Abstract
Ovarian cancer, the most deadly gynecologic malignancy, is often diagnosed late and at the advanced stage when the cancer cells have already migrated and invaded into other tissues and organs. Better understanding of the mechanism of metastasis in ovarian cancer cells is essential to the design of effective therapy. In this study, we investigated the function of scaffolding adaptor protein Gab2 in ovarian cancer cells. Gab2 is found to be overexpressed in a subset of ovarian tumors and cancer cell lines. Gab2 expression mainly regulates the migratory behaviors of ovarian cancer cells. Overexpression of Gab2 promotes the migration and invasion, and downregulates E-cadherin expression in ovarian cancer cells with low-Gab2 expression. Conversely, knockdown of Gab2 expression inhibits the migration and invasion, and promotes E-cadherin expression in ovarian cancer cells with high-Gab2 expression. By expressing Gab2 wild-type and Gab2 mutants that are defective in activation of the PI3K and Shp2-Erk pathways, we find that Gab2 inhibits E-cadherin expression and enhances the expression of Zeb1, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), and cell migration and invasion through the activation of the PI3K pathway. Knockdown of Zeb1 expression blocks Gab2-induced suppression of E-cadherin expression and increase in cell invasion. LY294002 and GDC-0941, inhibitors of PI3K, or Rapamycin, an inhibitor of PI3K downstream target mTOR, can reverse the effects of Gab2 on migration and invasion. Overall, our studies reveal that Gab2 overexpression, via activation of the PI3K-Zeb1 pathway, promotes characteristics of EMT in ovarian cancer cells.
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References
Abreu MT, Hughes WE, Mele K, Lyons RJ, Rickwood D, Browne BC et al. (2011). Gab2 regulates cytoskeletal organization and migration of mammary epithelial cells by modulating RhoA activation. Mol Biol Cell 22: 105–116.
Agarwal R, Carey M, Hennessy B, Mills GB . (2010). PI3K pathway-directed therapeutic strategies in cancer. Curr Opin Investig Drugs 11: 615–628.
Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S et al. (2004). The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3: 772–775.
Bast Jr RC, Hennessy B, Mills GB . (2009). The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 9: 415–428.
Battini JL, Rasko JE, Miller AD . (1999). A human cell-surface receptor for xenotropic and polytropic murine leukemia viruses: possible role in G protein-coupled signal transduction. Proc Natl Acad Sci USA 96: 1385–1390.
Bennett HL, Brummer T, Jeanes A, Yap AS, Daly RJ . (2008). Gab2 and Src co-operate in human mammary epithelial cells to promote growth factor independence and disruption of acinar morphogenesis. Oncogene 27: 2693–2704.
Bentires-Alj M, Gil SG, Chan R, Wang ZC, Wang Y, Imanaka N et al. (2006). A role for the scaffolding adapter GAB2 in breast cancer. Nat Med 12: 114–121.
Bocanegra M, Bergamaschi A, Kim YH, Miller MA, Rajput AB, Kao J et al. (2010). Focal amplification and oncogene dependency of GAB2 in breast cancer. Oncogene 29: 774–779.
Brown LA, Kalloger SE, Miller MA, Shih Ie M, McKinney SE, Santos JL et al. (2008). Amplification of 11q13 in ovarian carcinoma. Genes Chromosomes Cancer 47: 481–489.
Brummelkamp TR, Bernards R, Agami R . (2002). Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2: 243–247.
Brummer T, Schramek D, Hayes VM, Bennett HL, Caldon CE, Musgrove EA et al. (2006). Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein. J Biol Chem 281: 626–637.
Cheng JC, Auersperg N, Leung PC . (2011). Inhibition of p53 induces invasion of serous borderline ovarian tumor cells by accentuating PI3K/Akt-mediated suppression of E-cadherin. Oncogene 30: 1020–1031.
Daly RJ, Gu H, Parmar J, Malaney S, Lyons RJ, Kairouz R et al. (2002). The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer. Oncogene 21: 5175–5181.
Engelman JA . (2009). Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9: 550–562.
