Expression And Significance Of Hypoxia Inducible Factor-2 Alpha In Hepatocellular Carcinoma

Objective(1)To assess the association between hypoxic inducible factor-2alpha(HIF-2α) and hepatocellular carcinoma(HCC) by meta-analysis.(2)To assess the association between HIF-2α and HCC by immunohistochemistical staining, and analysis the relationship between HIF-2αexpression and angiogenesis,epithelial-mesenchymal transition(EMT)and tumor-associated macrophages(TAMs).Methods 1) Searching in various databases included Pub Med, Web of science,EMBASE, Cochrance Library, Chinese Bio Medical Literature Database and another databases for studies published in English or Chinese. The hazard ratio(HR)for overall survival and analyzed odds ratio were combined to evaluate the clinicopathological features of HIF-2α expression in HCC.(2)The expression of HIF-2αin 63 cases of HCC tumor tissues were examined by immunohistochemistry and analysis the relationship between HIF-2α and clinicopathological features. To assess the relationship between the expression of HIF-2α, epithelial-mesenchymal transition(EMT), angiogenesis and tumor-associated macrophages(TAM), the expression of vimentin,CD-34 and CD-68 were detected in HCC.Results(1) A total of 7 eligible studies comprising 1066 patients with HCC were identified after our full assessment according to inclusion criteria. All of the patients came from China. The results indicated that the association between HIF-2αexpression and prognostic values in HCC was inconspicuous, sensitivity testing are exactly in line with the previous, while the expression of HIF-2α was significantly associated with capsule infiltration, vein invasion, and histological grade.(2) Immunohistochemistry showed that HIF-2α mainly expressed in the cytoplasm, the rate of HIF-2α overexpression in HCC tissues was 74.6%, while in the paracarcinomatous group was 30.2% and normal control group was 13.3%, which showed significant difference between the three groups(P < 0.05). The expression of HIF-2α was correlated with tumor size, TNM stages, Edmondson grade, capsule or vascular invasion. HIF-2α expression had a significantly positive correlation with microvascular density(t=5.919, P < 0.001) and CD 68(r=0.559,P<0.001)but not vimentin(r=1.013, P=0.209). Survival analysis showed that the prognosis was poor in patients with HIF-2α overexpression(χ2=15.686, P<0.001). Cox regression demonstrated that the expression of HIF-2α(RR=3.964,95%CI: 2.235~7.028, P<0.001),tumor necrosis(RR=1.851, P= 0.009) and vascular invasion(RR= 1.929,P= 0.010)were the independent risk factors for survival in HCC patients.Conclusion(1) Expression of HIF-2α was associated with invasion and metastasis in HCC, but did not have a distinct significance in prognosis, according to the limited evidence. However, high quality, large sample size, and controlled trials are required.(2)HIF-2α associated with angiogenesis and TAM, but may not participate in EMT. It may be a potential tumor marker for prognosis of HCC.