The impact of high co-expression of Sp1 and HIF1α on prognosis of patients with hepatocellular cancer

Abstract

Transcription factor specificity protein 1 (Sp1) and hypoxia-inducible factor 1α (HIF1α) serve vital roles in tumor growth and metastasis. The present study aimed to evaluate the impact of co-expression of Sp1 and HIF1α 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/HIF1α 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 HIF1α were obtained from the TCGA RNAseq database. Clinicopathological characteristics, including age, height, weight, gender, race, ethnicity, family cancer history, serum α-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 HIF1α and their co-expression. The location and expression of Sp1 and HIF1α 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 HIF1α 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 HIF1α (≥2×103) 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 HIF1α). Based on the cutoff points for gene expression, patients were divided into 3 groups: G1 (both genes <2×103), G2 (either gene ≥2×103) and G3 (both genes ≥2×103). 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 HIF1α in HCC tissues were associated with poor prognosis; in particular, the co-expression of these two genes increased the risk of cancer mortality.

MicroRNA‑548b inhibits proliferation and invasion of hepatocellular carcinoma cells by directly targeting specificity protein�1

“…Previous studies reported that SP1 is expressed at high levels in a variety of human malignant tumors including colorectal cancer (41), osteosarcoma (42), lung cancer (43), and pancreatic cancer (44). Notably, SP1 was also found to be upregulated in HCC tissues and cell lines (30,31). Multivariate Cox regression analysis validated SP1 to be an independent predictor for the death rate of patients with HCC (31).…”

“…Multivariate Cox regression analysis validated SP1 to be an independent predictor for the death rate of patients with HCC (31). In addition, HCC patients with high SP1 expression have been demonstrated to be associated with poorer clinical outcomes compared with those with low expression (31). In addition, SP1 has been implicated in the occurrence and development of HCC through regulation of a number of biological processes (32)(33)(34).…”

“…3A). SP1 was previously reported to be implicated in the regulation of HCC progression (30)(31)(32)(33)(34), and was therefore chosen for further investigation. To examine whether miR-548b can directly bind to the 3'-UTR of SP1, luciferase reporter plasmids were chemically synthesized, and subsequently co-transfected with either miR-548b mimics or miR-NC in Huh7 and Hep3B cells.…”

Dietary restriction protects against diethylnitrosamine-induced hepatocellular tumorigenesis by restoring the disturbed gene expression profile

“…6(a)). Among the three TFs, SP1 has been reported to play an important role in HCC39, as is shown, genes including cdkn2b, smad3, cdkn2a, col4a1 , which were enriched in cancer and MAPK pathways, were down-stream genes of SP1 (Fig. 6(b)).…”

MiR-3662 suppresses hepatocellular carcinoma growth through inhibition of HIF-1α-mediated Warburg effect

“…HIF-1α is a subunit of the heterodimeric transcription factor HIF-1, and is increased in various human malignancies 37 – 39 . Overexpressed HIF-1α is closely associated with poor prognosis in HCC 40 . HIF-1α represents a potential therapeutic target in the treatment of liver cancer 33 .…”