Gene amplification of the transcription factor DP1 and CTNND1 in human lung cancer

• Published in: The Journal of pathology Vol. 222; no. 1; pp. 89 - 98
• Main Authors: Castillo, Sandra D., Angulo, Barbara, Suarez-Gauthier, Ana, Melchor, Lorenzo, Medina, Pedro P., Sanchez-Verde, Lydia, Torres-Lanzas, Juan, Pita, Guillermo, Benitez, Javier, Sanchez-Cespedes, Montse
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-09-2010; Wiley
• Subjects: Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Catenins - genetics; Cell Survival - genetics; chromosome 11; Chromosomes, Human, Pair 11 - genetics; Chromosomes, Human, Pair 13 - genetics; Cluster Analysis; copy number; CTNND1; Data processing; DNA microarrays; DP1 protein; E2F protein; Fluorescence in situ hybridization; Gene Amplification; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Genomes; genomics; Humans; Investigative techniques, diagnostic techniques (general aspects); Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical sciences; Mutation; Neoplasm Proteins - metabolism; Non-small cell lung carcinoma; oncogene; Oncogenes; Overexpression; p120ctn; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Pneumology; Polymerase chain reaction; RNA Interference; RNA, Small Interfering - genetics; RNA-mediated interference; siRNA; TFDP1; Transcription Factor DP1 - deficiency; Transcription Factor DP1 - genetics; Transcription Factor DP1 - metabolism; Transcription factors; Tumor cell lines; Tumor Cells, Cultured; Tumors; Tumors of the respiratory system and mediastinum; Human; Lung disease; Respiratory disease; Lung cancer; CTNND1; Malignant tumor; oncogene; Signal transduction; p120ctn; Gene amplification; Anatomic pathology; TFDP1; Bronchus disease; Transcription factor; Onc gene; Cancer
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2732

The search for novel oncogenes is important because they could be the target of future specific anticancer therapies. In the present paper we report the identification of novel amplified genes in lung cancer by means of global gene expression analysis. To screen for amplicons, we aligned the gene expression data according to the position of transcripts in the human genome and searched for clusters of over‐expressed genes. We found several clusters with gene over‐expression, suggesting an underlying genomic amplification. FISH and microarray analysis for DNA copy number in two clusters, at chromosomes 11q12 and 13q34, confirmed the presence of amplifications spanning about 0.4 and 1 Mb for 11q12 and 13q34, respectively. Amplification at these regions each occurred at a frequency of 3%. Moreover, quantitative RT–PCR of each individual transcript within the amplicons allowed us to verify the increased in gene expression of several genes. The p120ctn and DP1 proteins, encoded by two candidate oncogenes, CTNND1 and TFDP1, at 11q12 and 13q amplicons, respectively, showed very strong immunostaining in lung tumours with gene amplification. We then focused on the 13q34 amplicon and in the TFDP1 candidate oncogene. To further determine the oncogenic properties of DP1, we searched for lung cancer cell lines carrying TFDP1 amplification. Depletion of TFDP1 expression by small interference RNA in a lung cancer cell line (HCC33) with TFDP1 amplification and protein over‐expression reduced cell viability by 50%. In conclusion, we report the identification of two novel amplicons, at 13q34 and 11q12, each occurring at a frequency of 3% of non‐small cell lung cancers. TFDP1, which encodes the E2F‐associated transcription factor DP1 is a candidate oncogene at 13q34. The data discussed in this publication have been deposited in NCBIs Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series Accession No. GSE21168. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.