A novel hypoxia-driven gene signature that can predict the prognosis of hepatocellular carcinoma

Abstract

Hypoxia environment exists in already started hepatocellular carcinoma (HCC) and promotes its progression by driving changes in the gene expression profiles of cells. However, the status of hypoxia-driven genes in HCC is largely unknown. In the present study, 368 HCC tissues from The Cancer Genome Atlas were divided into high and low hypoxia groups according to their hypoxia signatures. A total of 1,142 differentially expressed genes (DEGs) were identified between the two groups, and 34 of these DEGs were highly expressed in HCC tissues compared with adjacent tissues, especially in HCC tissues from patients with stage III–IV HCC. After constructing a protein–protein interaction network and applying the least absolute shrinkage and selection operator Cox regression method for 34 DEGs, a three-gene signature (complement factor H related 3 [ CFHR3 ], egl-9 family hypoxia inducible factor 3 [ EGLN3 ], and chromogranin A [ CHGA ]) was constructed and had prognostic value to predicted outcome of patients with HCC. This three-gene signature was suitable for classifying patients with HCC in the International Cancer Genome Consortium. CFHR3 shows remarkable diagnostic value in HCC. Hypoxia decreased CFHR3 expression, but increased HCC cell proliferation and motility. Overexpression of CFHR3 in HCC cells under hypoxia reversed the stimulatory effects of hypoxia and suppressed cell proliferation and metastasis in vivo . In conclusion, we identified a novel hypoxia-driven gene signature ( CFHR3, EGLN3 , and CHGA ) for reliable prognostic prediction of HCC, and demonstrated that overexpression of CFHR3 may be a potential strategy to overcome hypoxia and treat HCC.

An inflammation‐associated ferroptosis signature optimizes the diagnosis, prognosis evaluation and immunotherapy options in hepatocellular carcinoma

“…36 Similarly, our previous study indicated that CFHR3 was respond to hypoxia, and reduced in HCC with hypoxic microenvironment. 37 Consistent with previous studies, through qRT-PCR, ADH4, CFHR3, FTCD and PON1 levels were found to reduce in the HCC tissues compared with adjacent tissues, and APOA5, CXCL8 and G6PD expression was elevated. It is worth noting that the risk model constructed by them exhibited higher diagnostic value than each single genes.…”

“…Elevated G6PD was observed in HCC tissues, while it promotes the progression of HCC via suppressing ferroptosis 36 . Similarly, our previous study indicated that CFHR3 was respond to hypoxia, and reduced in HCC with hypoxic microenvironment 37 . Consistent with previous studies, through qRT‐PCR, ADH4 , CFHR3 , FTCD and PON1 levels were found to reduce in the HCC tissues compared with adjacent tissues, and APOA5 , CXCL8 and G6PD expression was elevated.…”

Single-cell transcriptome analysis reveals the metabolic changes and the prognostic value of malignant hepatocyte subpopulations and predict new therapeutic agents for hepatocellular carcinoma

“…Overexpression of CFHR3 can affect the proliferation and apoptosis of hepatocellular carcinoma ( 62 ). Recent reports suggest that overexpression of CFHR3 may be a potential strategy for overcoming hypoxia and treating HCC ( 63 ). These studies confirm the significance and plausibility of these prognostic signatures.…”

Identifying the programmed cell death index of hepatocellular carcinoma for prognosis and therapy response improvement by machine learning: a bioinformatics analysis and experimental validation

“…They further developed a coagulation-related gene risk score to predict patient prognosis and treatment responses (50). Zeng et al developed a hypoxia-driven gene signature for predicting and improving outcomes for HCC patients (51). Liu et al established a prognostic model for HCC with cuproptosis-related genes and the RSF algorithm, which was used for patient risk stratification and treatment beneficiary selection (52).…”

“…Zeng et al. developed a hypoxia-driven gene signature for predicting and improving outcomes for HCC patients ( 51 ). Liu et al.…”