Gab2 expression in glioma and its implications for tumor invasion

Shi, Lihong; Sun, Xinwei; Zhang, Jin; Zhao, Chunling; Liu, Hongli; Liu, Zhijun; Fang, Chunyan; Wang, Xuejian; Zhao, Chunzhen; Zhang, Xiurong; Zhou, Fenghua; Lu, Shaoying; Luo, Rong; Zhang, Baogang

doi:10.3109/0284186x.2012.750032

Cited by 25 publications

(30 citation statements)

References 31 publications

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“…High levels of Gab2 expression have been detected in breast cancer cell lines and primary tumors [32, 39]. Our results also revealed that when the HER2 oncogene was overexpressed or present in T47D and HCC1954 cells, the expression of Gab2 was upregulated.…”

Section: Discussionsupporting

confidence: 67%

Gab2 Ablation Reverses the Stemness of HER2-Overexpressing Breast Cancer Cells

Zhang¹,

Chen²,

Gong³

et al. 2018

Cell Physiol Biochem

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Background/Aims: HER2 has been implicated in mammary tumorigenesis as well as aggressive tumor growth and metastasis. Its overexpression is related to a poor prognosis and chemoresistance in breast cancer patients. Although Grb2-associated binding protein 2 (Gab2) is important in the development and progression of human cancer, its effects and mechanisms in HER2-overexpressing breast cancer are unclear. Methods: Clone formation and MTT assays were used to examine cell proliferation. To detect the effect of Gab2 on the stemness of breast cancer cells, we used flow cytometry, a sphere formation assay, real-time PCR, and western blot. An animal model was created to validate the effect of Gab2 on tumor growth in vivo. Tissue slides were analyzed by immunohistochemistry. Results: Knockdown of Gab2 suppressed PI3K/AKT and MAPK/ERK pathway activity. Gab2 ablation also reduced the stemness of HER2-overexpressing breast cancer cells. In vivo, knockdown of Gab2 inhibited tumor growth. Conclusion: This study unveils a potential function of Gab2 in HER2-overexpressing breast cancer cells. Gab2 might be a potential target in the clinical therapy of HER2-overexpressing breast carcinoma.

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Section: Discussionsupporting

confidence: 67%

Gab2 Ablation Reverses the Stemness of HER2-Overexpressing Breast Cancer Cells

Zhang¹,

Chen²,

Gong³

et al. 2018

Cell Physiol Biochem

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“…LI-QIANG TIAN 1,2 , EN-QIN LIU 3 , XI-DE ZHU 2 , XIN-GONG WANG 2 , JIAN LI 2 and GUANG-MING XU cellular investigations, the downregulation of GAB2 inhibits the migration and invasion of glioma cells (17). Elucidating why the GAB2 gene is overexpressed and determining how it may be downregulated will assist in further understand the pathogenesis and progression of glioma, and offer novel therapeutic targets.…”

Section: Microrna-197 Inhibits Cell Proliferation By Targeting Gab2 Imentioning

confidence: 99%

“…Statistical analysis suggested that the upregulation of GAB2 was correlated with the World Health Organization (WHO) grade of glioma, and that patients with high expression levels of GAB2 exhibited reduced survival rates (17). In a previous animal experiment, knockdown of GAB2 inhibited the invasive ability of glioma cells in the brains of mice with severe combined immunodeficiency (17 …”

Section: Introductionmentioning

confidence: 99%

MicroRNA-197 inhibits cell proliferation by targeting GAB2 in glioblastoma

Tian

Liu

Zhu

et al. 2016

Molecular Medicine Reports

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Abstract. Glioblastoma is the most common type of primary brain tumor in adults, and is usually fatal in a short duration. Acquiring a better understanding of the pathogenic mechanisms of glioblastoma is essential to the design of effective therapeutic strategies. Grb2-associated binding protein 2 (GAB2) is a member of the daughter of sevenless/Gab family of scaffolding adapters, and has been reported to be important in the development and progression of human cancer. Previously, it has been reported that GAB2 is expressed at high levels in glioma, and may serve as a useful prognostic marker for glioma and a novel therapeutic target for glioma invasion intervention. Elucidating why GAB2 is overexpressed in glioma, and investigating how to downregulate it will assist in further understanding the pathogenesis and progression of the disease, and to offer novel targets for therapy. The present study used in situ hybridization to detect microRNA (miR)-197 expression levels and Targetscan to predict that the 3'-UTR of GAB2 was targeted by miR-197. Northern blotting and reverse transcription-quantitative polymerase chain reaction were also conducted in the current study. miR-197 is downregulated in glioblastoma tissues, compared with adjacent normal tissues, however it involvement continues to be detected in the disease. The results of the present study demonstrated that miR-197, as a tumor suppressor gene, inhibited proliferation by regulating GAB2 in glioblastoma cells. Furthermore, GAB2 was not only upregulated in glioma, but its expression levels were also associated with the grades of glioma severity. In addition, overexpression of GAB2 suppressed the expression of miR-197 in glioblastoma cells. Therefore, restoration of miR-197 and targeting GAB2 may be used, in conjunction with other therapies, to prevent the progression of glioblastoma. IntroductionMicroRNAs (miRNAs; miRs) are short, non-coding RNAs, which regulate target mRNA by binding predominantly to the 3'-untranslated region (3'-UTR), inducing either translational repression or the degradation of the mRNA target (1-3). Previously, the involvement of miRNAs in the phenotypic modulation of human glioma has been reported. For example, miRNA-21 knockdown disrupts glioma growth in vivo and exhibits synergistic cytotoxicity with neural precursor cell-delivered secretable tumor necrosis factor-related apoptosis-inducing ligand in human glioma (4); miRNA-34a acts as a tumor suppressor in brain tumors and glioma stem cells (5); and miRNA-181a sensitizes human U87MG malignant glioma cells to radiation by targeting B cell lymphoma 2 (6). Although miR-197 is downregulated in glioblastoma, its roles in malignant tumor progression remain to be elucidated (7).Grb2-associated binding protein (GAB)2 belongs to a family of evolutionarily conserved proteins consisting of three mammalian paralogues: GAB1, GAB2 and GAB3; Drosophila melanogaster homolog daughter of sevenless; and Caenorhabditis elegans homolog suppressor of clear. Family members exhibit 40-50% sequence homolog...

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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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Gab2 expression in glioma and its implications for tumor invasion

Cited by 25 publications

References 31 publications

Gab2 Ablation Reverses the Stemness of HER2-Overexpressing Breast Cancer Cells

Gab2 Ablation Reverses the Stemness of HER2-Overexpressing Breast Cancer Cells

MicroRNA-197 inhibits cell proliferation by targeting GAB2 in glioblastoma

Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways

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