Mechanism Study On Gab2-mediated Hepatocarcinogenesis

Hepatocellular carcinoma(HCC)is one of the most common and deadliest malignancies worldwide.HCC accounts for 85%-90%of primary liver cancers with 500,000 new cases as well as 250,000 deaths of HCC all over the world every year.The main factors for the high mortality rate of HCC patients are due to the lack of effective treatments,the increasing resistance to conventional radiotherapy and chemotherapy,and high rate of recurrence.Though there are advanced therapeutic strategy and many target genes for HCC treatment,it is hard to overcome the difficulty of high recrudescence.Therefore,it is urgent to discover a new hub protein,that can recruit a variety of effects molecule,to ameliorate the low efficiency of HCC treatment.Gab2 as a docking protein can recruit various intracellular downstream signal proteins to function in cell proliferation,survival,apoptosis and differentiation.It acts as a proto-oncogene,as dominantly overexpression has been detected in several types of cancer,for instance,breast cancer,melanoma,ovarian carcinoma and lung cancer.The latest study has shown that Gab2 is highly expressed in hepatocellular carcinoma and modulates the process of the development of liver cancer by ERK signaling.However,there are a number of unknown signal regulating mechanism and its function on hepatic cell growth require more exploration.Our previous studies found that GRB2-associated-binding protein 2(Gab2),a scaffolding/adaptor protein,governs the development of fatty liver disease.Here,we further demonstrate that Gab2 mediates hepatocellular carcinogenesis.Compared to the faint expression in para-carcinoma tissue,Gab2 was highly expressed in approximately 60～70%of human hepatocellular carcinoma(HCC)specimens.Deletion of Gab2 dramatically suppressed diethylene nitrite(DEN)-induced HCC in mice.The oncogenic effects of Gab2 in HepG2 cells were promoted by Gab2 overexpression but attenuated by Gab2 knockout.Furthermore,Gab2 knockout in HepG2 cells restrained cell proliferation,cell migration and xenograft tumour formation in nude mice.Signalling pathway analysis with protein kinase inhibitors showed that oncogenic regulation by Gab2 in hepatic cells involved multiple signalling pathways,including the Extracellular regulated protein kinases(ERK),Protein kinase B(AKT)and Janus kinase(Jak)pathways,especially those that mediate inflammatory signalling.Interleukin 6(IL-6)signalling was increased by Gab2 overexpression and impaired by Gab2 deletion via the regulation of Janus kinase 2(Jak2)and Signal transducer and activator of transcription 3(STAT3)phosphorylation and the expressiorn of downstream genes,such as B-cell lymphoma 2(Bcl-2),c-Myc,Matrix metalloproteinase-7(MMP7),and cyclin Dl,in HepG2 cells.These data indicate that Gab2 mediates the pathological progression of HCC by integrating multiple signalling pathways and suggest that Gab2 might be a powerful therapeutic target for HCC.