P63 and p73 Isoform Expression in Non-small Cell Lung Cancer and Corresponding Morphological Normal Lung Tissue Marco Lo Iacono, PhD, Valentina Monica,

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p63 and p73 Isoform Expression in Non-small Cell Lung Cancer and Corresponding Morphological Normal Lung Tissue Marco Lo Iacono, PhD, Valentina Monica, MS, Silvia Saviozzi, PhD, Paolo Ceppi, MS, Enrico Bracco, PhD, Mauro Papotti, MD, Giorgio V. Scagliotti, MD Journal of Thoracic Oncology Volume 6, Issue 3, Pages 473-481 (March 2011) DOI: 10.1097/JTO.0b013e31820b86b0 Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 p53 family members transcripts expression levels in non-small cell lung cancer (NSCLC) patients tissues. Box plot diagrams showing the normalized expression levels ΔCt (CtTarget − Ctreference) of p53 family members in 46 NSCLC and paired nontumoral tissues. A, p53, p63 and p73 expression levels. B, p63 N-terminal isoforms expression levels. C, p73 N-terminal isoforms expression levels. The line within the boxes indicates the median expression level. The top edge of the boxes represents the 75th, and the bottom edge represents the 25th percentile. The range is shown as a vertical edge. Journal of Thoracic Oncology 2011 6, 473-481DOI: (10.1097/JTO.0b013e31820b86b0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 p63 and p73 N-terminal isoforms expression pattern in non-small cell lung cancer (NSCLC) patients. Modulations of p63 and p73 N-terminal isoforms were analyzed with paired t test, and **p < 0.05 and ***p < 0.01 are found to be significant. Black arrows indicate the direction of N-terminal isoforms modulation in tumors. Δ2p73, Δ2/3p73, and ΔNp63 transcripts were significantly up-modulated, whereas TAp63, ΔNp73, and ΔN′p73 isoforms were down-modulated in NSCLC. Solid block shows general expression level of p53 family members, whereas dotted blocks indicate gene-specific N-terminal isoforms. The filled lines correspond to a cutoff of ±2-fold change (ΔΔCT ±1). Journal of Thoracic Oncology 2011 6, 473-481DOI: (10.1097/JTO.0b013e31820b86b0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Immunohistochemical detection of N-terminal p63/p73 isoforms in lung cancer. Tumor samples with “low” (A, C, E, and G) and “high” N-terminal isoforms expression (B, D, F, and H). Both p63 N-terminal isoforms were predominantly expressed in nuclear compartment (B and D, respectively). TAp73 isoforms (TAp73, Δ2p73) localized in both nuclear and cytoplasmic compartment (F), whereas ΔNp73 was chiefly expressed in cytoplasm (H). Original magnification, ×200. Journal of Thoracic Oncology 2011 6, 473-481DOI: (10.1097/JTO.0b013e31820b86b0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Expression level/modulation of p63 and p73 N-terminal isoforms affect nonsquamous non-small cell lung cancer patients survival. For each isoform, transcript/protein expression levels have been dichotomized into two groups of “high” (filled line) and “low” (dotted line) expression using k-means/median value, and Kaplan–Meier analysis was carried out on the two groups. In nonsquamous cell carcinoma tumors, the high Δ2p73 transcript/protein expression was associated to unfavorable outcome (p ≪ 0.01 and p = 0.03, respectively, u pper panel). Transcript modulation: p63 and p73 N-terminal isoforms expression levels were clustered into three groups: up-regulation, down-regulation, or not regulated. Regulated according to their fold change using log2(FC) ±1 as threshold. Kaplan–Meier analysis showed that TAp63, ΔNp63, and ΔN′p73 down-modulations were correlated with poor patients survival (p < 0.01, p = 0.03, and p = 0.04, respectively, lower panel). Journal of Thoracic Oncology 2011 6, 473-481DOI: (10.1097/JTO.0b013e31820b86b0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 In morphological normal lung specimens, TAp63 and ΔN′p73 gene expression levels correlate with poor patients survival. For each isoform, transcript/protein expression levels have been dichotomized into two groups of “high” (filled line) and “low” (dotted line) expression using k-means/median value, and Kaplan–Meier analysis was carried out on the two groups. In the whole patients cohort of morphological normal lung specimens, the high TAp63 and ΔN′p73 expression levels correlate with poor prognosis (upper panel). Statistical relevance of this analysis increases when patients with squamous carcinoma were excluded (lower panel). Journal of Thoracic Oncology 2011 6, 473-481DOI: (10.1097/JTO.0b013e31820b86b0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions