Overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating chemokine expression

Duckworth, Carrie A.; Zhang, L; Carroll, Steven L.; Ethier, Stephen P.; Cheung, Hiu Wing

doi:10.1038/onc.2015.472

Cited by 51 publications

(43 citation statements)

References 35 publications

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“…GAB2, a member of the mammalian Grb2-associated binding (Gab) scaffolding/adapter family, contains an N-terminal PH domain, a tyrosine residue domain and a proline-rich domain (45,46). Previously, GAB2 was found to be upregulated in multiple types of human cancer, such as renal cell carcinoma (31), hepatocellular carcinoma (33), gastric (47), ovarian (48) and breast cancer (49). GAB2 is also overexpressed in CRC tissues, and this overexpression was obviously assocated with lymph node metastasis, distant metastasis and TNM stage (29).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-485 plays tumour-suppressive roles in colorectal cancer by directly targeting GAB2

Yan

et al. 2018

Oncol Rep

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Colorectal cancer (CRC) is reported to be the third most common cancer and the fourth leading cause of cancer-related deaths around the world. MicroRNA-485 (miR-485) has been reported to be aberrantly expressed and play important roles in several types of human malignancy. However, the expression level, biological functions and underlying molecular mechanisms of miR-485 in CRC remain unclear. Therefore, the aim of the present study was to determine miR-485 expression levels and their clinical significance in CRC and to explore the functions and underlying mechanisms of miR-485 in this disease. In the present study, miR-485 was lowly expressed in CRC tissues and cell lines. Decreased miR-485 expression was associated with tumour size, lymph node metastasis, distant metastasis and TNM stage. Functional assays indicated that upregulation of miR-485 impaired CRC cell proliferation, invasion and induced cell apoptosis. Grb2-associated binding 2 (GAB2) was identified as a direct target of miR-485 in CRC. GAB2 was upregulated in CRC tissues and was negatively correlated with the miR-485 expression level. Furthermore, GAB2 knockdown simulated the tumour-suppressing roles of miR-485 overexpression in CRC cells. Moreover, restored GAB2 expression reversed the effects of miR-485 overexpression in CRC cells. In addition, miR-485 suppressed the AKT and ERK signalling pathways in CRC by directly targeting GAB2. Collectively, these findings demonstrate that miR-485 may play tumour suppressive roles in CRC by directly targeting GAB2 and indirectly regulating AKT and ERK signalling pathways, suggesting that miR-485 may be a potential therapeutic target for patients with this disease.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-485 plays tumour-suppressive roles in colorectal cancer by directly targeting GAB2

Yan

et al. 2018

Oncol Rep

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“…Notably, overexpression of Gab2 in CRC cells induced tumor growth and angiogenesis in mouse xenografts through enhancing VEGF expression. Consistent with our findings, Gab2 was reported to be an inducer of tumor angiogenesis essential for melanoma and ovarian cancer [24, 25]. Our results provided new evidence supporting the involvement of Gab2 in driving tumor angiogenesis.…”

