aHIF: A natural antisense transcript overexpressed in human renal cancer and during hypoxia

Background: Nonpapillary renal carcinoma is the predominant form of human kidney cancer and represents a distinct disease entity, morphologically and molecularly, from papillary renal carcinoma. We have discovered a natural antisense transcript that is complementary to the 3' untranslated region of hypoxia inducible factor alpha (HIF1 alpha) messenger RNA (mRNA) and is strikingly overexpressed specifically in nonpapillary kidney cancer. HIF1 alpha. encodes a protein that is known to have two important functions: 1) to act as a transcription factor for hypoxia inducible genes and 2) to stabilize p53 protein during hypoxia, Because of the importance of HIF1 alpha, we have characterized this natural antisense transcript, which we have named "aHIF," Methods: Differential display, reverse transcription-polymerase chain reaction, ribonuclease protection, and DNA-sequencing methods were used in our analysis, Results and Conclusions: We show the following: 1) aHIF is a natural antisense transcript derived from HTF1 alpha gene sequences encoding the 3' untranslated region of HIF1 alpha mRNA; 2) aHIF is specifically overexpressed in all nonpapillary clear-cell renal carcinomas examined, but not in the papillary renal carcinomas examined; 3) aHIF is overexpressed in an established nonpapillary renal carcinoma cell line under both normoxic (i.e., normal aerobic) and hypoxic conditions; and 4) although aHIF is not further induced by hypoxia in nonpapillary disease, it can be induced in lymphocytes where there is a concomitant decrease in HTF1 alpha. mRNA, To our knowledge, this is the first case of overexpression of a natural antisense transcript exclusively associated with a specific human malignant disease.