SH3BGRL3 Protein as a Potential Prognostic Biomarker for Urothelial Carcinoma: A Novel Binding Partner of Epidermal Growth Factor Receptor

Cheng Yao Chiang, Chin Chen Pan, Hong Yi Chang, Ming-Derg Lai, Tzong Shin Tzai, Yuh-Shyan Tsai, Pin Ling, Hsiao-Sheng Liu, Bi-Fang Lee, Hong-Lin Cheng, Chung-Liang Ho, Shu-Hui Chen, Nan-Haw Chow

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Abstract

Purpose: Mass spectrometry based biomarker discovery has clinical benefit. To identify novel biomarkers for urothelial carcinoma, we performed quantitative proteomics on pooled urine pairs from patients with and without urothelial carcinoma. Experimental Design: Shot-gun proteomics using liquid chromatography- tandem mass spectrometry and stable isotope dimethyl labeling identified 219 candidate proteins. The potential implication of SH3 domain binding glutamic acid-rich protein like 3 (SH3BGRL3) was examined by immunoblotting of the urine (n = 13) and urothelial tumors (n = 32). Additional immunohistochemistry was performed on bladder cancer array (n = 1145) and correlated with tumor aggressiveness. Then, biologic functions and signaling pathways of SH3BGRL3 were explored using stable cell lines. Results: The detectable urine SH3BGRL3 in patients with urothelial carcinoma was positively associated with higher histologic grading and muscle invasiveness of urothelial carcinoma. SH3BGRL3 is expressed in 13.9% (159/1145) of bladder cancer cohort and is positively associated with muscle invasion (P = 0.0028).SH3BGRL3expression is associated with increased risk of progression in patients with nonmuscle-invasive bladder cancer (P=0.032).SH3BGRL3 expression is significantly associated with a high level of epidermal growth factor receptor (EGFR) in bladder cancer (P < 0.0001). SH3BGRL3 promotes the epithelial mesenchymal transition, cell migration, and proliferation of urothelial carcinoma in vitro. SH3BGRL3 interacts with phosphor-EGFR at Y1068, Y1086, and Y1173 through Grb2 by its proline-rich motif, and activates the Akt-associated signaling pathway. Conclusions: Evaluation of SH3BGRL3 expression status or urine content mayidentify a subset of patients with bladder cancer who may require more intensive treatment. SH3BGRL3 deserves further investigation as a cotargeting candidate for designing EGFR-based cancer therapies.

Original languageEnglish
Pages (from-to)5601-5611
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number24
DOIs
Publication statusPublished - 2015 Dec 15

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src Homology Domains
Epidermal Growth Factor Receptor
Glutamic Acid
Biomarkers
Carcinoma
Urinary Bladder Neoplasms
Proteins
Urine
Proteomics
Isotope Labeling
Muscles
Neoplasms
Epithelial-Mesenchymal Transition
Firearms
Tandem Mass Spectrometry
Immunoblotting
Proline
Liquid Chromatography
Cell Movement
Mass Spectrometry

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

@article{b04430936ea747239cee34de86797db9,
title = "SH3BGRL3 Protein as a Potential Prognostic Biomarker for Urothelial Carcinoma: A Novel Binding Partner of Epidermal Growth Factor Receptor",
abstract = "Purpose: Mass spectrometry based biomarker discovery has clinical benefit. To identify novel biomarkers for urothelial carcinoma, we performed quantitative proteomics on pooled urine pairs from patients with and without urothelial carcinoma. Experimental Design: Shot-gun proteomics using liquid chromatography- tandem mass spectrometry and stable isotope dimethyl labeling identified 219 candidate proteins. The potential implication of SH3 domain binding glutamic acid-rich protein like 3 (SH3BGRL3) was examined by immunoblotting of the urine (n = 13) and urothelial tumors (n = 32). Additional immunohistochemistry was performed on bladder cancer array (n = 1145) and correlated with tumor aggressiveness. Then, biologic functions and signaling pathways of SH3BGRL3 were explored using stable cell lines. Results: The detectable urine SH3BGRL3 in patients with urothelial carcinoma was positively associated with higher histologic grading and muscle invasiveness of urothelial carcinoma. SH3BGRL3 is expressed in 13.9{\%} (159/1145) of bladder cancer cohort and is positively associated with muscle invasion (P = 0.0028).SH3BGRL3expression is associated with increased risk of progression in patients with nonmuscle-invasive bladder cancer (P=0.032).SH3BGRL3 expression is significantly associated with a high level of epidermal growth factor receptor (EGFR) in bladder cancer (P < 0.0001). SH3BGRL3 promotes the epithelial mesenchymal transition, cell migration, and proliferation of urothelial carcinoma in vitro. SH3BGRL3 interacts with phosphor-EGFR at Y1068, Y1086, and Y1173 through Grb2 by its proline-rich motif, and activates the Akt-associated signaling pathway. Conclusions: Evaluation of SH3BGRL3 expression status or urine content mayidentify a subset of patients with bladder cancer who may require more intensive treatment. SH3BGRL3 deserves further investigation as a cotargeting candidate for designing EGFR-based cancer therapies.",
author = "Chiang, {Cheng Yao} and Pan, {Chin Chen} and Chang, {Hong Yi} and Ming-Derg Lai and Tzai, {Tzong Shin} and Yuh-Shyan Tsai and Pin Ling and Hsiao-Sheng Liu and Bi-Fang Lee and Hong-Lin Cheng and Chung-Liang Ho and Shu-Hui Chen and Nan-Haw Chow",
year = "2015",
month = "12",
day = "15",
doi = "10.1158/1078-0432.CCR-14-3308",
language = "English",
volume = "21",
pages = "5601--5611",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "24",

