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JNCI Journal of the National Cancer Institute 1999 91(2):143-151; doi:10.1093/jnci/91.2.143
© 1999 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 91, No. 2, 143-151, January 20, 1999
© 1999 Oxford University Press

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

Catherine A. Thrash-Bingham, Kenneth D. Tartof

Affiliations of authors: C. A. Thrash-Bingham, Fox Chase Cancer Center, Philadelphia, PA; K. D. Tartof, Urologic Oncology Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD.

Correspondence to: Kenneth D. Tartof, Ph.D., National Institutes of Health, Bldg. 10, Rm. 2B47, Bethesda, MD 20892-1501 (e-mail: kdtartof{at} helix.nih.gov).

K. D. Tartof would like to dedicate this work to Dr. Alfred Knudson on the occasion of the 25th anniversary of his two-hit hypothesis and for making this research possible. We thank Dr. Donald Chapman and C. Strobe for their expertise and equipment used in the hypoxia experiments and B. Bingham for comments on statistical analyses.

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 HIF1{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 HIF1{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.


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