Combination treatment of bortezomib and epirubicin increases the expression of TNFRSF10 A/B, and induces TRAIL-mediated cell death in colorectal cancer cells.

Colorectal cancer is one of the most common cancers worldwide, affecting the colon and rectum. A major problem in the treatment of colorectal cancer is acquired chemoresistance, including resistance against death receptor-induced apoptosis. Therefore, investigating new biomarkers for the treatment of the disease and sensitization strategies against TRAIL might be of high clinical importance. TNFRSF10A/B are known as death receptors for TRAIL-induced apoptotic cell death. In this study, we used multiple bioinformatic tools and experimental analyses to investigate the role of TRAIL receptors TNFRSF10A and TNFRSF10B in colorectal cancer. We also identified the potential effect of bortezomib and epirubicin in the induction of TRAIL-mediated apoptotic cell death. Here, we showed that TNFRSF10 A/B expressions are upregulated in various tumor types, including COAD, and its high expression is decreased with the different clinicopathological parameters in COAD. We also found an association between TNFRSF10 A/B expression and tumor molecular subtypes. We further detected the association between the expression of TNFRSF10 A/B and immune cell tumor infiltration, including B cells, CD8+ T cells, neutrophils and dendritic cells. In addition, we showed that combining bortezomib and epirubicin treatment leads to the upregulation of TNFRSF10 A/B in colorectal cancer cells in vitro. The increase in the expression of death receptors was correlated with higher active caspase-3 levels following the incubation of cells with recombinant TRAIL protein, which is a ligand for TNFRSF10 A/B receptors. Our results suggest that TNFRSF10 A/B may be a marker to differentiate tumor molecular subtypes in colorectal cancer. The expression of TNFRSF10 A/B may be associated with the recruitment of immune cells into tumors and the development of tumor suppression. The combination of bortezomib and epirubicin treatment might sensitize colorectal cancer cells to TRAIL-induced apoptosis via the upregulation of death receptor.

NLRP13 inflammasome complex is hypermethylated in familial Mediterranean fever and global methylation correlates with the disease severity.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by variations in the MEFV gene, which encodes the pyrin protein, a member of the inflammasomes. Despite the complex pathogenesis of FMF, epigenetic changes also play roles in the disease progression. In our previous study, we observed a relationship between NLRP13, which is one of the members of the inflammasome complex and has a pyrin domain in its structure, and the MEFV gene using the STRING database. In this study, we examined NLRP13 expression and methylation status in 40 patients with FMF attack and 20 healthy individuals. We then investigated the global DNA methylation status of patients with FMF in the attack period and control groups. We further examined the relationship between the clinical manifestation and global methylation as well as NLRP13 gene expression of patients with FMF and healthy individuals. As a result, we showed that hypomethylation in patients with FMF leads to different clinical outcomes in terms of disease severity. In addition, the data indicated that NLRP13 inflammasome is epigenetically controlled in patients with FMF and the presence of amyloidosis may affect the hypermethylation of this gene. Moreover, NLRP13 was silenced because of the hypermethylation of the promoter. The increase of methylation level at the promoter region participated in the inactivation of NLRP13. In the current study, we not only found a new gene that plays a role in the pathogenesis of FMF disease, but also new evidence for the epigenetic regulation of the disease.

RGS10 suppression by DNA methylation is associated with low survival rates in colorectal carcinoma.

Colorectal cancer is known as the third most common cancer in both women and men. Genetic and epigenetic changes are major players contributing to colorectal carcinogenesis. Regulator of G-protein signaling 10 (RGS10) is a member of the RGS proteins, which negatively regulate several signaling pathways including cell survival and proliferation. We and others have previously shown that RGS10 expression is modulated by epigenetic modifications in ovarian cancer and suppression of RGS10 partially contributes to chemoresistance. Here, we further analyzed the roles and regulation of RGS10 in colon adenocarcinoma (COAD), using broad bioinformatics tools. We analyzed the expression profiles, promoter methylation state, prognostic value and effect of a hypomethylating agent on RGS10 expression. Results showed that RGS10 expression is higher in normal colon tissues than in tumor tissues. In addition, there is a negative correlation between DNA methylation and RGS10 transcript expression. We also observed that gene expression and promoter methylation of RGS10 in colorectal carcinoma patients were differently expressed depending on the tumor stage and microsatellite stability. DNA methylation was significantly increased in 18 probes of RGS10, which belongs to the high-risk group in COAD. In addition, pharmacological inhibition of DNA methyltransferase with decitabine reduced the six CpGsite-specific RGS10 hypermethylation in COAD. We also experimentally confirmed that RGS10 promoter activity was inhibited by treatment with decitabine in the HT-29 colorectal cell line. We further showed that decitabine treatment increases the RGS10 transcript expression in three different colorectal carcinoma cell lines. These results suggest that RGS10 expression is suppressed in the development of colorectal cancer and inhibition of DNA methylation may contribute to increasing overall survival rates of COAD patients.