Section: Discussionsupporting

confidence: 92%

Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels

Ding

Luo

Fan

et al. 2017

J Exp Clin Cancer Res

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BackgroundGrb2-associated binder 2 (Gab2) is a scaffolding protein that serves as a critical signaling amplifier downstream of tyrosine kinase receptors. Our previous study has shown that Gab2 induces epithelial-to-mesenchymal transition (EMT) and promotes metastasis in colorectal cancer (CRC). However, the role of Gab2 in CRC growth and angiogenesis remains unclear.MethodsThe expression of vascular endothelial growth factor (VEGF) in different colorectal tissues was detected by immunohistochemistry and qRT-PCR to evaluate its correlation with Gab2. Lentiviral vectors bearing Gab2 gene and its small interfering RNAs were constructed and transfected into CRC cell lines. The effects of Gab2 on the cell proliferation in vitro and tumorigenesis in vivo, were examined via CCK‑8 assay, colony formation assay as well as tumorigenicity assay respectively. Moreover, to assess its potential role in tumor growth and angiogenesis, the expression of Ki67, CD34 and vascular endothelial growth factor receptor-2 (VEGFR2) were detected by immunohistochemistry in CRC cells tumors. Finally, we evaluated the impact of Gab2 on the expression of c-Myc and VEGF, and the probable effect of mechanistic targeted extracellular signal-regulated kinase (ERK) pathway in suppressing tumor growth and angiogenesis.ResultsUp-regulation of Gab2 expression was found to be positively correlated with VEGF in CRC tissues. Exogenous expression of Gab2 obviously promoted, whereas silencing of Gab2 inhibited, proliferation and clone formation of human CRC cells in vitro. Of note, Gab2 enhanced tumorigenesis and tumor growth in mouse xenografts with high Ki67 expression, and led to an increased vessel density with strong CD34 and VEGFR2 activity. In addition, elevated Gab2 expression obviously up-regulated the expression of VEGF, and stimulated the activation of its downstream genes, ERK1/2 and c-Myc in CRC cells. Instead, down-regulated Gab2 expression significantly reduced the levels of VEGF, and inhibited the transduction of ERK/c-Myc pathway. Finally, we revealed that mechanistic target of mitogen-activated protein kinase (MEK) could attenuate Gab2-induced tumor growth and angiogenesis via altering VEGF and c-Myc levels.ConclusionsThe results from our study suggest that Gab2 promotes intestinal tumor growth and angiogenesis through upregulation of VEGF expression mediated by the MEK/ERK/c-Myc pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0524-2) contains supplementary material, which is available to authorized users.

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“…Forced expression of Gab2 can promote the proliferation and invasion of melanoma and breast cancer cells (35, 39). Overexpression of Gab2 promotes tumor angiogenesis by increasing the expression of multiple chemokines in ovarian cancer (40), and Gab2 also promotes the growth of cancer cells in lung cancer (41) and glioma (42). …”

Section: Discussionmentioning

confidence: 99%

Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways

et al. 2017

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Our previous studies have found that Growth factor receptor-bound protein 2–associated binding protein 2 (Gab2)—a docking protein—governs the development of fatty liver disease. Here, we further demonstrate that Gab2 mediates hepatocarcinogenesis. Compared with a faint expression in para-carcinoma tissue, Gab2 was highly expressed in ∼60–70% of human hepatocellular carcinoma (HCC) specimens. Deletion of Gab2 dramatically suppressed diethylnitrosamine-induced HCC in mice. The oncogenic effects of Gab2 in HepG2 cells were promoted by Gab2 overexpression but were rescued by Gab2 knockdown. Furthermore, Gab2 knockout in HepG2 cells restrained cell proliferation, migration and tumor growth in nude mice. Signaling pathway analysis with protein kinase inhibitors demonstrated that oncogenic regulation by Gab2 in hepatic cells involved multiple signaling molecules, including ERK, Akt, and Janus kinases (Jaks), especially those that mediate inflammatory signaling. IL-6 signaling was increased by Gab2 overexpression and impaired by Gab2 deletion via regulation of Jak2 and signal transducer and activator of transcription 3 phosphorylation and the expression of downstream genes, such as Bcl-2 (B-cell lymphoma 2), c-Myc, MMP7 (matrix metalloproteinase-7), and cyclin D1 in vitro and in vivo. These data indicate that Gab2 mediates the pathologic progression of HCC by integrating multiple signaling pathways and suggest that Gab2 might be a powerful therapeutic target for HCC.—Cheng, J., Zhong, Y., Chen, S., Sun, Y., Huang, L., Kang, Y., Chen, B., Chen, G., Wang, F., Tian, Y., Liu, W., Feng, G.-S., Lu, Z. Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways.

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Overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating chemokine expression

Cited by 51 publications

References 35 publications

MicroRNA-485 plays tumour-suppressive roles in colorectal cancer by directly targeting GAB2

MicroRNA-485 plays tumour-suppressive roles in colorectal cancer by directly targeting GAB2

Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels

Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways

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