Skip to main content
Top
Published in: Annals of Surgical Oncology 4/2014

01-12-2014 | Translational Research and Biomarkers

Clinical Significance of GAB2, a Scaffolding/Docking Protein Acting Downstream of EGFR in Human Colorectal Cancer

Authors: Tae Matsumura, MD, Keishi Sugimachi, MD, PhD, Yusuke Takahashi, MD, PhD, Ryutaro Uchi, MD, Genta Sawada, MD, Masami Ueda, MD, Hidenari Hirata, MD, Shotaro Sakimura, MD, Hiroki Ueo, MD, Yuki Takano, MD, Junji Kurashige, MD, PhD, Yoshiaki Shinden, MD, Hidetoshi Eguchi, MD, PhD, Tomoya Sudo, MD, PhD, Hirofumi Yamamoto, MD, PhD, Yuichiro Doki, MD, PhD, Masaki Mori, MD, PhD, FACS, Koshi Mimori, MD, PhD

Published in: Annals of Surgical Oncology | Special Issue 4/2014

Login to get access

Abstract

Purpose

Recent studies indicated that the scaffolding adaptor protein GAB2 (GRB2-associated binding protein 2) plays a critical role in the proliferation and migration of various cancers. This study aimed to determine the role of aberrant GAB2 expression in human colorectal cancer (CRC).

Methods

Quantitative real-time reverse transcription polymerase chain reaction was used to evaluate GAB2 mRNA expression in 152 CRC tissues samples to determine the clinicopathological significance of GAB2 expression. We also performed in vitro proliferation assays using siGAB2-transfected CRC cells.

Results

GAB2 expression in tumor colorectal tissues was significantly higher than in normal colorectal tissues (p = 0.0212). High GAB2 expression levels were associated with malignant clinicopathologic potential factors, including lymphatic invasion (p = 0.0003), venous invasion (p = 0.0170), and liver metastasis (p = 0.0144). The survival rate of patients with high GAB2 expression levels was significantly lower than that of patients with low GAB2 expression (p = 0.0074). Multivariate analysis indicated that GAB2 expression was a factor affecting lymph node metastasis. Cell proliferation was significantly suppressed by siGAB2 expression in CRC cells in vitro.

