SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling.

Santanu Dasgupta, Jin Sung Jang, Chunbo Shao, Nitai D. Mukhopadhyay, Upneet K. Sokhi, Swadesh K. Das, Mariana Brait, Conover Talbot, Rex C. Yung, Shahnaz Begum, William H. Westra, Mohammad Obaidul Hoque, Ping Yang, Joanne E. Yi, Stephan Lam, Adi F. Gazdar, Paul B. Fisher, Jin Jen, David Sidransky

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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.

Original languageEnglish (US)
Pages (from-to)381-393
Number of pages13
JournalJournal of molecular medicine (Berlin, Germany)
Volume91
Issue number3
StatePublished - Mar 2013

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Down-Regulation
Growth
Neoplasms
Biopsy
Cell Line
Catenins
Loss of Heterozygosity
Human Chromosomes
Phosphatidylinositol 3-Kinases
Lung Neoplasms
Proteins
Genome
DNA
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dasgupta, S., Jang, J. S., Shao, C., Mukhopadhyay, N. D., Sokhi, U. K., Das, S. K., ... Sidransky, D. (2013). SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling. Journal of molecular medicine (Berlin, Germany), 91(3), 381-393.

SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling. / Dasgupta, Santanu; Jang, Jin Sung; Shao, Chunbo; Mukhopadhyay, Nitai D.; Sokhi, Upneet K.; Das, Swadesh K.; Brait, Mariana; Talbot, Conover; Yung, Rex C.; Begum, Shahnaz; Westra, William H.; Hoque, Mohammad Obaidul; Yang, Ping; Yi, Joanne E.; Lam, Stephan; Gazdar, Adi F.; Fisher, Paul B.; Jen, Jin; Sidransky, David.

In: Journal of molecular medicine (Berlin, Germany), Vol. 91, No. 3, 03.2013, p. 381-393.

Research output: Contribution to journalArticle

Dasgupta, S, Jang, JS, Shao, C, Mukhopadhyay, ND, Sokhi, UK, Das, SK, Brait, M, Talbot, C, Yung, RC, Begum, S, Westra, WH, Hoque, MO, Yang, P, Yi, JE, Lam, S, Gazdar, AF, Fisher, PB, Jen, J & Sidransky, D 2013, 'SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling.', Journal of molecular medicine (Berlin, Germany), vol. 91, no. 3, pp. 381-393.
Dasgupta, Santanu ; Jang, Jin Sung ; Shao, Chunbo ; Mukhopadhyay, Nitai D. ; Sokhi, Upneet K. ; Das, Swadesh K. ; Brait, Mariana ; Talbot, Conover ; Yung, Rex C. ; Begum, Shahnaz ; Westra, William H. ; Hoque, Mohammad Obaidul ; Yang, Ping ; Yi, Joanne E. ; Lam, Stephan ; Gazdar, Adi F. ; Fisher, Paul B. ; Jen, Jin ; Sidransky, David. / SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling. In: Journal of molecular medicine (Berlin, Germany). 2013 ; Vol. 91, No. 3. pp. 381-393.
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AU - Mukhopadhyay, Nitai D.

AU - Sokhi, Upneet K.

AU - Das, Swadesh K.

AU - Brait, Mariana

AU - Talbot, Conover

AU - Yung, Rex C.

AU - Begum, Shahnaz

AU - Westra, William H.

AU - Hoque, Mohammad Obaidul

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AU - Lam, Stephan

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AU - Jen, Jin

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