra13, SHARP2) is associated with the hypoxic response and high tumour grade in human breast cancers.
Br J Cancer. 2004; 91(5):954-8 [PubMed] Free Access to Full Article Related Publications
DEC1, also known as SHARP-2 or Stra13, plays important roles in embryonic development, proliferation, apoptosis and cell differentiation in the mouse. DEC1 was recently identified as hypoxically induced in cDNA microarray studies of the human renal carcinoma cell line RCC4, to be regulated through hypoxia-inducible factor (HIF)-1alpha and via HIF-1alpha, able to block adipocyte differentiation. Nevertheless, its distribution and role in hypoxia and differentiation in human breast cancer are unknown. We therefore examined the pattern and level of expression of DEC1 using immunohistochemistry in whole tissue sections in normal, in situ and invasive breast carcinomas, and correlated the level of expression of DEC1 and clinicopathological factors and hypoxic tumour markers in 253 invasive carcinomas on tissue microarrays. We observed an increase in DEC1 expression during progression from normal to in situ and invasive carcinoma. Expression was not restricted to the tumour cell element but was also observed in endothelial, fibroblasts and inflammatory cells. There was a significant positive correlation between DEC1 and tumour grade (P=0.01), HIF-1alpha (P=0.04) and the hypoxically regulated gene angiogenin (P<0.0001), but no significant associations were observed with patient age (P=0.15), lymph node status (P=0.8), tumour size (P=0.3), oestrogen receptor (P=0.45), epidermal growth factor receptor (P=0.27) or Chalkley vessel count (P=0.45). There was no difference in relapse-free (P=0.84) or overall (P=0.78) survival. These findings suggest that DEC1 plays an important role in the progression to invasive breast cancer and that it may provide a mechanism by which hypoxia blocks tumour differentiation, and may contribute to a more aggressive phenotype. Reversing this phenotype may alter the biological behaviour of individual tumours.

Currie MJ, Hanrahan V, Gunningham SP, et al.
Expression of vascular endothelial growth factor D is associated with hypoxia inducible factor (HIF-1alpha) and the HIF-1alpha target gene DEC1, but not lymph node metastasis in primary human breast carcinomas.
J Clin Pathol. 2004; 57(8):829-34 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Vascular endothelial growth factor D (VEGF-D) induces angiogenesis and lymphangiogenesis. Nodal metastasis is recognised as a powerful prognostic marker in breast carcinoma, but the molecular mechanisms underlying this process are unknown. Although it has been suggested that VEGF-D may regulate nodal metastasis, this is based largely on animal models, its role in human disease being unclear.
AIMS: To measure the pattern and degree of VEGF-D protein expression in normal and neoplastic human breast tissues.
METHODS: The pattern and degree of VEGF-D expression was measured in normal tissue and invasive carcinomas, and expression was correlated with clinicopathological parameters, hypoxia markers, and survival. Because other VEGF family members are affected by oestrogen, whether VEGF-D is regulated by oestrogen in breast cancer cell lines was also assessed.
RESULTS: VEGF-D was significantly positively associated with hypoxia inducible factor (HIF-1alpha) (p = 0.03) and the HIF-1alpha regulated gene DEC1 (p = 0.001), but not lymph node status, the number of involved lymph nodes, patient age, tumour size, tumour grade, lymphovascular invasion, oestrogen receptor, progesterone receptor, c-erb-B2, or tumour histology (all p>0.05). There was no significant relation between tumour VEGF-D expression and relapse free (p = 0.78) or overall (p = 0.94) survival. VEGF-D expression was enhanced by oestrogen in MCF-7 and T47D breast cancer cells, and was blocked by hydroxytamoxifen.
CONCLUSION: These findings support a role for hypoxia and oestrogen induced VEGF-D in human breast cancer and also suggest that tamoxifen and related oestrogen antagonists may exert some of their antitumour effects through the abrogation of VEGF-D induced function.

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