Hypoxia-inducible factor-1 (HIF-1) is a pivotal factor that regulates cellular responses to hypoxia and is presumably linked to regulation of angiogenesis and tumor growth. We assessed the difference in transcription activity of two HIF-1alpha polymorphic variants (P582S and A588T), along with molecular epidemiological study among head and neck squamous cell carcinoma (HNSCC) patients. Both HIF-1alpha variants revealed significantly higher transcription activity than wild-type (WT) did, under normoxic and hypoxic conditions (P < 0.02). Furthermore, tumors from HNSCC patients with heterozygous alleles having P582S or A588T had significantly increased numbers of microvessels compared with those with homozygous WT (P = 0.02). In addition, all patients with tumors of T1 (below 2 cm diameter) were WT, while 14 of 47 patients with tumors of > or =T2 were heterozygous. The elevated transactivation capacity of variant forms of HIF-1alpha implies a role of HIF-1alpha polymorphisms in generating individually different tumor progression.

Tumor hypoxia has been reported to cause a functional loss in DNA mismatch repair (MMR) system as a result of downregulation of MMR genes, although the precise molecular mechanisms remain unclear. In this study, we focused on the downregulation of a key MMR gene, MLH1, and demonstrated that hypoxia-inducible transcription repressors, differentiated embryo chondrocytes (DEC1 and 2), participated in its transcriptional regulation via their bindings to E-box-like motif(s) in MLH1 promoter region. In all cancer cell lines examined, hypoxia increased expression of DEC1 and 2, known as hypoxia-inducible genes, but decreased MLH1 expression in an exposure time-dependent manner at both the mRNA and protein levels. Co-transfection reporter assay revealed that DEC1 and, to greater extent, DEC2 as well as hypoxia-repressed MLH1 promoter activity. We further found that the action was remarkably inhibited by trichostatin A, and identified a possible DEC-response element in the MLH1 promoter. In vitro electrophoretic gel mobility shift and chromatin immunoprecipitation assays demonstrated that DEC1 or 2 directly bounds to the suggested element, and transient transfection assay revealed that overexpression of DEC2 repressed endogenous MLH1 expression in the cells. Hypoxia-induced DEC may impair MMR function through repression of MLH1 expression, possibly via the histone deacethylasemediated mechanism in cancer cells.

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The abnormalities of the fragile histidine triad ( FHIT ) gene in tissue samples of oral squamous cell carcinomas (SCCs) along with several leukoplakias and an erythroplakia were examined to determine whether the FHIT gene is actually a frequent target in vivo for alteration during oral carcinogenesis. Abnormal transcripts of the FHIT gene were found in eight of 15 oral SCCs. Although these abnormal transcripts varied widely, deletion patterns incorporating a deletion of exon 5 were the most common. Loss of heterozygosity (LOH) analysis demonstrated that the abnormal FHIT transcripts found in cancer cells were attributable to abnormalities of the FHIT gene. Abnormal FHIT transcripts were also observed in two of seven premalignant lesions. Interestingly, in the case of one patient with a premalignant lesion showing an abnormal FHIT transcript, subsequent oral SCC developed during a 3-year follow-up period. On the other hand, in the two patients from whom both leukoplakia and SCC samples were taken simultaneously, abnormal FHIT transcripts were found only in the SCCs. Although the functional role of FHIT remains to be clarified, these results suggest that the FHIT alteration is actually involved in carcinogenesis of the oral epithelium. © 2000 Cancer Research Campaign

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