}

TY - JOUR

T1 - SH3BGRL3 Protein as a Potential Prognostic Biomarker for Urothelial Carcinoma

T2 - A Novel Binding Partner of Epidermal Growth Factor Receptor

AU - Chiang, Cheng Yao

AU - Pan, Chin Chen

AU - Chang, Hong Yi

AU - Lai, Ming-Derg

AU - Tzai, Tzong Shin

AU - Tsai, Yuh-Shyan

AU - Ling, Pin

AU - Liu, Hsiao-Sheng

AU - Lee, Bi-Fang

AU - Cheng, Hong-Lin

AU - Ho, Chung-Liang

AU - Chen, Shu-Hui

AU - Chow, Nan-Haw

PY - 2015/12/15

Y1 - 2015/12/15

N2 - Purpose: Mass spectrometry based biomarker discovery has clinical benefit. To identify novel biomarkers for urothelial carcinoma, we performed quantitative proteomics on pooled urine pairs from patients with and without urothelial carcinoma. Experimental Design: Shot-gun proteomics using liquid chromatography- tandem mass spectrometry and stable isotope dimethyl labeling identified 219 candidate proteins. The potential implication of SH3 domain binding glutamic acid-rich protein like 3 (SH3BGRL3) was examined by immunoblotting of the urine (n = 13) and urothelial tumors (n = 32). Additional immunohistochemistry was performed on bladder cancer array (n = 1145) and correlated with tumor aggressiveness. Then, biologic functions and signaling pathways of SH3BGRL3 were explored using stable cell lines. Results: The detectable urine SH3BGRL3 in patients with urothelial carcinoma was positively associated with higher histologic grading and muscle invasiveness of urothelial carcinoma. SH3BGRL3 is expressed in 13.9% (159/1145) of bladder cancer cohort and is positively associated with muscle invasion (P = 0.0028).SH3BGRL3expression is associated with increased risk of progression in patients with nonmuscle-invasive bladder cancer (P=0.032).SH3BGRL3 expression is significantly associated with a high level of epidermal growth factor receptor (EGFR) in bladder cancer (P < 0.0001). SH3BGRL3 promotes the epithelial mesenchymal transition, cell migration, and proliferation of urothelial carcinoma in vitro. SH3BGRL3 interacts with phosphor-EGFR at Y1068, Y1086, and Y1173 through Grb2 by its proline-rich motif, and activates the Akt-associated signaling pathway. Conclusions: Evaluation of SH3BGRL3 expression status or urine content mayidentify a subset of patients with bladder cancer who may require more intensive treatment. SH3BGRL3 deserves further investigation as a cotargeting candidate for designing EGFR-based cancer therapies.

AB - Purpose: Mass spectrometry based biomarker discovery has clinical benefit. To identify novel biomarkers for urothelial carcinoma, we performed quantitative proteomics on pooled urine pairs from patients with and without urothelial carcinoma. Experimental Design: Shot-gun proteomics using liquid chromatography- tandem mass spectrometry and stable isotope dimethyl labeling identified 219 candidate proteins. The potential implication of SH3 domain binding glutamic acid-rich protein like 3 (SH3BGRL3) was examined by immunoblotting of the urine (n = 13) and urothelial tumors (n = 32). Additional immunohistochemistry was performed on bladder cancer array (n = 1145) and correlated with tumor aggressiveness. Then, biologic functions and signaling pathways of SH3BGRL3 were explored using stable cell lines. Results: The detectable urine SH3BGRL3 in patients with urothelial carcinoma was positively associated with higher histologic grading and muscle invasiveness of urothelial carcinoma. SH3BGRL3 is expressed in 13.9% (159/1145) of bladder cancer cohort and is positively associated with muscle invasion (P = 0.0028).SH3BGRL3expression is associated with increased risk of progression in patients with nonmuscle-invasive bladder cancer (P=0.032).SH3BGRL3 expression is significantly associated with a high level of epidermal growth factor receptor (EGFR) in bladder cancer (P < 0.0001). SH3BGRL3 promotes the epithelial mesenchymal transition, cell migration, and proliferation of urothelial carcinoma in vitro. SH3BGRL3 interacts with phosphor-EGFR at Y1068, Y1086, and Y1173 through Grb2 by its proline-rich motif, and activates the Akt-associated signaling pathway. Conclusions: Evaluation of SH3BGRL3 expression status or urine content mayidentify a subset of patients with bladder cancer who may require more intensive treatment. SH3BGRL3 deserves further investigation as a cotargeting candidate for designing EGFR-based cancer therapies.

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U2 - 10.1158/1078-0432.CCR-14-3308

DO - 10.1158/1078-0432.CCR-14-3308

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