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Human enhancer of filamentation 1 Is a mediator of hypoxia-inducible factor-1alpha-mediated migration in colorectal carcinoma cells.

ABSTRACT: Human enhancer of filamentation 1 (HEF1; also known as NEDD9 or Cas-L) is a scaffolding protein that is implicated in regulating diverse cellular processes, such as cellular attachment, motility, cell cycle progression, apoptosis, and inflammation. Here, we identify HEF1 as a novel hypoxia-inducible factor-1alpha (HIF-1alpha)-regulated gene and reveal that HEF1 mediates hypoxia-induced migration of colorectal carcinoma cells. HEF1 is highly expressed in cultured colorectal carcinoma cells exposed to hypoxia and in the hypoxic areas of human colorectal cancer (CRC) specimens. Moreover, our data show that HIF-1alpha mediates the effects of hypoxia on induction of HEF1 expression via binding to a hypoxia-responsive element of the HEF1 promoter. Importantly, the induction of HEF1 expression significantly enhances hypoxia-stimulated HIF-1alpha transcriptional activity by modulating the interaction between HIF-1alpha and its transcriptional cofactor p300. Inhibition of HEF1 expression also reduced the levels of hypoxia-inducible genes, including those that regulate cell motility. Cell migration was reduced dramatically following knockdown of HEF1 expression under hypoxic conditions. Thus, this positive feedback loop may contribute to adaptive responses of carcinoma cells encountering hypoxia during cancer progression.

SUBMITTER: Kim SH

PROVIDER: S-EPMC2871069 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Human enhancer of filamentation 1 Is a mediator of hypoxia-inducible factor-1alpha-mediated migration in colorectal carcinoma cells.

Kim Sun-Hee SH Xia Dianren D Kim Sang-Wook SW Holla Vijaykumar V Menter David G DG Dubois Raymond N RN

Cancer research 20100504 10

Human enhancer of filamentation 1 (HEF1; also known as NEDD9 or Cas-L) is a scaffolding protein that is implicated in regulating diverse cellular processes, such as cellular attachment, motility, cell cycle progression, apoptosis, and inflammation. Here, we identify HEF1 as a novel hypoxia-inducible factor-1alpha (HIF-1alpha)-regulated gene and reveal that HEF1 mediates hypoxia-induced migration of colorectal carcinoma cells. HEF1 is highly expressed in cultured colorectal carcinoma cells expose ...[more]

PMID: 20442290

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Project description:BACKGROUND: Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator of genes regulating oxygen homeostasis. The HIF-1 protein is composed of two HIF-1alpha and HIF-1beta/aryl hydrocarbon receptor nuclear translocator (ARNT) subunits. The prognostic relevance of HIF-1alpha protein overexpression has been shown in breast cancer. The impact of HIF-1alpha alternative splice variant expression on breast cancer prognosis in terms of metastasis risk is not well known. METHODS: Using real-time quantitative reverse transcription PCR assays, we measured mRNA concentrations of total HIF-1alpha and 4 variants in breast tissue specimens in a series of 29 normal tissues or benign lesions (normal/benign) and 53 primary carcinomas. In breast cancers HIF-1alpha splice variant levels were compared to clinicopathological parameters including tumour microvessel density and metastasis-free survival. RESULTS: HIF-1alpha isoforms containing a three base pairs TAG insertion between exon 1 and exon 2 (designated HIF-1alphaTAG) and HIF-1alpha736 mRNAs were found expressed at higher levels in oestrogen receptor (OR)-negative carcinomas compared to normal/benign tissues (P = 0.009 and P = 0.004 respectively). In breast carcinoma specimens, lymph node status was significantly associated with HIF-1alphaTAG mRNA levels (P = 0.037). Significant statistical association was found between tumour grade and HIF-1alphaTAG (P = 0.048), and total HIF-1alpha (P = 0.048) mRNA levels. HIF-1alphaTAG mRNA levels were also inversely correlated with both oestrogen and progesterone receptor status (P = 0.005 and P = 0.033 respectively). Univariate analysis showed that high HIF-1alphaTAG mRNA levels correlated with shortened metastasis free survival (P = 0.01). CONCLUSIONS: Our results show for the first time that mRNA expression of a HIF-1alphaTAG splice variant reflects a stage of breast cancer progression and is associated with a worse prognosis.See commentary: http://www.biomedcentral.com/1741-7015/8/45.

Project description:BackgroundThe results from the published studies on the association between hypoxia-inducible factor -1alpha (HIF-1alpha) polymorphisms and cancer risk are conflicting. In this meta-analysis, we aimed to investigate the association between HIF-1alpha 1772 C/T and 1790 G/A polymorphisms and cancer.MethodsThe meta-analysis for 1772 C/T polymorphism included 4131 cancer cases and 5387 controls, and for 1790 G/A polymorphism included 2058 cancer cases and 3026 controls. Allelic and genotypic comparisons between cases and controls were evaluated. Subgroup analyses by cancer types, ethnicity, and gender were also performed. We included prostate cancer in male subgroup, and female specific cancers in female subgroup.ResultsFor the 1772 C/T polymorphism, the analysis showed that the T allele and genotype TT were significantly associated with higher cancer risk: odds ratio (OR) = 1.29 [95% confidence interval (CI, 1.01, 1.65)], P = 0.04, P(heterogeneity) < 0.00001, and OR = 2.18 [95% CI (1.32, 3.62)], P = 0.003, P(heterogeneity) = 0.02, respectively. The effect of the genotype TT on cancer especially exists in Caucasians and female subjects: OR = 2.40 [95% CI (1.26, 4.59)], P = 0.008, P(heterogeneity) = 0.02, and OR = 3.60 [95% CI (1.17, 11.11)], P = 0.03, P(heterogeneity) = 0.02, respectively. For the 1790 G/A polymorphism, the pooled ORs for allelic frequency comparison and dominant model comparison suggested a significant association of 1790 G/A polymorphism with a decreased breast cancer risk: OR = 0.28 [95% CI (0.08, 0.90)], P = 0.03, P(heterogeneity) = 0.45, and OR = 0.29 [95% CI (0.09, 0.97)], P = 0.04, P(heterogeneity) = 0.41, respectively. The frequency of the HIF-1alpha 1790 A allele was very low and only two studies were included in the breast cancer subgroup.ConclusionsOur meta-analysis suggests that the HIF-1alpha 1772 C/T polymorphism is significantly associated with higher cancer risk, and 1790 G/A polymorphism is significantly associated with decreased breast cancer risk. The effect of the 1772 C/T polymorphism on cancer especially exists in Caucasians and female subjects. Only female specific cancers were included in female subgroup, which indicates that the 1772 C/T polymorphism is significantly associated with an increased risk for female specific cancers. The association between the 1790 G/A polymorphism and lower breast cancer risk could be due to chance.

Dataset Information

Human enhancer of filamentation 1 Is a mediator of hypoxia-inducible factor-1alpha-mediated migration in colorectal carcinoma cells.

Publications

Human enhancer of filamentation 1 Is a mediator of hypoxia-inducible factor-1alpha-mediated migration in colorectal carcinoma cells.

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