Dataset Information

KCNMA1 Expression is Downregulated in Colorectal Cancer via Epigenetic Mechanisms.

ABSTRACT: KCNMA1 is a gene located at 10q22 that encodes the pore-forming ?-subunit of the large-conductance Ca2+-activated K? channel. KCNMA1 is down-regulated in gastric carcinoma tumors, through hypermethylation of its promoter. In the present study, we have evaluated the expression levels of KCNMA1 both in a mouse model of Colorectal Cancer (CRC) and in human CRC samples. Additionally, epigenetic mechanisms of KCNMA1 gene regulation were investigated. We observed a significant down-regulation of KCNMA1 both in a human and mouse model of CRC. No differences in KCNMA1 levels were, however, observed at different TNM stages. We also wanted to determine whether the modulation in KCNMA1 was dependent on epigenetic mechanisms. A statistically significant inverse correlation between KCNMA1 expression and mir-17-5p levels was observed in patients with CRC. Furthermore, in the tumor samples, we found a significant hypermethylation of the promoter, in the loci cg24113782 and cg25655799, compared to healthy tissue. Overall, our data suggest the possible use of KCNMA1 as a therapeutic target in the early stages of CRC.

SUBMITTER: Basile MS

PROVIDER: S-EPMC6406553 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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KCNMA1 Expression is Downregulated in Colorectal Cancer via Epigenetic Mechanisms.

Basile Maria Sofia MS Fagone Paolo P Mangano Katia K Mammana Santa S Magro Gaetano G Salvatorelli Lucia L Li Destri Giovanni G La Greca Gaetano G Nicoletti Ferdinando F Puleo Stefano S Pesce Antonio A

Cancers 20190219 2

KCNMA1 is a gene located at 10q22 that encodes the pore-forming α-subunit of the large-conductance Ca2+-activated K⁺ channel. KCNMA1 is down-regulated in gastric carcinoma tumors, through hypermethylation of its promoter. In the present study, we have evaluated the expression levels of KCNMA1 both in a mouse model of Colorectal Cancer (CRC) and in human CRC samples. Additionally, epigenetic mechanisms of KCNMA1 gene regulation were investigated. We observed a sign ...[more]

PMID: 30791468

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Project description:BACKGROUND: Exposure to energy restriction during childhood and adolescence is associated with a lower risk of developing colorectal cancer (CRC). Epigenetic dysregulation during this critical period of growth and development may be a mechanism to explain such observations. Within the Netherlands Cohort Study on diet and cancer, we investigated the association between early life energy restriction and risk of subsequent CRC characterized by the (promoter) CpG island methylation phenotype (CIMP). METHODOLOGY/PRINCIPAL FINDINGS: Information on diet and risk factors was collected by baseline questionnaire (n = 120,856). Three indicators of exposure were assessed: place of residence during the Hunger Winter (1944-45) and World War II years (1940-44), and father's employment status during the Economic Depression (1932-40). Methylation specific PCR (MSP) on DNA from paraffin embedded tumor tissue was performed to determine CIMP status according to the Weisenberger markers. After 7.3 years of follow-up, 603 cases and 4631 sub-cohort members were available for analysis. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals for CIMP+ (27.7%) and CIMP- (72.3%) tumors according to the three time periods of energy restriction, adjusted for age and gender. Individuals exposed to severe famine during the Hunger Winter had a decreased risk of developing a tumor characterized by CIMP compared to those not exposed (HR 0.65, 95%CI: 0.45-0.92). Further categorizing individuals by an index of '0-1' '2-3' or '4-7' genes methylated in the promoter region suggested that exposure to the Hunger Winter was associated with the degree of promoter hypermethylation ('0-1 genes methylated' HR = 1.01, 95%CI:0.74-1.37; '2-3 genes methylated' HR = 0.83, 95% CI:0.61-1.15; '4-7 genes methylated' HR = 0.72, 95% CI:0.49-1.04). No associations were observed with respect to the Economic Depression and WWII years. CONCLUSIONS: This is the first study indicating that exposure to a severe, transient environmental condition during adolescence and young adulthood may result in persistent epigenetic changes that later influence CRC development.

Project description:BackgroundEpithelial-mesenchymal transition (EMT) plays a crucial role in the progression and aggressiveness of colorectal carcinoma. E-cadherin is the best-characterized molecular marker of EMT, but its prognostic significance for patients with CRC remains inconclusive.MethodologyEligible studies were searched from the PubMed, Embase and Web of Science databases. Correlation between E-cadherin expression and clinicopathological features and prognosis was analyzed. Subgroup analysis was also performed according to study location, number of patients, quality score of studies and cut-off value.Principal findingsA total of 27 studies comprising 4244 cases met the inclusion criteria. Meta-analysis suggested that downregulated E-cadherin expression had an unfavorable impact on overall survival (OS) of CRC (n?=?2730 in 14 studies; HR?=?2.27, 95%CI: 1.63-3.17; Z?=?4.83; P?=?0.000). Subgroup analysis indicated that low E-cadherin expression was significantly associated with worse OS in Asian patients (n?=?1054 in 9 studies; HR?=?2.86, 95%CI: 2.13-3.7, Z?=?7.11; P?=?0.000) but not in European patients (n?=?1552 in 4 studies; HR?=?1.14, 95%CI: 0.95-1.35, Z?=?1.39; P?=?0.165). In addition, reduced E-cadherin expression indicated an unfavorable OS only when the cut off value of low E-cadherin expression was >50% (n?=?512 in 4 studies; HR?=?2.08, 95%CI 1.45-2.94, Z?=?4.05; P?=?0.000). Downregulated E-cadherin expression was greatly related with differentiation grade, Dukes' stages, lymphnode status and metastasis. The pooled OR was 0.36(95%CI: 0.19-0.7, Z?=?3.03, P?=?0.002), 0.34(95%CI: 0.21-0.55, Z?=?6.61, P?=?0.000), 0.49(95%CI: 0.32-0.74, Z?=?3.02, P?=?0.002) and 0.45(95%CI: 0.22-0.91, Z?=?3.43, P?=?0.001), respectively.ConclusionsThis study showed that low or absent E-cadherin expression detected by immunohistochemistry served as a valuable prognostic factor of CRC. However, downregulated E-cadherin expression seemed to be associated with worse prognosis in Asian CRC patients but not in European CRC patients. Additionally, this meta-analysis suggested that the negative threshold of E-cadherin should be >50% when we detected its expression in the immunohistochemistry stain.

Dataset Information

KCNMA1 Expression is Downregulated in Colorectal Cancer via Epigenetic Mechanisms.

Publications

KCNMA1 Expression is Downregulated in Colorectal Cancer via Epigenetic Mechanisms.

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