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?-Catenin Regulation in Sporadic Colorectal Carcinogenesis: Not as Simple as APC.

ABSTRACT: Background:The wnt/APC/?-catenin pathway is a critical initiator in colorectal carcinogenesis in both hereditary and sporadic colorectal cancer (CRC). The progression of this process remains incompletely understood, although inflammation is pivotal. Drivers of inflammation are elevated in malignant tissue and have been shown to regulate ?-catenin expression. Interleukin-17A (IL-17A) is protumorigenic at elevated levels via COX-2 stimulation. Elevated peroxisome proliferator-activated receptor ? (PPAR?) expression has reduced risk of carcinogenesis and good overall prognosis in established CRC. Activation of PPAR? has inhibitory effect on ?-catenin. Methods:Using qPCR and IHC, we compared ?-catenin, PPAR?, COX-2, and IL-17A in the colonic mucosa of patients with sporadic CRC, inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS), against a normal control population. Results:?-catenin mRNA and protein expression progressively increased from the Normal group, through IBS and IBD reaching statistical significance in CRC. COX-2 mRNA levels increased similarly with statistical significance in IBD and CRC. However, COX-2 protein expression was inverted with significant expression in the Normal and IBS groups and reduced levels in IBD and CRC. PPAR? mRNA expression was unchanged in IBD and CRC but was significantly elevated in the IBS. IL-17A mRNA was significantly reduced in IBS and CRC but unchanged in IBD. There were no differences in all parameters tested in the Normal and IBS groups. Conclusion:?-catenin is confirmed as a major driver of colorectal carcinogenesis but is controlled by many more players other than APC. Elevated levels of PPAR? may have an anticarcinogenic effect. The role of COX-2 expression, especially its posttranscriptional regulation in colorectal cancer, needs further elucidation.

SUBMITTER: Fredericks E

PROVIDER: S-EPMC6116401 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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<i>β</i>-Catenin Regulation in Sporadic Colorectal Carcinogenesis: Not as Simple as APC.

Fredericks Ernst E Dealtry Gill G Roux Saartjie S

Canadian journal of gastroenterology & hepatology 20180816

<h4>Background</h4>The wnt/APC/<i>β</i>-catenin pathway is a critical initiator in colorectal carcinogenesis in both hereditary and sporadic colorectal cancer (CRC). The progression of this process remains incompletely understood, although inflammation is pivotal. Drivers of inflammation are elevated in malignant tissue and have been shown to regulate <i>β</i>-catenin expression. Interleukin-17A (IL-17A) is protumorigenic at elevated levels via COX-2 stimulation. Elevated peroxisome proliferator ...[more]

PMID: 30186819

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Project description:BackgroundThe association between colorectal cancer (CRC) and smoking has not been consistent. Incomplete smoking history and association to a specific subset of CRC tumors have been proposed as explanations. The adenomatous polyposis coli (APC) gene has been reported to have a "gatekeeper" function in the colonic mucosa.MethodsTo evaluate the hypothesis that cigarette smoking is associated with adenoma and carcinoma development and further to investigate whether this association is due to mutations in the APC gene, we used a study population consisting of 133 cases (45 adenomas and 88 carcinomas) and 334 controls. All tumors were sequenced in the mutation cluster region (MCR) of the APC gene. Cases and controls were drawn from a homogeneous cohort of Norwegian origin.ResultsThe mutational spectra of the APC gene revealed no difference in frequencies of mutations in cases based on ever and never smoking status. An overall case-control association was detected for adenomas and "ever smoking" OR = 1.73 (95% CI 0.83-3.58). For CRC cases several smoking parameters for dose and duration were used. We detected an association for all smoking parameters and "duration of smoking > 30 years", yielded a statistically significant OR = 2.86 (1.06-7.7). When cases were divided based on APC truncation mutation status, an association was detected in adenomas without APC mutation in relation to "ever smoking", with an OR = 3.97 (1.26-12.51). For CRC cases without APC mutation "duration of smoking > 30 years", yielded a statistically significant OR = 4.06 (1.20-13.7). The smoking parameter "starting smoking > or = 40 years ago" was only associated with CRC cases with APC mutations, OR = 2.0 (0.34-11.95). A case-case comparison revealed similar findings for this parameter, OR = 2.24 (0.73-6.86).ConclusionOur data suggest an association between smoking and adenoma and CRC development. This association was strongest for cases without APC truncation mutation. This may implicate other factors in development of these tumors. The association detected between smoking and CRC cases with APC mutation was in relationship to the smoking parameter "starting smoking > or = 40 years ago", a time period long enough to proceed CRC initiation.

Dataset Information

?-Catenin Regulation in Sporadic Colorectal Carcinogenesis: Not as Simple as APC.

Publications

<i>β</i>-Catenin Regulation in Sporadic Colorectal Carcinogenesis: Not as Simple as APC.

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