Skip to main content


Log in

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

  • Original Article
  • Published:
Tumor Biology


Grb2-associated binding protein 2 (GAB2), a key member of the family of Gab scaffolding adaptors, is important in the phospoinositide3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) signaling pathways, and is closely associated with cell proliferation, cell transformation, and tumor progression. But its role in hepatocellular carcinoma (HCC) is still unknown. In this study, we investigated the expression of GAB2 and its potential clinical and biological significances in HCC. Western bolt and immunohistochemistrical analyses revealed that GAB2 was obviously upregulated in HCC tissues. Meanwhile, GAB2 was significantly associated with histological grade, tumor size, and the proliferation marker Ki-67 through our further analysis. The Kaplan-Meier survival curves also showed that increased GAB2 expression was directly correlated with poor prognosis in HCC patients and served as an independent prognostic marker of overall survival. Moreover, serum starvation-refeeding, RNA interference, CCK-8, EDU, colony formation, and flow-cytometry analyses were all performed with the purpose of investigating GAB2’s regulation of HCC cell proliferation. Our results indicated that GAB2 progressively accumulated when cells entered into S phase. Consistently, cell proliferation was distinctly hindered by small interfering RNA. More interestingly, we discovered that GAB2 promoted cell proliferation by enhancing ERK signaling and GAB2-induced cell proliferation was inhibited by the inhibition of ERK activation. Finally, GAB2 was verified to be able to confer doxorubicin resistance in HCC cells. In summary, these data demonstrated that GAB2 might promote HCC cell proliferation by enhancing ERK signaling, and all above findings provided a potential therapeutic strategy for the treatment of HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others


  1. Bosetti C, Turati F, La Vecchia C. Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol. 2014;28:753–70.

    Article  PubMed  Google Scholar 

  2. Patel M, Shariff MI, Ladep NG, Thillainayagam AV, Thomas HC, Khan SA, et al. Hepatocellular carcinoma: diagnostics and screening. J Eval Clin Pract. 2012;18:335–42.

    Article  PubMed  Google Scholar 

  3. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127:S5–16.

    Article  PubMed  Google Scholar 

  4. Cauchy F, Fuks D, Belghiti J. HCC: current surgical treatment concepts. Langenbeck’s Arch Surg/Dtsch Ges Chir. 2012;397:681–95.

    Article  CAS  Google Scholar 

  5. Kaibori M, Ishizaki M, Saito T, Matsui K, Kwon AH, Kamiyama Y. Risk factors and outcome of early recurrence after resection of small hepatocellular carcinomas. Am J Surg. 2009;198:39–45.

    Article  PubMed  Google Scholar 

  6. Ding CB, Yu WN, Feng JH, Luo JM. Structure and function of GAB2 and its role in cancer (review). Mol Med Rep. 2015;12:4007–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Adams SJ, Aydin IT, Celebi JT. GAB2—a scaffolding protein in cancer. Mol Cancer Res: MCR. 2012;10:1265–70.

    Article  CAS  PubMed  Google Scholar 

  8. Duckworth C, Zhang L, Carroll SL, Ethier SP, Cheung HW. Overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating chemokine expression. Oncogene. 2015.

  9. Bocanegra M, Bergamaschi A, Kim YH, Miller MA, Rajput AB, Kao J, et al. Focal amplification and oncogene dependency of GAB2 in breast cancer. Oncogene. 2010;29:774–9.

    Article  CAS  PubMed  Google Scholar 

  10. Yajima I, Kumasaka MY, Thang ND, Goto Y, Takeda K, Yamanoshita O, et al. RAS/RAF/MEK/ERK and PI3K/PTEN/AKT signaling in malignant melanoma progression and therapy. Dermatol Res Pract. 2012;2012:354191.

    PubMed  Google Scholar 

  11. Aumann K, Lassmann S, Schopflin A, May AM, Wohrle FU, Zeiser R, et al. The immunohistochemical staining pattern of GAB2 correlates with distinct stages of chronic myeloid leukemia. Hum Pathol. 2011;42:719–26.

    Article  CAS  PubMed  Google Scholar 

  12. Ding C, Luo J, Li L, Li S, Yang L, Pan H, et al. GAB2 facilitates epithelial-to-mesenchymal transition via the mek/erk/mmp signaling in colorectal cancer. J Exp Clin Cancer Res: CR. 2016;35:5.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Brummer T, Schramek D, Hayes VM, Bennett HL, Caldon CE, Musgrove EA, et al. Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the GAB2 docking protein. J Biol Chem. 2006;281:626–37.

