Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer. The novel sensitive biomarkers and therapeutic targets are urgently needed for the early diagnosis of HCC and improvement of clinical outcomes. Glia maturation factor-β (GMFB) is a growth and differentiation factor for both glia and neurons and has been found to be tightly involved in inflammation and neurodegeneration conditions. In our study, the expression level of GMFB was significantly up-regulated in patients with HCC and positively co-expression with tumor node metastases (TNM) stage and histopathological grade of HCC. The high expression level of GMFB was remarkably associated with poor overall survival, which mainly occurred in males rather than females. Multivariate analysis revealed GMFB to be an independent prognostic factor for overall survival in patients with HCC. Results of Gene Ontology (GO) and KEGG pathways analysis showed that down-regulation of pathways related to protein translation and mitochondria function were enriched. Protein-protein interaction analysis revealed the central role of mitochondria protein in HCC. The downregulation of genes involved in glycolysis and gluconeogenesis was observed among the co-expression genes of GMFB. Knockdown of GMFB in Hep3B significantly inhibited proliferation, migration, and invasion of Hep3B cells, and also downregulated the expression levels of some of metal matrix proteinase (MMP), increased mtDNA copy number and loss of mitochondrial transmembrane potential. GMFB influences the malignancy rate of HCC possibly through regulation of the expression of MMPs, mtDNA function and glycolysis. We proposed that GMFB was a promising HCC diagnostic and prognostic biomarker and therapeutic target in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the main component of primary liver cancer, accounting for 75%-85%, and remains the second leading cause of the death rate of cancers worldwide [1, 2]
We initially used the Oncomine database to analyze the expression profiles, and found that the Glia maturation factor-b (GMFB) transcription levels were markedly higher in breast cancer, head and neck cancer and liver cancer compared to the normal tissues (Figure 1A)
The analysis of The Cancer Genome Atlas (TCGA) datasets revealed that the expression of GMFB in HCC was associated with tumor node metastases (TNM) stage 1-3 (Figure 1D) and pathological grade 1-3 (Figure 1E)
Summary
Hepatocellular carcinoma (HCC) is the main component of primary liver cancer, accounting for 75%-85%, and remains the second leading cause of the death rate of cancers worldwide [1, 2]. The major risk factors of HCC showed regional differences. Among the most important risk factors, chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), heavy alcohol intake, obesity and type 2 diabetes were highlighted [3]. Previous studies have identified biomarkers, such as Alphafetoprotein (AFP), apyrimidinic endodeoxyribonuclease 1 (APEX1), glypican 3 (GPC3), Golgi protein-73 (GP73), and Dickkopf-1 (DKK1), for HCC diagnosis [9,10,11,12,13]. Its sensitivity and specificity are low and its expression can be influenced by several non-HCC related factors [14]. The early and specific diagnosis of HCC remains challenging
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