Tumor-associated CpG demethylation augments hypoxia-induced effects by positive autoregulation of HIF-1α.

Hypoxia-inducible factor 1α (HIF-1α) is frequently overexpressed in human cancers and controls the expression of several genes that have been implicated in tumor growth and progression. Activity of HIF-1α in cancer cells is regulated at the transcriptional, translational and posttranslational level by multiple inter- and coacting molecular pathways. In this report, we reveal for the first time that tumor-associated CpG demethylation facilitates positive autoregulation of HIF-1α, resulting in amplification of hypoxia-induced transactivation of HIF-1α target genes. The HIF-1α promoter harbors a hypoxia response element that is normally repressed by methylation of a CpG dinucleotide located in the core element. In colon cancer cell lines and in primary colon cancer specimens, however, we found frequent aberrant demethylation of this element, enabling binding of HIF-1α to its own promoter resulting in autotransactivation of HIF-1α expression. Our results provide novel and highly unexpected insights into the complexity of HIF-1α regulation in cancer cells and implicate that tumor-associated CpG demethylation augments HIF-1α-mediated effects on malignant cell growth.

Autoantibodies in lung cancer: possibilities for early detection and subsequent cure.

BACKGROUND: People with lung cancer usually present at a late stage in the course of their disease when their chances of long-term survival are low. At present there is little to offer for early diagnosis, even in those at high risk of developing the disease. Autoantibodies have been shown to be present in the circulation of people with various forms of solid tumour before cancer-associated antigens can be detected, and these molecules can be measured up to 5 years before symptomatic disease. OBJECTIVE: To assess the potential of a panel of tumour-associated autoantibody profiles as an aid to other lung cancer screening modalities. METHODS: Plasma from normal controls (n = 50), patients with non-small cell lung cancer (n = 82) and patients with small cell lung cancer (n = 22) were investigated for the presence of autoantibodies to p53, c-myc, HER2, NY-ESO-1, CAGE, MUC1 and GBU4-5 by enzyme-linked immunosorbent assay. RESULTS: Raised levels of autoantibodies were seen to at least 1/7 antigens in 76% of all the patients with lung cancer plasma tested, and 89% of node-negative patients, with a specificity of 92%. There was no significant difference between the detection rates in the lung cancer subgroups, although more patients with squamous cell carcinomas (92%) could be identified. CONCLUSION: Measurement of an autoantibody response to one or more tumour-associated antigens in an optimised panel assay may provide a sensitive and specific blood test to aid the early detection of lung cancer.