The impact of high co-expression of Sp1 and HIF1 alpha on prognosis of patients with hepatocellular cancer

摘要

Transcription factor specificity protein 1 (Sp1) and hypoxia-inducible factor 1 alpha (HIF1 alpha) serve vital roles in tumor growth and metastasis. The present study aimed to evaluate the impact of co-expression of Sp1 and HIF1a on the prognosis of patients with hepatocellular cancer (HCC) using The Cancer Genome Atlas (TCGA) database and to validate the association between the expression levels of Sp1/HIF1 alpha in HCC specimens and patient survival using immunohistochemical analysis. A total of 214 eligible patients with HCC from TCGA database were collected for the study. The expression profile of Sp1 and HIF1a were obtained from the TCGA RNAseq database. Clinicopathological characteristics, including age, height, weight, gender, race, ethnicity, family cancer history, serum a-fetoprotein (AFP), surgical procedures and TNM stage were collected. The Cox proportional hazards regression model and Kaplan-Meier curves were used to assess the relative factors. Receiver operating characteristic (ROC) curves for cancer-specific survival (CSS) prediction were plotted to compare the prediction ability of expression of Sp1 and HIF1a and their co-expression. The location and expression of Sp1 and HIF1a in the HCC tissues were detected by immunohistochemistry (IHC) to verify the association between these two genes and CSS. The results demonstrated that the expressions of Sp1 and HIF1a were significantly increased in the succumbed group (P=0.001), compared with the surviving group. The CSS rates were 60.1% at 3 years (1,067 days), 35.8% at 5 years (1,823 days) and 9.5% at 10 years (3,528 days). Multivariate Cox regression analysis demonstrated that only the high expression levels of Sp1 and HIF1 alpha (>= 2x10(3)) were independent predictors for cancer mortality, with P=0.001 and P=0.029, respectively. The area under the curve for the ROC was found to be higher using the combination testing for two genes (0.751) in predicting cancer mortality, compared to a single gene (0.632 for Sp1 and 0.717 for HIF1a). Based on the cutoff points for gene expression, patients were divided into 3 groups: G1 (both genes <2x10(3)), G2 (either gene >= 2x10(3)) and G3 (both genes >= 2x10(3)). The risk of cancer mortality increased with high expression of genes, and G3 exhibited a greater risk than G2 when compared with the G1 group (HR=5.420, 95% CI 2.767-10.616, P=0.001; HR=3.270, 95% CI 1.843-5.803, P=0.001). The IHC staining results indicated that patients who died of cancer presented with significantly higher expression levels of these genes compared with those that did not (P=0.001). In summary, high expression levels of Sp1 and HIF1a in HCC tissues were associated with poor prognosis; in particular, the co-expression of these two genes increased the risk of cancer mortality.