Hepatic cyclooxygenase-2 overexpression induced spontaneous hepatocellular carcinoma formation in mice

Abstract

Cyclooxygenase (COX)-2 is upregulated in hepatocellular carcinoma (HCC). However, the direct causative effect of COX-2 in spontaneous HCC formation remains unknown. We thus investigate the role and molecular pathogenesis of COX-2 in HCC by using liver-specific COX-2 transgenic (TG) mice. We found spontaneous HCC formation with elevated inflammatory infiltrates and neovessels in male TG mice (3/21, 14.3%), but not in any of male WT mice (0/19). Reduced representation bisulfite sequencing (RRBS) and gene expression microarrays were performed in the HCC tumor and non-HCC liver tissues to investigate the molecular mechanisms of COX-2-driven HCC. By RRBS, DNA promoter hypermethylation was identified in HCC from TG mice. Induction of promoter hypermethylation was associated with reduced tet methylcytosine dioxygenase 1 (TET1) expression by COX-2. TET1 could catalyze the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) and prevents DNA hypermethylation. In keeping with this, loss of 5hmC was demonstrated in COX-2-induced HCC. Consistently, COX-2 overexpression in human HCC cell lines could reduce both TET1 expression and 5hmc levels. Integrative analyses of DNA methylation and gene expression profiles further identified significantly downregulated genes including LTBP1, ADCY5 and PRKCZ by promoter methylation in COX-2-induced HCC. Reduced expression of LTBP1, ADCY5 and PRKCZ by promoter hypermethylation was further validated in human HCCs. Bio-functional investigation revealed that LTBP1 inhibited cell proliferation in HCC cell lines, suggesting its potential role as a tumor suppressor in HCC. Gene expression microarrays revealed that signaling cascades (AKT (protein kinase B), STK33 (Serine/Threonine kinase 33) and MTOR (mechanistic target of rapamycin) pathways) were enriched in COX-2-induced HCC. In conclusion, this study demonstrated for the first time that enhanced COX-2 expression in hepatocytes is sufficient to induce HCC through inducing promoter hypermethylation by reducing TET1, silencing tumor-suppressive genes and activating key oncogenic pathways. Inhibition of COX-2 represents a mechanism-based target for HCC prevention.

COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment

“…Previous studies have also revealed that COX-2 can be induced by various stimuli, including hypoxia (15,16). In the context of HCC, COX-2 expression in tumour tissues is closely associated with the spontaneous initiation, development and treatment effects of HCC (17)(18)(19). As the predominant product of COX-2, prostaglandin E2 (PGE2) can achieve diverse biological effects primarily through its binding to a family of receptors to promote angiogenesis, cell survival and the metastasis of cancer cells (20,21).…”

Antitumor effects of Tv1 venom peptide in liver cancer

“…Recently it was demonstrated that enhanced COX-2 expression in hepatocytes is sufficient to induce HCC, and its inhibition may provide a potential approach for preventing and treating liver cancer. 36 COX-2 and PGE2 levels were both significantly decreased following Tv1 treatment in 1MEA cells (Fig. 2b).…”

“…COX-2 is overexpressed in many premalignant, malignant, and metastatic cancers, including HCC, and is therapeutically targetable. 36,37 COX-2 expression is undetectable in most normal tissues, and is highly induced by pro-inflammatory cytokines, mitogens, oncogenes and growth factors. The tumorigenicity of 1MEA cells is associated with human growth factor (HGF) upregulation, which promotes EMT and carcinogenesis via upregulating COX-2 and Akt.…”

A systemic insight into astrocytoma biology across different grades

“…Reported to be downregulated in COX-2 induced hepatocellular carcinoma, where it might act as a tumor suppressor (H. Chen et al, 2017) DUSP26 Acts a tissue specific tumor suppressor and downregulation of the gene has been linked to tumorigenesis (Patterson, Brummer, Daly, & O'Brien et al, 2010)…”