Feeley KM, Wells M . (2001). Precursor lesions of ovarian epithelial malignancy. Histopathology 38: 87–95.
Fleuren ED, O'Toole S, Millar EK, McNeil C, Lopez-Knowles E, Boulghourjian A et al. (2010). Overexpression of the oncogenic signal transducer Gab2 occurs early in breast cancer development. Int J Cancer 127: 1486–1492.
Gu H, Neel BG . (2003). The ‘Gab’ in signal transduction. Trends Cell Biol 13: 122–130.
Gu H, Pratt JC, Burakoff SJ, Neel BG . (1998). Cloning of p97/Gab2, the major SHP-2 binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation. Mol Cell 2: 729–740.
Horst B, Gruvberger-Saal SK, Hopkins BD, Bordone L, Yang Y, Chernoff KA et al. (2009). Gab2-mediated signaling promotes melanoma metastasis. Am J Pathol 174: 1524–1533.
Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E et al. (2004). Cancer statistics, 2004. CA Cancer J Clin 54: 8–29.
Karst AM, Levanon K, Drapkin R . (2011). Modeling high-grade serous ovarian carcinogenesis from the fallopian tube. Proc Natl Acad Sci USA 108: 7547–7552.
Ke Y, Wu D, Princen F, Nguyen T, Pang Y, Lesperance J et al. (2007). Role of Gab2 in mammary tumorigenesis and metastasis. Oncogene 26: 4951–4960.
Kolasa IK, Rembiszewska A, Felisiak A, Ziolkowska-Seta I, Murawska M, Moes J et al. (2009). PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients. Cancer Biol Ther 8: 21–26.
Kong D, Dan S, Yamazaki K, Yamori T . (2010). Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39. Eur J Cancer 46: 1111–1121.
Kosary C . (2007). Chapter 16: Cancers of the Ovary in SEER Survival Monograph: Cancer Survival Among Adults: US SEER Program, 1988–2001, Patient and Tumor Characteristics. NIH Pub. No. 07-6215 NCI: Bethesda, MD, USA, pp 133–144.
Kurman RJ, Shih Ie M . (2010). The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 34: 433–443.
Larue L, Bellacosa A . (2005). Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 24: 7443–7454.
Levanon K, Crum C, Drapkin R . (2008). New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol 26: 5284–5293.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943–1947.
Luo J, Manning BD, Cantley LC . (2003). Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4: 257–262.
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science 304: 554.
Sheng Q, Liu X, Fleming E, Yuan K, Piao H, Chen J et al. (2010). An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell 17: 298–310.
Shih Ie M, Kurman RJ . (2004). Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol 164: 1511–1518.
Shih Ie M, Sheu JJ, Santillan A, Nakayama K, Yen MJ, Bristow RE et al. (2005). Amplification of a chromatin remodeling gene, Rsf-1/HBXAP, in ovarian carcinoma. Proc Natl Acad Sci USA 102: 14004–14009.
Spandidos A, Wang X, Wang H, Seed B . (2010). PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification. Nucleic Acids Res 38: D792–D799.
Tan DS, Agarwal R, Kaye SB . (2006). Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet Oncol 7: 925–934.
Tan DS, Ang JE, Kaye SB . (2008). Ovarian cancer: can we reverse drug resistance? Adv Exp Med Biol 622: 153–167.
Wells A, Yates C, Shepard CR . (2008). E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis 25: 621–628.
Wohrle FU, Daly RJ, Brummer T . (2009). Function, regulation and pathological roles of the Gab/DOS docking proteins. Cell Commun Signal 7: 22.
Yang J, Weinberg RA . (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14: 818–829.
Acknowledgements
We thank Dr Sam Mok for the HOSE lines. This work is supported by the Department of Pathology, University of Colorado, Anschutz Medical Campus and in part by the National Institutes of Health grant R01-AI51612 (to HG).
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Wang, Y., Sheng, Q., Spillman, M. et al. Gab2 regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells. Oncogene 31, 2512–2520 (2012). https://doi.org/10.1038/onc.2011.435
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DOI: https://doi.org/10.1038/onc.2011.435
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