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Quantitative TP73 Transcript Analysis in Hepatocellular Carcinomas

¹ Center for Cancer Research and Cancer Therapy, Institute of Molecular Biology and ² Department of Bone Marrow Transplantation, University of Essen Medical School, Essen, Germany, and ³ Institute of Pathology, University of Leipzig, Leipzig, Germany

Purpose: The p53 family member p73 displays significant homology to p53, but data from primary tumors demonstrating increased expression levels of p73 in the absence of any gene mutations argue against a classical tumor suppressor function. A detailed analysis of the p73 protein in tumor tissues has revealed expression of two classes of p73 isoforms. Whereas the proapoptotic, full-length, transactivation-competent p73 protein (TA-p73) has a putative tumor suppressor activity similar to p53, the antiapoptotic, NH₂-terminally truncated, transactivation-deficient p73 protein (TA-p73) has been shown to possess oncogenic activity. The oncogenic proteins can be generated by the following two different mechanisms: (a) aberrant splicing (p73ex2, p73ex2/3, N'-p73) and (b) alternative promoter usage of a second intronic promoter (N-p73). The purpose of our study was to elucidate the origin of TA-p73 isoforms in hepatocellular carcinomas.

Experimental Design: We analyzed the underlying mechanisms of p73 overexpression in cancer cells by quantification of p73 transcripts from 10 hepatocellular carcinoma patients using isoform-specific real-time reverse transcription-PCR.

Results: Our data demonstrate that only aberrantly spliced TA-p73 transcripts from the TA promoter show significantly increased expression levels in the tumor whereas the N-p73 transcript generated from the second promoter is not significantly up-regulated.

Conclusions: Although we only analyzed 10 patient samples the results strongly suggest that the elevated activity of the first promoter (TA promoter) accounts for high-level expression of both full-length TA-p73 and aberrantly spliced TA-p73 isoforms in hepatocellular carcinoma tissues.

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