Relationship between the Expression of CES2, UGT1A1, and GUSB in colorectal cancer tissues and aberrant methylation

Abstract

Irinotecan (CPT-11) is considered an important drug in the treatment of colorectal cancer, but its continuous administration reduces its sensitivity and influences the curative effect. The metabolism of CPT-11 is mainly controlled by carboxy-lesterase (CES), UDP-glucuronosyltransferase 1A (UGT1A), and β-glucuronidase (GUSB). Studies to date have shown that methylation acts as an important mechanism for gene expression to suppress the metabolic enzymes of many chemotherapeutics. This study, which selected 99 colorectal cancer patients, 23 of whom had paracancerous tissues and eight of whom had large intestine adenomas, aimed to investigate the correlation between the protein expression of the CPT-11 metabolic enzyme genes CES2, UGT1A1, and GUSB and various clinical pathological parameters of colorectal cancer tissues, as well as the relationship between methylation regulation and the gene expression of CES2, UGT1A1, and GUSB. We used immunohistochemistry staining, methylation-specific PCR, and clinical status to reveal the possible regulatory targets of chemotherapeutic resistance in colorectal cancer and to provide new ideas and countermeasures to reverse anti-cancer drug resistance and chemosensitization. The results showed that the expression of CES2, UGTA1A1, and GUSB varies in colorectal pathology tissues and that the expression of CES2 is somewhat related to tumor staging. This relationship is likely caused by the gene regulation of UGT1A1 and GUSB, and other regulation mechanisms may also be involved. The methylation of the CES2 gene is irrelevant to the morbidity associated with colorectal cancer. The GUSB gene showed no significant differences in methylation, and the hemi-methylation was also positive, the regulating ability of which needs to be verified. The potential role of these genes in the colorectal cancer progresion, which may be directly related to the methylation regulation of UGT1A1, requires further research. The promoter of the UGT1A1 gene in colorectal cancer cells is methylated, which is an important mechanism of UGT1A1 gene silencing and can be regarded as the target point of research for CPT-11 drug resistance and control mechanisms for the reversal of drug resistance. Key words: colorectal cancer, DNA methylation, CES2, UGT1A1, GUSB, CPT-11Neoplasma 61, 1, 2014 doi:10.4149/neo_2014_014Colorectal cancer is considered to be a malignant tumor with one of the highest incidence and mortality rates. In late, recurrent, or metastatic colorectal cancer cases, pharmacotherapy serves as the main strategy for current chemotherapy. Current studies on the drugs used in the treatment of colorectal cancer have mainly focused on the screening of new target points, such as the epidermal growth factor receptor (EGFR) inhibitor and cyclooxygenase (COX)-2 inhibitor, which have demonstrated good therapeutic effects in the initial stage of therapy. However, along with the development of drug resistance, the therapeutic effects also vary between these drugs. The drug resistance gene mechanism has always been ...

CES2, ABCG2, TS and Topo-I Primary and Synchronous Metastasis Expression and Clinical Outcome in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Regimen

“…In particular, CES2 is highly expressed in colon tumors, playing a key role in the metabolic activation of CPT-11 [ 9 , 10 ]. Recent results have shown that the expression of CES2 is related to tumor staging [ 11 ].…”

Influence of UGT1A1 gene methylation level in colorectal cancer cells on the sensitivity of the chemotherapy drug CPT-11

“…After being treated by DAC, the IC 50 value of the cells in each group except RK0 decreased; the IC 50 decline was not obvious in ls174T, DLD-1, HCT-116 and HCT-15 cells with positive UGT1A1 methylation [5] but significantly obvious in LoVo and HT-29 cells with negative UGT1A1 methylation [5], indicating that the methylation status of UGT1A1 could significantly affect the CPT-11 chemosensitivity, and the affecting degree varied with the type of colorectal cancer. While IC 50 value in the RK0 cells with low expression of UGT1A1 increased instead, indicating that this abnormal rise might be related to the process of demethylation ( Table 1).…”

“…The author [5] has proved from the clinical perspective that aberrant methylation is the characteristic factor for regulating CPT-11 metabolic enzymes, and the aberrant methylation of UGT1A1 exists in tumor tissues. The role of its SN-39G for regulating enzyme enables it to have the potential to be the potential target of the process.…”

“…Transfection efficiency of siRNA in colorectal cancer cellsThe flow cytometry was used to test the transfection efficiency of siRNA and after the FAM-labeled negative control, siRNA was transfected for 6 hours. With the increase of the final transfection concentration of siRNA(5,10,20, 30, 40, 50, 80 nmol/L), the transfection efficiency increased accordingly(25…”

Epigenetics and microRNAs in UGT1As

“…DNA methylation may indirectly downregulate the activation of target genes by inhibiting the expression of TFs. In 2014, Xie et al also reported that in 99 patients with colorectal cancer, UGT1A1 promoter methylation could inhibit gene expression, thereby affecting the metabolic level of irinotecan (CPT-11) [ 50 ]. In summary, DNA methylation is expected to be a new target for drug resistance mechanisms.…”