Low APOA-1 Expression in Hepatocellular Carcinoma Patients Is Associated With DNA Methylation and Poor Overall Survival

Abstract

Background: Hepatocellular carcinoma (HCC) is the most frequent fatal malignancy, and it has a poor prognosis. Apolipoprotein 1 (APOA-1), the main protein component of high-density lipoproteins, is involved in numerous biological processes. Thus, this study was performed to detect the clinical significance of APOA-1 mRNA, APOA-1 expression, and APOA-1DNA methylation in patients with HCC.Methods: Data mining was performed using clinical and survival data from the Cancer Genome Atlas (TCGA) and Oncomine databases. The serum concentration of APOA-1 was measured in 316 patients with HCC and 100 healthy individuals at Renmin Hospital of Wuhan University, and the intact clinical information was reviewed and determined using univariate and multivariate Cox hazard models.Results: Bioinformatic analysis revealed that APOA-1 mRNA was present at lower levels in the serum of patients with HCC than in that of healthy individuals, and there was a strong negative correlation between levels of APOA-1 mRNA and APOA-1 DNA methylation. High expression of APOA-1 transcription correlated with better overall survival (p = 0.003), and APOA-1 hypermethylation correlated with progress-free survival (p = 0.045) in HCC sufferers. Next, the clinical data analysis demonstrated that APOA-1 protein levels in the serum were significantly lower in patients with HCC than in healthy controls. Furthermore, the expression of APOA-1 was significantly associated with some significant clinical indexes, and elevated APOA-1 expression was significantly associated with favorable (OS; HR:1.693, 95% CI: 1.194–2.401, p = 0.003) and better progression-free survival (PFS; HR = 1.33, 95% CI = 1.194–2.401, p = 0.045). Finally, enrichment analysis suggested that co-expressed genes of APOA-1 were involved in lipoprotein metabolism and FOXA2/3 transcription factor networks.Conclusion: APOA-1 mRNA expression is negatively regulated by DNA methylation in HCC. Low expression of APOA-1 might be a potential risk biomarker to predict survival in patients with HCC.

Quantitative proteomics assay reveals G protein-coupled receptor kinase 4-induced HepG2 cell growth inhibition

“…By inhibiting the MAPK pathway, APOA1 alone delayed the cell cycle and decreased the growth of HCC cells [ 40 ]. Nevertheless, low levels of APOA1 in HCC patients were associated with poor prognoses [ 41 , 42 ]. Such adverse outcomes might be brought on by a tumor load that damages the liver severely or by hepatic function loss after radiotherapy, chemotherapy, or surgery.…”

Apolipoprotein A-1 downregulation promotes basal-like breast cancer cell proliferation and migration associated with DNA methylation

“…For instance, in renal clear cell carcinoma, poor OS and DFS are linked to increased APOA1 mRNA levels (25). Reportedly, APOA1 functions as a tumor suppressor, and its reduced methylation can be considered a promising prognostic marker in liver cancer (26). In colorectal cancer, decreased serum levels of APOA1 are linked to higher staging, systemic inflammation and poor patient prognosis (12,13).…”

“…However, the level of methylation may fluctuate as a result of the genetic regulatory processes underlying diverse pathological disorders (29,30). According to previous studies, low expression of APOA1 in renal cell carcinoma may result from increased DNA methylation of the APOA1 gene (25) and Guo et al (26) revealed that patients with liver cancer with high levels of APOA1 DNA methylation had significantly longer progression-free survival time than those with low methylation. However, the correlation between DNA methylation and APOA1 expression level in BLBC has not been reported yet.…”

The Role of Ferroptosis and Cuproptosis in Curcumin against Hepatocellular Carcinoma

“…Quantitative proteomic analysis showed that the expression of APOA1 protein was significantly down-regulated by 22% in HCC with hepatitis C virus (HCV) [ 44 ]. Guo et al reported that the expression level of APOA1 mRNA in the serum of HCC patients with liver cancer was significantly lower than that of healthy people, and high expression of APOA1 mRNA obviously correlated with better overall survival in the Chinese cohort [ 45 ]. These independent studies support the credibility of our results.…”