Expression Profiles of the Regulatory Master p63 Gene in Pulmonary Adenocarcinoma Recapitulate the Normal and Developmental Lung
Giuseppe Pelosi, Federica Perrone, Elena Tamborini, Elena De Paoli, Alessandra Fabbri, Paolo Scanagatta, Rose-Anne Romano, Stefano La Rosa, Ugo Pastorino, Mauro Papotti. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; State University of New York at Buffalo, Center for Excellence in Bioinformatics and Life Sciences, Buffalo, NY; Unsubria University at Varese, Varese, Italy; San Luigi Gonzaga Hospital and University of Turin, Turin, Italy
Background: Little is known about the role of p63 gene, an important player in the development of squamous epithelia and pulmonary squamous cell carcinoma (SQC), in the growth of lung adenocarcinoma (AD).
Design: One hundred twenty consecutive AD were assessed by immunohistochemistry (IHC) for the presence of transactivating (TA) and non-TA (hence simply p40) isoform assessment, by interphase fluorescence in situ hybridization (FISH) for p63 gene status, and by quantitative (q)-PCR for mRNA levels of α, β, γ, δ, and ε isoforms, whether TA- or non-TA. Fifteen SQC samples, a few human spontaneous abortion specimens and delta-Np63(p40) gene-knockout (KO) mice were used as controls. AD were classified according to the last IASLC/ATS/ERS classification.
Results: TA isoforms were found by IHC in 20% of AC (range 10-70% tumor cells) regardless of their growth patterns or variants, whereas non-TA (p40) isoforms were seen in only 1-2% tumor cells of up to 5% AC but were consistently accumulated in all SQC samples. By q-PCR, AD showed a prevalence of TA-α over β isoforms, whereas the reverse held true for SQC in which prevailed non-TA-α over β, γ, δ and ε, in that order. In human fetuses, TA and non-TA were early acquired during development but never expressed by alveolar cells, and p40-KO mice normally developed lungs. No relationship was observed between p63 gene status as assessed by FISH and protein expression or mRNA accumulation, as well as no survival or clinical association was found.
Conclusions: The expression of the diverse p63 gene isoforms in lung AD recapitulates the normal and developmental lung and is highly conserved among different species. Non-TA isoform expression is likely to reflect the growth of bronchial epithelium-derived tumor cells but they are not required for the development of alveolar cells, whether in humans or mice. The consistent combination of p40 positivity in SQC and p40 negativity in AD reflects the different role of p63 gene in the cell lineage-dependent tumor development and may have diagnostic implications.
Monday, March 4, 2013 1:00 PM
Poster Session II # 296, Monday Afternoon