Conclusions

GAB2 expression was associated with lymph node metastasis and may play a role in the growth and metastasis of CRC. These results suggest that GAB2 is a potential therapeutic target in CRC.
Literature
1.
go back to reference Soerjomataram I, Lortet-Tieulent J, Parkin DM, et al. Global burden of cancer in 2008: a systematic analysis of disability-adjusted life-years in 12 world regions. Lancet. 2012;380:1840–50.PubMedCrossRef Soerjomataram I, Lortet-Tieulent J, Parkin DM, et al. Global burden of cancer in 2008: a systematic analysis of disability-adjusted life-years in 12 world regions. Lancet. 2012;380:1840–50.PubMedCrossRef
3.
6.
go back to reference Meng S, Chen Z, Munoz-Antonia T, Wu J. Participation of both Gab1 and Gab2 in the activation of the ERK/MAPK pathway by epidermal growth factor. Biochem J. 2005;391:143–51.PubMedCentralPubMedCrossRef Meng S, Chen Z, Munoz-Antonia T, Wu J. Participation of both Gab1 and Gab2 in the activation of the ERK/MAPK pathway by epidermal growth factor. Biochem J. 2005;391:143–51.PubMedCentralPubMedCrossRef
8.
go back to reference Jackson JG, St Clair P, Sliwkowski MX, et al. Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the Anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects. Cancer Res. 2004;64:2601–9.PubMedCrossRef Jackson JG, St Clair P, Sliwkowski MX, et al. Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the Anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects. Cancer Res. 2004;64:2601–9.PubMedCrossRef
9.
go back to reference Adams SJ, Aydin IT, Celebi JT. GAB2—a scaffolding protein in cancer. Mol Cancer Res. 2012;10:1265–70.PubMedCrossRef Adams SJ, Aydin IT, Celebi JT. GAB2—a scaffolding protein in cancer. Mol Cancer Res. 2012;10:1265–70.PubMedCrossRef
10.
go back to reference Bentires-Alj M, Gil SG, Chan R, et al. A role for the scaffolding adapter GAB2 in breast cancer. Nat Med. 2006;12:114–21.PubMedCrossRef Bentires-Alj M, Gil SG, Chan R, et al. A role for the scaffolding adapter GAB2 in breast cancer. Nat Med. 2006;12:114–21.PubMedCrossRef
11.
go back to reference Mira A, Isella C, Renzulli T, et al. The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer. Oncogene. 2009;28:4444–55.PubMedCrossRef Mira A, Isella C, Renzulli T, et al. The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer. Oncogene. 2009;28:4444–55.PubMedCrossRef
12.
go back to reference Fleuren ED, O’Toole S, Millar EK, et al. Overexpression of the oncogenic signal transducer Gab2 occurs early in breast cancer development. Int J Cancer. 2010;127:1486–92.PubMedCrossRef Fleuren ED, O’Toole S, Millar EK, et al. Overexpression of the oncogenic signal transducer Gab2 occurs early in breast cancer development. Int J Cancer. 2010;127:1486–92.PubMedCrossRef
13.
go back to reference Yang Y, Wu J, Demir A, et al. GAB2 induces tumor angiogenesis in NRAS-driven melanoma. Oncogene. 2013;32:3627–37.PubMedCrossRef Yang Y, Wu J, Demir A, et al. GAB2 induces tumor angiogenesis in NRAS-driven melanoma. Oncogene. 2013;32:3627–37.PubMedCrossRef
14.
go back to reference Wang Y, Sheng Q, Spillman MA, Behbakht K, et al. Gab2 regulates the migratory behaviors and E-cadherin expression via activation of the PI3 K pathway in ovarian cancer cells. Oncogene. 2012;31:2512–20.PubMedCentralPubMedCrossRef Wang Y, Sheng Q, Spillman MA, Behbakht K, et al. Gab2 regulates the migratory behaviors and E-cadherin expression via activation of the PI3 K pathway in ovarian cancer cells. Oncogene. 2012;31:2512–20.PubMedCentralPubMedCrossRef
16.
go back to reference Bocanegra M, Bergamaschi A, Kim YH, et al. Focal amplification and oncogene dependency of GAB2 in breast cancer. Oncogene. 2010;29:774–9.PubMedCrossRef Bocanegra M, Bergamaschi A, Kim YH, et al. Focal amplification and oncogene dependency of GAB2 in breast cancer. Oncogene. 2010;29:774–9.PubMedCrossRef
18.
go back to reference Zatkova A, Schoch C, Speleman F, et al. GAB2 is a novel target of 11q amplification in AML/MDS. Gene Chromosome Cancer. 2006;45:798–807.CrossRef Zatkova A, Schoch C, Speleman F, et al. GAB2 is a novel target of 11q amplification in AML/MDS. Gene Chromosome Cancer. 2006;45:798–807.CrossRef
19.
20.
