GAB2 promotes cell proliferation by activating the ERK signaling pathway in hepatocellular carcinoma

Chen, Yuyan; Liu, Qingqing; Wu, Miaomiao; Li, Manhua; Ding, Haifang; Shan, Xiaohang; Liu, Jinxia; Tao, Tao; Ni, Runzhou; Chen, Xudong

doi:10.1007/s13277-016-5019-9

Cited by 29 publications

(24 citation statements)

References 29 publications

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“…These findings indicate that Gab2 might be a tumor-associated protein. Two recent studies investigated Gab2 expression in HCC samples and confirm our results (26, 27). Gab2 is also associated with tumor behavior in other types of malignancies, such as breast cancer (28), melanoma (29), ovarian cancer (30), lung cancer (31), glioma (32), and gastric cancer (33).…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways

et al. 2017

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“…Indeed, it has previously been shown to function as a proto-oncogene within melanoma, hepatocellular carcinoma, and breast, colorectal, and ovarian cancers. [49][50][51] Although the association with rs948662 that exceeded the multiple-testing correction threshold was for overall GCT risk, we observed increased point estimates of similar magnitude and nominal associations for this variant and ovarian and intracranial tumors and germinomas.…”

Section: Discussionmentioning

confidence: 61%

Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology group

Marcotte

Pankratz

Amatruda

et al. 2017

Genes Chromosomes & Cancer

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Introduction Germ cell tumors (GCT) are a rare form of childhood cancer that originate from the primordial germ cell. Recent genome-wide association studies (GWAS) have identified susceptibility alleles for adult testicular GCT (TGCT). Here we test whether these SNPs are associated with GCT in the pediatric and adolescent population. Methods This case-parent triad study includes individuals with GCT diagnosed between ages 0–19. We evaluated 26 SNPs from GWAS of adult TGCT and estimated main effects for pediatric GCT within complete trios (N=366) using the transmission disequilibrium test. We used Estimation of Maternal, Imprinting and interaction effects using Multinomial modelling to evaluate maternal effects in non-Hispanic white trios and dyads (N=244). A Bonferroni correction was used to account for multiple comparisons. Results A variant in SPRY4 (rs4624820) was associated with reduced risk of GCT (OR [95% CI]: 0.70 [0.57, 0.86]). A variant in BAK1 (rs210138) was positively associated with GCT (OR [95% CI]: 1.70 [1.32, 2.18]), with a particularly strong estimated effect for testis tumors (OR [95% CI]: 3.31 [1.89, 5.79]). Finally, a SNP in GAB2 (rs948662) was associated with increased risk for GCT (OR [95% CI]: 1.56 [1.20, 2.03]). Nominal associations (p<0.05) were noted for eight additional loci. Maternal effects were observed for KITLG SNP rs4474514 (OR [95% CI]: 1.66 [1.21, 2.28]) and rs7221274 (OR [95% CI]: 2.07 [1.43, 2.99]), near TEX14, RAD51C, and PPM1E. Conclusions We observed associations between SNPs in SPRY4, BAK1, and GAB2 and GCTs. This analysis suggests there may be common genetic risk factors for GCT in all age groups.

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“…It has been previously reported that aberrant Gab2 signaling is associated with human tumorigenesis [29–31]. Gab2 is involved in many cancerous behaviors, including cellular growth, survival, proliferation, and migration [28–31].…”

Section: Discussionmentioning

confidence: 99%

“…siRNA sequences for human Gab2 were combination of 5-CCTGAATGTGT GCCTTAAA-3, and 5-GCCAACTCTGTTCACGTTT-3 [29]. Gab2 siRNAs were synthesized by Genechem (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

microRNA-302c-3p inhibits renal cell carcinoma cell proliferation by targeting Grb2-associated binding 2 (Gab2)

Mao

Pan

et al. 2017

Oncotarget

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The expression and biological function of Grb2-associated binding 2 (Gab2) in renal cell carcinoma (RCC) cells was tested here. We showed that Gab2 expression was significantly elevated in human RCC tissues and RCC cells. It was correlated with over-activation of Akt and downregulation of microRNA-302c-3p (“miR-302c-3p”), a putative Gab2-targeting microRNA. Knockdown of Gab2 inhibited Akt activation and 786-O RCC cell proliferation. Reversely, forced over-expression of Gab2 led to Akt hyper-activation to facilitate 786-O cell proliferation. Exogenous expression of miR-302c caused Gab2 downregulation, Akt inhibition and 786-O cell proliferation inhibition. On the other hand, miR-302c-3p depletion by expressing its anti-sense (“antagomiR-302c”) led to Gab2 upregulation, Akt activation and increased 786-O cell proliferation. Significantly, miR-302c-3p failed to affect the proliferation of 786-O cells with shRNA-depleted Gab2. Together, we suggest that miR-302c-3p depletion in human RCC cells leads to Gab2 over-expression, Akt hyper-activation and cell proliferation.

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GAB2 promotes cell proliferation by activating the ERK signaling pathway in hepatocellular carcinoma

Cited by 29 publications

References 29 publications

Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways

Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways

Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology group

microRNA-302c-3p inhibits renal cell carcinoma cell proliferation by targeting Grb2-associated binding 2 (Gab2)

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