Functional polymorphisms of the cyclooxygenase-2 gene and prognosis of hepatocellular carcinoma - a cohort study in Chinese people

Abstract

ABSTRACT. Cyclooxygenase-2 (COX-2) influences carcinogenesis through regulation of angiogenesis, apoptosis, cytokine expression, and immune response suppression. It has been well established that COX-2 is overexpressed in a variety of human cancers, such as hepatocellular carcinoma (HCC). In this study, we aimed to evaluate the association between COX-2 polymorphisms and prognosis of HCC. We genotyped 200 HCC patients of Chinese Han descent for COX-2 gene polymorphisms (-765G>C and -1195G>A) using PCR-RFLP. Data were statistically analyzed using the Kaplan-Meier method and the Cox's proportional hazard regression model. We found that patients with the COX-2 -1195AG and -1195AG + AA genotypes demonstrated significantly decreased disease-free survival (DFS) as compared with those carrying the -1195GG genotype (P < 0.05). However, the COX-2 -765G>C polymorphism was not associated with DFS (P > 0.05). Moreover, by Cox regression analysis, blood alpha fetoprotein ≤400 ng/mL before the operation and the -1195G>A polymorphism were found to be of prognostic significance (P < 0.05), while the -765G>C polymorphism was not (P > 0.05). In summary, post-operation progression of HCC is more likely to occur in patients with the -1195AG genotype and the A allele. On the other hand, the -765G>C polymorphism is not an independent influence factor of HCC prognosis.

Angiogenesis of hepatocellular carcinoma: An immunohistochemistry study

“…Regarding COX-2 expression, the literature data even indicates that COX-2 does not mediate the process of fibrosis[6,29,30], or, contrary, COX-2 plays roles in fibrogenesis and hepatocarcinogenesis via metalloproteinases/mismatch repair proteins MMP-2 and MMP-9 or through activation of β-catenin[3], one of the mediators of epithelial mesenchymal transition[19]. Although COX-2 stimulates HCV replication and HCV stimulates COX-2 expression via oxidative stress[3], we did not find differences between COX-2 expression in patients with or without hepatitis.…”

“…Cyclooxygenase-2 (COX-2) is an enzyme encoded by the PTGS2 gene, which belongs to the group of endogenous tumor factors that might stimulate genesis and progression of HCC[6]. There are three isoforms: constitutive COX-1, inducible COX-2, and COX-3[3,7].…”

“…There are three isoforms: constitutive COX-1, inducible COX-2, and COX-3[3,7]. If COX-1 is present in nearly all types of tissues, being responsible for the synthesis of prostaglandins in normal conditions, COX-2 is induced by cellular stress or tumor promoters, being responsible for the synthesis of prostaglandins involved in inflammation, cell growth, tumor development and progression[3,6,8]. Although the therapeutic inhibition of COX enzymes and prostaglandins was supposed to be linked to lower risk and better survival of HCC[9], the exact mechanism of inhibition and criteria of identification of those cases that can benefit by anti-COX therapy are still unknown.…”

The MMP2 rs243865 polymorphism increases the risk of prostate cancer: A meta-analysis

“…MMPs are zinc metalloproteases that degrade ECM collagens, which are important in tissue remodeling and repair during development and inflammation [ 19 ]. Among the MMP genes, gelatinase A, encoded by the MMP2 gene, has been specifically correlated to tumor pathogenesis [ 20 , 21 ]. Furthermore, the MMP2 promoter contains several cis-acting regulatory elements, which modulate MMP2 expression through transcription factors, such as p53 and Sp1 [ 22 , 23 ].…”

Association of aspirin and nonaspirin NSAIDs therapy with the incidence risk of hepatocellular carcinoma: a systematic review and meta-analysis on cohort studies

“…The main anticancer mechanism is the suppression of the COX-2 signaling pathway. The expression of COX-2 is associated with hepatocarcinogenesis by enhancing cell proliferation, apoptosis inhibition and angiogenesis induction (van Rees and Ristimaki, 2001; Hu, 2002; Sung et al , 2004; Wu, 2006; Liang et al , 2016). Indeed, Márquez-Rosado et al (2005) revealed the ability of NSAIDs to prevent hepatocarcinogenesis by suppressing COX-2 in mouse models.…”