go back to reference Herrera Abreu MT, Hughes WE, Mele K, et al. Gab2 regulates cytoskeletal organization and migration of mammary epithelial cells by modulating RhoA activation. Mol Biol Cell. 2011;22:105–16.PubMedCrossRef Herrera Abreu MT, Hughes WE, Mele K, et al. Gab2 regulates cytoskeletal organization and migration of mammary epithelial cells by modulating RhoA activation. Mol Biol Cell. 2011;22:105–16.PubMedCrossRef
21.
go back to reference Ke Y, Wu D, Princen F, et al. Role of Gab2 in mammary tumorigenesis and metastasis. Oncogene. 2007;26:4951–60.PubMedCrossRef Ke Y, Wu D, Princen F, et al. Role of Gab2 in mammary tumorigenesis and metastasis. Oncogene. 2007;26:4951–60.PubMedCrossRef
22.
go back to reference Jorissen RN, Gibbs P, Christie M, et al. Metastasis-associated gene expression changes predict poor outcomes in patients with Dukes stage B and C colorectal cancer. Clin Cancer Res. 2009;15:7642–51.PubMedCentralPubMedCrossRef Jorissen RN, Gibbs P, Christie M, et al. Metastasis-associated gene expression changes predict poor outcomes in patients with Dukes stage B and C colorectal cancer. Clin Cancer Res. 2009;15:7642–51.PubMedCentralPubMedCrossRef
23.
go back to reference Bild AH, Yao G, Chang JT, et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2006;439:353–7.PubMedCrossRef Bild AH, Yao G, Chang JT, et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2006;439:353–7.PubMedCrossRef
24.
go back to reference Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.PubMedCentralPubMedCrossRef Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.PubMedCentralPubMedCrossRef
25.
go back to reference Mermel CH, Schumacher SE, Hill B, et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alternation in human cancers. Genome Biol. 2011;12:41.CrossRef Mermel CH, Schumacher SE, Hill B, et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alternation in human cancers. Genome Biol. 2011;12:41.CrossRef
26.
go back to reference Cance WG, Kurenova E, Marlowe T, et al. Disrupting the scaffold to improve focal adhesion kinase targeted cancer therapeutics. Sci Signal. 2013;6(268):pe10.PubMedCentralPubMed Cance WG, Kurenova E, Marlowe T, et al. Disrupting the scaffold to improve focal adhesion kinase targeted cancer therapeutics. Sci Signal. 2013;6(268):pe10.PubMedCentralPubMed
27.
go back to reference Azusa A, Takeo M, Hiroyuki O, et al. PIK3CA overexpression is a possible prognostic factor for favorable survival in ovarian clear cell carcinoma. Hum Pathol. 2013;44:199–207.CrossRef Azusa A, Takeo M, Hiroyuki O, et al. PIK3CA overexpression is a possible prognostic factor for favorable survival in ovarian clear cell carcinoma. Hum Pathol. 2013;44:199–207.CrossRef
28.
go back to reference Bertelsen BI, Steine SJ, Sandvei R, et al. Molecular analysis of the PI3 K-AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation. Int J Cancer. 2006;118:1877–83.PubMedCrossRef Bertelsen BI, Steine SJ, Sandvei R, et al. Molecular analysis of the PI3 K-AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation. Int J Cancer. 2006;118:1877–83.PubMedCrossRef
29.
go back to reference Chan F, Lee JT, Navolanic PM, et al. Involvement of PI3 K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia. 2003;17:590–603.CrossRef Chan F, Lee JT, Navolanic PM, et al. Involvement of PI3 K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia. 2003;17:590–603.CrossRef
Metadata
Title
Clinical Significance of GAB2, a Scaffolding/Docking Protein Acting Downstream of EGFR in Human Colorectal Cancer
Authors
Tae Matsumura, MD
Keishi Sugimachi, MD, PhD
Yusuke Takahashi, MD, PhD
Ryutaro Uchi, MD
Genta Sawada, MD
Masami Ueda, MD
Hidenari Hirata, MD
Shotaro Sakimura, MD
Hiroki Ueo, MD
Yuki Takano, MD
Junji Kurashige, MD, PhD
Yoshiaki Shinden, MD
Hidetoshi Eguchi, MD, PhD
Tomoya Sudo, MD, PhD
Hirofumi Yamamoto, MD, PhD
Yuichiro Doki, MD, PhD
Masaki Mori, MD, PhD, FACS
Koshi Mimori, MD, PhD
Publication date
01-12-2014
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue Special Issue 4/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-014-3889-x

Other articles of this Special Issue 4/2014

Annals of Surgical Oncology 4/2014 Go to the issue