aHIF: a Natural Antisense Transcript Overexpressed in Human Renal Cancer and During Hypoxia

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Abstract
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 (HIF1alpha) messenger RNA (mRNA) and is strikingly overexpressed specifically in nonpapillary kidney cancer. HIF1alpha 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 HIF1alpha, we have characterized this natural antisense transcript, which we have named "aHIF." Differential display, reverse transcription-polymerase chain reaction, ribonuclease protection, and DNA-sequencing methods were used in our analysis. We show the following: 1) aHIF is a natural antisense transcript derived from HIF1alpha gene sequences encoding the 3' untranslated region of HIF1alpha 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 HIF1alpha mRNA. To our knowledge, this is the first case of overexpression of a natural antisense transcript exclusively associated with a specific human malignant disease.