Inactivation of Both FHIT and p53 Cooperate in Deregulating Proliferation-Related Pathways in Lung Cancer Francesca Andriani, PharmD, Elena Roz, MD,

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Inactivation of Both FHIT and p53 Cooperate in Deregulating Proliferation-Related Pathways in Lung Cancer Francesca Andriani, PharmD, Elena Roz, MD, Roberto Caserini, MLT, Davide Conte, MLT, Ugo Pastorino, MD, Gabriella Sozzi, PhD, Luca Roz, PharmD Journal of Thoracic Oncology Volume 7, Issue 4, Pages 631-642 (April 2012) DOI: 10.1097/JTO.0b013e318244aed0 Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Analysis of cell cycle-dependent expression of selected FHIT-regulated genes. Synchronization of NCI-H460 cells was used to evaluate periodicity of expression. A, Cells were arrested in S-phase using a double thymidine block and cell synchrony was monitored by flow cytometry of propidium-iodide–stained cells. The number of cells is plotted against DNA content for different time points: upon release from thymidine, most cells were blocked in S-phase, then progressed into G2 phase (0–5 hours) and finally reentered in G1 phase after 10 hours (upper panel). Cells were also arrested first with thymidine and then with nocodazole to obtain G2/M block (lower panel). B, Real-time PCR analysis of CCNB2 expression after synchronization using either double thymidine or nocodazole block showing periodicity of expression of this gene in relation to cell cycle distribution with predominant expression in G2/M phase. Journal of Thoracic Oncology 2012 7, 631-642DOI: (10.1097/JTO.0b013e318244aed0) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 FHIT knockdown regulates proliferation-related genes. Normal human bronchial epithelial (NHBE) cells (A) and HEK-293 cells (B) were transiently transfected with FHIT oligo siRNA or control siRNA (siGAPDH or siScrambled). FHIT expression is reduced in both cell lines (A and B, left panels). Silencing of FHIT resulted in changes in expression of different cell cycle-related genes analyzed by real-time PCR (A and B, right panels). Expression data are normalized on cells transfected with scrambled oligo siRNA. Asterisk (*) indicates genes whose expression was regulated more than 1.2 fold. Journal of Thoracic Oncology 2012 7, 631-642DOI: (10.1097/JTO.0b013e318244aed0) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Stable down-modulation of FHIT regulates genes involved in cell cycle control in HBEC-KT and HBEC-KT modified to silence p53 expression (HBEC-KT p53–). A, Knockdown of FHIT was obtained transducing the cells with a retroviral vector carrying a shRNA targeting FHIT transcript (sh-FHIT). A retroviral vector containing a scrambled sequence was used as control (SCRAMB). FHIT expression was estimated by Western Blot analysis and was reduced in both cell lines. Actin was used as a protein loading control. B, Transcriptional changes in expression of a subset of genes involved in cell cycle control which are either upregulated (left) or downregulated (right) in HBEC3KT and HBEC-KTp53– after reduction of FHIT transcript. The results are expressed as level of mRNA relative to untransfected control cells. Journal of Thoracic Oncology 2012 7, 631-642DOI: (10.1097/JTO.0b013e318244aed0) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 FHIT and p53 status impinge upon expression of proliferation-related genes in non-small cell lung cancer (NSCLC) cell lines and primary tumors. A, Calu-1 lung cancer cells stably transfected with plasmid constructs driving inducible expression of either FHIT (Calu1-FHIT) or p53 (Calu1-p53) were treated with 10 mM Ponasterone A for 3 days before RNA extraction and real-time PCR analysis. Results are expressed as fold change in the expression level relative to untreated cells. B, Real-time PCR analysis of proliferation related genes in 55 primary NSCLC samples. Results are expressed as median expression level (6SD) of samples with inactivation of both FHIT and p53 (FHIT–/p53–, n = 23) relative to the median expression level of samples of other groups (n = 36). * p < 0.05 for differences between the two groups. Journal of Thoracic Oncology 2012 7, 631-642DOI: (10.1097/JTO.0b013e318244aed0) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions