Loss of Sh3gl2/endophilin A1 is a common event in urothelial carcinoma that promotes malignant behavior

Shyama Majumdar, Edward M. Gong, Dolores Di Vizio, Jonathan Dreyfuss, David Degraff, Martin H. Hager, Peter J. Park, Joaquim Bellmunt, Robert J. Matusik, Jonathan E. Rosenberg, Rosalyn M. Adam

Research output: Contribution to journalArticle

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Abstract

Urothelial carcinoma (UC) causes substantial morbidity and mortality worldwide. However, the molecular mechanisms underlying urothelial cancer development and tumor progression are still largely unknown. Using informatics analysis, we identified Sh3gl2 (endophilin A1) as a bladder urothelium-enriched transcript. The gene encoding Sh3gl2 is located on chromosome 9p, a region frequently altered in UC. Sh3gl2 is known to regulate endocytosis of receptor tyrosine kinases implicated in oncogenesis, such as the epidermal growth factor receptor (EGFR) and c-Met. However, its role in UC pathogenesis is unknown. Informatics analysis of expression profiles as well as immunohistochemical staining of tissue microarrays revealed Sh3gl2 expression to be decreased in UC specimens compared to nontumor tissues. Loss of Sh3gl2 was associated with increasing tumor grade and with muscle invasion, which is a reliable predictor of metastatic disease and cancer-derived mortality. Sh3gl2 expression was undetectable in 19 of 20 human UC cell lines but preserved in the low-grade cell line RT4. Stable silencing of Sh3gl2 in RT4 cells by RNA interference 1) enhanced proliferation and colony formation in vitro, 2) inhibited EGF-induced EGFR internalization and increased EGFR activation, 3) stimulated phosphorylation of Src family kinases and STAT3, and 4) promoted growth of RT4 xenografts in subrenal capsule tissue recombination experiments. Conversely, forced re-expression of Sh3gl2 in T24 cells and silenced RT4 clones attenuated oncogenic behaviors, including growth and migration. Together, these findings identify loss of Sh3gl2 as a frequent event in UC development that promotes disease progression.

Original languageEnglish (US)
Pages (from-to)749-760
Number of pages12
JournalNeoplasia (United States)
Volume15
Issue number7
DOIs
StatePublished - Jan 1 2013

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Carcinoma
Epidermal Growth Factor Receptor
Informatics
Neoplasms
Cell Line
Urothelium
src-Family Kinases
Mortality
Receptor Protein-Tyrosine Kinases
Growth
RNA Interference
Endocytosis
Epidermal Growth Factor
Heterografts
Genetic Recombination
Capsules
Disease Progression
Carcinogenesis
Urinary Bladder
Clone Cells

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Majumdar, Shyama ; Gong, Edward M. ; Di Vizio, Dolores ; Dreyfuss, Jonathan ; Degraff, David ; Hager, Martin H. ; Park, Peter J. ; Bellmunt, Joaquim ; Matusik, Robert J. ; Rosenberg, Jonathan E. ; Adam, Rosalyn M. / Loss of Sh3gl2/endophilin A1 is a common event in urothelial carcinoma that promotes malignant behavior. In: Neoplasia (United States). 2013 ; Vol. 15, No. 7. pp. 749-760.
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abstract = "Urothelial carcinoma (UC) causes substantial morbidity and mortality worldwide. However, the molecular mechanisms underlying urothelial cancer development and tumor progression are still largely unknown. Using informatics analysis, we identified Sh3gl2 (endophilin A1) as a bladder urothelium-enriched transcript. The gene encoding Sh3gl2 is located on chromosome 9p, a region frequently altered in UC. Sh3gl2 is known to regulate endocytosis of receptor tyrosine kinases implicated in oncogenesis, such as the epidermal growth factor receptor (EGFR) and c-Met. However, its role in UC pathogenesis is unknown. Informatics analysis of expression profiles as well as immunohistochemical staining of tissue microarrays revealed Sh3gl2 expression to be decreased in UC specimens compared to nontumor tissues. Loss of Sh3gl2 was associated with increasing tumor grade and with muscle invasion, which is a reliable predictor of metastatic disease and cancer-derived mortality. Sh3gl2 expression was undetectable in 19 of 20 human UC cell lines but preserved in the low-grade cell line RT4. Stable silencing of Sh3gl2 in RT4 cells by RNA interference 1) enhanced proliferation and colony formation in vitro, 2) inhibited EGF-induced EGFR internalization and increased EGFR activation, 3) stimulated phosphorylation of Src family kinases and STAT3, and 4) promoted growth of RT4 xenografts in subrenal capsule tissue recombination experiments. Conversely, forced re-expression of Sh3gl2 in T24 cells and silenced RT4 clones attenuated oncogenic behaviors, including growth and migration. Together, these findings identify loss of Sh3gl2 as a frequent event in UC development that promotes disease progression.",
author = "Shyama Majumdar and Gong, {Edward M.} and {Di Vizio}, Dolores and Jonathan Dreyfuss and David Degraff and Hager, {Martin H.} and Park, {Peter J.} and Joaquim Bellmunt and Matusik, {Robert J.} and Rosenberg, {Jonathan E.} and Adam, {Rosalyn M.}",
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Majumdar, S, Gong, EM, Di Vizio, D, Dreyfuss, J, Degraff, D, Hager, MH, Park, PJ, Bellmunt, J, Matusik, RJ, Rosenberg, JE & Adam, RM 2013, 'Loss of Sh3gl2/endophilin A1 is a common event in urothelial carcinoma that promotes malignant behavior', Neoplasia (United States), vol. 15, no. 7, pp. 749-760. https://doi.org/10.1593/neo.121956

Loss of Sh3gl2/endophilin A1 is a common event in urothelial carcinoma that promotes malignant behavior. / Majumdar, Shyama; Gong, Edward M.; Di Vizio, Dolores; Dreyfuss, Jonathan; Degraff, David; Hager, Martin H.; Park, Peter J.; Bellmunt, Joaquim; Matusik, Robert J.; Rosenberg, Jonathan E.; Adam, Rosalyn M.

In: Neoplasia (United States), Vol. 15, No. 7, 01.01.2013, p. 749-760.

Research output: Contribution to journalArticle

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T1 - Loss of Sh3gl2/endophilin A1 is a common event in urothelial carcinoma that promotes malignant behavior

AU - Majumdar, Shyama

AU - Gong, Edward M.

AU - Di Vizio, Dolores

AU - Dreyfuss, Jonathan

AU - Degraff, David

AU - Hager, Martin H.

AU - Park, Peter J.

AU - Bellmunt, Joaquim

AU - Matusik, Robert J.

AU - Rosenberg, Jonathan E.

AU - Adam, Rosalyn M.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Urothelial carcinoma (UC) causes substantial morbidity and mortality worldwide. However, the molecular mechanisms underlying urothelial cancer development and tumor progression are still largely unknown. Using informatics analysis, we identified Sh3gl2 (endophilin A1) as a bladder urothelium-enriched transcript. The gene encoding Sh3gl2 is located on chromosome 9p, a region frequently altered in UC. Sh3gl2 is known to regulate endocytosis of receptor tyrosine kinases implicated in oncogenesis, such as the epidermal growth factor receptor (EGFR) and c-Met. However, its role in UC pathogenesis is unknown. Informatics analysis of expression profiles as well as immunohistochemical staining of tissue microarrays revealed Sh3gl2 expression to be decreased in UC specimens compared to nontumor tissues. Loss of Sh3gl2 was associated with increasing tumor grade and with muscle invasion, which is a reliable predictor of metastatic disease and cancer-derived mortality. Sh3gl2 expression was undetectable in 19 of 20 human UC cell lines but preserved in the low-grade cell line RT4. Stable silencing of Sh3gl2 in RT4 cells by RNA interference 1) enhanced proliferation and colony formation in vitro, 2) inhibited EGF-induced EGFR internalization and increased EGFR activation, 3) stimulated phosphorylation of Src family kinases and STAT3, and 4) promoted growth of RT4 xenografts in subrenal capsule tissue recombination experiments. Conversely, forced re-expression of Sh3gl2 in T24 cells and silenced RT4 clones attenuated oncogenic behaviors, including growth and migration. Together, these findings identify loss of Sh3gl2 as a frequent event in UC development that promotes disease progression.

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