title: SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling.
abstract: The purpose of this study was to identify key genetic pathways involved in non-small cell lung cancer (NSCLC) and understand their role in tumor progression. We performed a genome wide scanning using paired tumors and corresponding 16 mucosal biopsies from four follow-up lung cancer patients on Affymetrix 250K-NSpI array platform. We found that a single gene SH3GL2 located on human chromosome 9p22 was most frequently deleted in all the tumors and corresponding mucosal biopsies. We further validated the alteration pattern of SH3GL2 in a substantial number of primary NSCLC tumors at DNA and protein level. We also overexpressed wild-type SH3GL2 in three NSCLC cell lines to understand its role in NSCLC progression. Validation in 116 primary NSCLC tumors confirmed frequent loss of heterozygosity of SH3GL2 in overall 51 % (49/97) of the informative cases. We found significantly low (p = 0.0015) SH3GL2 protein expression in 71 % (43/60) primary tumors. Forced overexpression of wild-type (wt) SH3GL2 in three NSCLC cell lines resulted in a marked reduction of active epidermal growth factor receptor (EGFR) expression and an increase in EGFR internalization and degradation. Significantly decreased in vitro (p = 0.0015-0.030) and in vivo (p = 0.016) cellular growth, invasion (p = 0.029-0.049), and colony formation (p = 0.023-0.039) were also evident in the wt-SH3GL2-transfected cells accompanied by markedly low expression of activated AKT(Ser(473)), STAT3 (Tyr(705)), and PI3K. Downregulation of SH3GL2 interactor USP9X and activated ß-catenin was also evident in the SH3GL2-transfected cells. Our results indicate that SH3GL2 is frequently deleted in NSCLC and regulates cellular growth and invasion by modulating EGFR function.
authors.affiliation: Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA. sdasgupta@vcu.edu
authors.forename: Santanu
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Jin Sung
authors.initials: JS
authors.lastname: Jang
authors.forename: Chunbo
authors.initials: C
authors.lastname: Shao
authors.forename: Nitai D
authors.initials: ND
authors.lastname: Mukhopadhyay
authors.forename: Upneet K
authors.initials: UK
authors.lastname: Sokhi
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Mariana
authors.initials: M
authors.lastname: Brait
authors.forename: Conover
authors.initials: C
authors.lastname: Talbot
authors.forename: Rex C
authors.initials: RC
authors.lastname: Yung
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Begum
authors.forename: William H
authors.initials: WH
authors.lastname: Westra
authors.forename: Mohammad Obaidul
authors.initials: MO
authors.lastname: Hoque
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Yi
authors.forename: Stephan
authors.initials: S
authors.lastname: Lam
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Jin
authors.initials: J
authors.lastname: Jen
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C107640:SH3GL2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors