Downregulation of the coxsackie and adenovirus receptor in cancer cells by hypoxia depends on HIF-1alpha.

Loss of the coxsackie and adenovirus receptor (CAR) has been found in various human cancers. Underlying mechanisms, however, are still poorly understood. Therefore, the objective of this study was to investigate the function of hypoxia, a ubiquitous phenomenon in carcinomas, in CAR regulation. In our approach, hypoxia and treatment with cobalt-(II)-chloride (CoCl(2)) induced a downregulation of CAR protein and mRNA expression, as well as a suppression of CAR gene promoter activity in AGS (gastric), SW480 (colon) and PC3 (prostate) cancer cells. In line with these findings we noted a decreased adenoviral uptake under hypoxic conditions. Aiming to further elucidate the molecular basis of this observation, a full-length hypoxia-inducible factor-1alpha (HIF-1alpha) cDNA was ectopically overexpressed in the AGS cell line diminishing CAR expression and CAR gene promoter activity. In line with these findings, exposure of HIF-1alpha-deficient AGS cells to hypoxia did not alter CAR mRNA expression level. On the basis of these data, it may be suggested that loss of CAR in human cancer cell lines under hypoxic conditions occurs in an HIF-1alpha-dependent manner.

Expression and function of the coxsackie and adenovirus receptor in Barrett's esophagus and associated neoplasia.

Cell surface presence of the coxsackie and adenovirus receptor (CAR) is considered a crucial prerequisite for the uptake of attenuated adenovirus. In cancers, however, a frequent loss of CAR has been noted potentially hampering the success of adenovirus-based therapy. In esophageal Barrett's carcinomas and its precursor lesions CAR presence has not been systematically determined yet. Immunohistochemical assessment in tissue specimens of 111 patients revealed CAR-positivity in all cases of Barrett's esophagus, including various degrees of intraepithelial neoplasia. In contrast, no considerable CAR presence was seen in squamous esophageal epithelium. Among Barrett's carcinomas, 93% displayed CAR presence, whereas CAR-negativity was observed preferentially in advanced cancers. Aiming to evaluate whether this loss of CAR impacts tumor-biologic properties of esophageal adenocarcinomas we studied cell lines OE19 and OE33 and observed an increased proliferation, migration and invasion upon siRNA-mediated functional CAR knock down. In conclusion, our results indicate that CAR may provide a valuable target for adenovirus-based therapy of Barrett's carcinomas and its precursor lesions. These data do also suggest that CAR does not contribute substantially to carcinogenesis in Barrett's esophagus, however, it may be speculated that loss of CAR promotes tumor progression in advanced stages of Barrett's carcinomas.