Up-regulation and stabilization of HIF-1alpha in colorectal carcinomas.

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates gene expression in critical pathways involved in tumor growth and metastases. In our study we evaluated the expression of HIF-1alpha transcript and protein by quantitative real time PCR and by immunohistochemistry in a total of 78 colorectal carcinomas (CRCs) and in 8 samples of normal colorectal mucosa in order to identify the impact on prognosis of HIF-1alpha overexpression in CRCs. Our study demonstrates a significant up-regulation of HIF-1alpha mRNA as well as a high frequency of the protein immunoreactivity in colorectal cancers compared to normal samples. However, no significant correlation was found between HIF-1alpha immunohistochemical expression and any of the clinico-pathological parameters evaluated, with the only exception of the positive association between HIF-1alpha immunoreactivity and the presence of tumor necrosis. Analogously, high levels of HIF-1alpha mRNA were found to be correlated with a poor grade of tumor differentiation but no other significant association was observed. Despite the careful selection of the tumor samples, our findings do not appear to confirm, for colorectal cancers, the significant association between HIF-1alpha overexpression and tumor aggressiveness or unfavorable prognosis demonstrated for cancers of other sites. The lack of prognostic impact of HIF-1 in this site could be explained by an intricate interaction between the survival program mediated by HIF-1 and the genetic background of tumors cells in which its activation occurs.