p63 and p73 Isoform Expression in Non-small Cell Lung Cancer and Corresponding Morphological Normal Lung Tissue

Background: The TP73 and TP63 genes are members of the p53 tumor suppressor family and are expressed in different N-terminal isoforms either with proapoptotic (transactivation domain, TA) and antiapoptotic (N-terminally truncated, Delta N) function. Unlike p53, the role of p73 and p63 in tumor is controversial. It has been recently hypothesized that altered Delta N:TA expression ratio, rather than single isoform overexpression, plays a role in the pathogenesis of many diseases, including lung cancer. Methods: Isoform-specific, real-time polymerase chain reaction and immunohistochemistry analysis on matched cancer and corresponding normal tissues from surgically resected non-small cell lung cancers (NSCLCs) have been performed aiming to explore the expression levels of each p63 and p73 N-terminal isoforms and their Delta N:TA expression ratio. Results: For both p63 and p73, a N-terminal isoform-specific modulation that alter Delta N:TA isoform balance was identified. In particular, Delta Np63 isoform was significantly up-modulated, whereas TAp63 was slightly down-modulated in NSCLC specimens. Likewise, Delta 2p73 and Delta 2/3p73 were up-modulated, whereas Delta Np73 and Delta N'p73 isoforms were down-modulated. Moreover, a higher TAp63 and Delta N'p73 transcripts expression, detected in the normal tissue surrounding the tumors, correlates with poor patient outcome, representing independent prognostic factors for overall survival (Delta N'p73: p = 0.049, hazard ratio = 3.091, 95% confidence interval = 1.005-9.524 and TAp63: p = 0.001, hazard ratio = 8.091, 95% confidence interval = 2.254-29.05). Conclusion: Our findings suggest that p63 and p73 altered Delta N:TA expression ratio occurs in NSCLC likely contributing to the molecular pathogenesis of this tumor.