    Article  CAS  PubMed  Google Scholar 

  14. Yan X, Zhou H, Zhang T, Xu P, Zhang S, Huang W, et al. Downregulation of foxp2 promoter human hepatocellular carcinoma cell invasion. Tumour Biol. 2015;36:9611–9.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang S, Shi W, Chen Y, Xu Z, Zhu J, Zhang T, et al. Overexpression of syf2 correlates with enhanced cell growth and poor prognosis in human hepatocellular carcinoma. Mol Cell Biochem. 2015;410:1–9.

    Article  CAS  PubMed  Google Scholar 

  16. Ni W, Chen B, Zhou G, Lu C, Xiao M, Guan C, et al. Overexpressed nuclear BAG-1 in human hepatocellular carcinoma is associated with poor prognosis and resistance to doxorubicin. J Cell Biochem. 2013;114:2120–30.

    Article  CAS  PubMed  Google Scholar 

  17. Xiong Y, Hu B, Wei L, Jiang D, Zhu M. Upregulated expression of polycomb protein Ring1 contributes to poor prognosis and accelerated proliferation in human hepatocellular carcinoma. Tumour Biol. 2015;36:9579–88.

    Article  CAS  PubMed  Google Scholar 

  18. Fornaro L, Vivaldi C, Caparello C, Sacco R, Rotella V, Musettini G, et al. Dissecting signaling pathways in hepatocellular carcinoma: new perspectives in medical therapy. Future Oncol. 2014;10:285–304.

    Article  CAS  PubMed  Google Scholar 

  19. Lee SH, Jeong EG, Nam SW, Lee JY, Yoo NJ, Lee SH. Increased expression of GAB2, a scaffolding adaptor of the tyrosine kinase signalling, in gastric carcinomas. Pathology. 2007;39:326–9.

    Article  CAS  PubMed  Google Scholar 

  20. Ke Y, Wu D, Princen F, Nguyen T, Pang Y, Lesperance J, et al. Role of GAB2 in mammary tumorigenesis and metastasis. Oncogene. 2007;26:4951–60.

    Article  CAS  PubMed  Google Scholar 

  21. Shi L, Sun X, Zhang J, Zhao C, Li H, Liu Z, et al. GAB2 expression in glioma and its implications for tumor invasion. Acta Oncol. 2013;52:1739–50.

    Article  CAS  PubMed  Google Scholar 

  22. Wang Y, Sheng Q, Spillman MA, Behbakht K, Gu H. GAB2 regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells. Oncogene. 2012;31:2512–20.

    Article  CAS  PubMed  Google Scholar 

  23. Wang WJ, Mou K, Wu XF, Zhang JZ, Ren G, Qi JD, et al. Grb2-associated binder 2 silencing impairs growth and migration of h1975 cells via modulation of PI3K-AKT signaling. Int J Clin Exp Pathol. 2015;8:10575–84.

    PubMed  PubMed Central  Google Scholar 

  24. Horst B, Gruvberger-Saal SK, Hopkins BD, Bordone L, Yang Y, Chernoff KA, et al. GAB2-mediated signaling promotes melanoma metastasis. Am J Pathol. 2009;174:1524–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liu H, Li G, Zeng W, Zhang P, Fan F, Tu Y, et al. Combined detection of GAB1 and GAB2 expression predicts clinical outcome of patients with glioma. Med Oncol. 2014;31:77.

    Article  CAS  PubMed  Google Scholar 

  26. Rao CV, Kurkjian CD, Yamada HY. Mitosis-targeting natural products for cancer prevention and therapy. Curr Drug Targets. 2012;13:1820–30.

    Article  CAS  PubMed  Google Scholar 

  27. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66.

    Article  CAS  PubMed  Google Scholar 

  28. Lau MT, Leung PC. The PI3K/AKT/MTOR signaling pathway mediates insulin-like growth factor 1-induced E-cadherin down-regulation and cell proliferation in ovarian cancer cells. Cancer Lett. 2012;326:191–8.

    Article  CAS  PubMed  Google Scholar 

  29. Duchartre Y, Kim YM, Kahn M. The Wnt signaling pathway in cancer. Crit Rev Oncol Hematol. 2015.

  30. Andradas C, Caffarel MM, Perez-Gomez E, Salazar M, Lorente M, Velasco G, et al. The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene. 2011;30:245–52.

    Article  CAS  PubMed  Google Scholar 

Download references


This study was supported by the National Natural Science Foundation of China (no. 81401985) and the Scientific Research and Innovation Project of Nantong University (no. 2015092)

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Runzhou Ni or Xudong Chen.

Ethics declarations

Conflicts of interest


Additional information

Yuyan Chen and Qingqing Liu contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Y., Liu, Q., Wu, M. et al. GAB2 promotes cell proliferation by activating the ERK signaling pathway in hepatocellular carcinoma. Tumor Biol. 37, 11763–11773 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: