Browsing by Subject "Colorectal cancer"

Now showing 1 - 4 of 4
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    Aspirin intervention, inflammation and the oral microbiome
    (2020-10) Onyeaghala, Guillaume
    Specific pro-inflammatory oral taxa have been shown to be increased in the gut microbiome of individuals with colorectal cancer (CRC). Aspirin is associated with decreased risk of colorectal cancer, potentially by modulating the gut and the oral microbiome. However, it remains unclear how pro-inflammatory oral taxa would respond to anti-inflammatory agents such as aspirin. In this dissertation, we aimed to evaluate the effect of aspirin intervention on specific pro-inflammatory oral taxa and inferred functional traits linked to inflammation in a 6-week double-blind placebo-controlled trial.In the first manuscript, we evaluated the effect of aspirin intervention on the relative abundance of pro-inflammatory oral taxa. We found that the change over-time in the relative abundance of 9 out of the 12 pre-specified taxa at the genus level, and 1 out of 2 pre-specified taxa at the family level differed between the aspirin and placebo groups. These preliminary findings suggest that aspirin may change the relative abundance of oral taxa associated with inflammation. In manuscript 2, we evaluated the effect of aspirin intervention on the relative abundance of inferred functional traits linked to the pro-inflammatory bacterial metabolite, lipopolysaccharide (LPS). We did not find an association between aspirin intervention and the change in relative abundance of inferred functional traits for LPS. However, we observed a positive correlation between the relative abundance of pro-inflammatory oral taxa and the relative abundance of inferred functional traits for LPS. These findings are in line with the current literature on bacterial virulence factors. Lastly, we investigated whether inflammation-related oral taxa and inflammation-related gut taxa are correlated and whether oral and gut microbiome communities respond similarly to aspirin. Our results show that aspirin may induce changes in oral and gut alpha diversity in a similar fashion. In addition, our findings of an inverse correlation between SCFA-producing gut taxa and pro-inflammatory oral taxa suggest that studying oral taxa may be important to understanding the link between inflammation and the gut microbiome. Overall, these findings are in line with a growing body of evidence highlighting the role of the oral microbiome in chronic inflammatory disorders of the intestine, including CRC.
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    Functional characterization of the candidate colorectal cancer gene CNOT1
    (2013-12) Zhao, Lei
    A Sleeping Beauty transposon-mediated forward genetic screen in mice identified Cnot1 as a candidate colorectal cancer gene (CRC). CNOT1 is a central subunit of the CCR4-NOT (CNOT) deadenylase complex that regulates mRNA expression through multiple mechanisms, such as deadenylation. Our study suggests a model that CNOT1 protects cells from severe endoplasmic reticulum (ER) stress induced apoptosis through limiting the levels of TXNIP via promoting deadenylation and degradation of TXNIP mRNA transcripts. We also fund that CNOT1 plays a role in limiting cellular ER stress. Given that TXNIP is activated to promote apoptosis in response to extreme cellular stresses, such as ER stress, and that cancer cells commonly experience high levels of ER stress, increased activity of CNOT1 may be a mechanism that allows cancer cells to survive by protecting against cell stress-induced apoptosis.
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    Inflammatory processes and risk of cancer: epidemiological research.
    (2010-05) Prizment, Anna E
    Chronic inflammation has been implicated in cancer etiology but it is unclear whether inflammation causes cancer or results from tumor growth. To address these questions, we examined three hypotheses about the role of inflammation in incident cancers in large prospective cohorts. In the first manuscript, we hypothesized that increased levels of circulating acute-phase reactants, which are markers of inflammation, such as white blood cells, fibrinogen, factor VIII, von Willebrand factor, and C-reactive protein (CRP) (positive reactants) and decreased levels of albumin (a negative reactant) are associated with increased risk of subsequent colorectal cancer (CRC) in a prospective cohort - ARIC. After multivariate adjustment, there were statistically significant associations of CRC risk with two individual markers and a summary inflammation Z- score. For the highest versus lowest quartile, hazard ratios HR (95% confidence interval) were 1.50 (95%CI, 1.05; 2.15) for fibrinogen (p-trend across quartiles was 0.03); 1.97 (95%CI, 1.13; 3.43) for CRP (p-trend=0.02); and 1.65 (95%CI, 1.15; 2.35) for Z-score (p-trend=0.01). To our knowledge, no previous studies have examined a summary inflammation score in relation to incident cancers. The second manuscript hypothesized that the frequency of NSAIDs use was inversely associated with incident ovarian and endometrial cancers in the IWHS cohort of elderly women. We found that compared to women who reported no use of aspirin, the multivariate-adjusted HRs of ovarian cancer for those who used aspirin less than 2, 2-5 times, and 6 or more times per week were 0.83, 0.77 and 0.61, respectively (p-trend=0.04). We did not observe associations between non-aspirin NSAIDs use and ovarian cancer risk or between any NSAIDs use and endometrial cancer risk. The third manuscript examined whether elderly women (65+) suffering from an inflammatory autoimmune disease - psoriasis - have an increased risk of total, breast, lung, or colon cancers in the IWHS cohort linked to Medicare. We observed an association between psoriasis and colon cancer risk: multivariate-adjusted HR=1.57 (95%CI, 1.02; 2.42) for those with versus without psoriasis. This association was stronger for severe psoriasis. Findings from these studies give further support to the hypothesis that chronic inflammation may play a role in colorectal and ovarian carcinogenesis.
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    The roles of KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, Member 1) and CFTR (cystic fibrosis transmembrane conductance regulator) in mouse and human GI cancers
    (2013-09) Than, Bich (Elaine) Le Ngoc
    The ion-channel genes Kcnq1 and Cftr were identified as gastrointestinal (GI) tract cancer susceptibility genes in multiple Sleeping Beauty DNA transposon-based forward genetic screens in mice. Kcnq1 encodes for the pore-forming alpha subunit of a voltage-gated potassium channel and Cftr encodes for the chloride conductance channel. These ion channels act together to maintain ion homeostasis in the cellular and extracellular environment. To confirm that Kcnq1 and Cftr have a functional role in GI tract cancer, mouse models in which targeted mutant alleles of Kcnq1 and Cftr were intogressed into the intestinal tumor susceptible ApcMin strain of mice. Results demonstrated that Kcnq1 mutant mice developed significantly more intestinal tumors, especially in the proximal small intestine and colon, with some of these tumors in the proximal small intestine progressing to adenocarcinomas. Gross tissue abnormalities and neoplasia were also observed in the rectum, pancreas and stomach. Similarly, Cftr mutant mice developed significantly more intestinal tumors, both in the colon and the entire small intestine. Colon organoid formation was significantly increased in organoids created from Kcnq1 mutant and Cftr mutant mice compared with wildtype littermate controls, suggesting a role for Kcnq1 and Cftr in regulation of the intestinal crypt stem cell compartment. To identify gene expression changes due to loss of Kcnq1 and Cftr, we carried out microarray studies in the colon and proximal small intestine. We identified an overlapping set of altered genes involved in innate immune responses, goblet and Paneth cell function, ion channels, intestinal stem cells, EGFR and other growth regulatory signaling pathways. We also found genes implicated in inflammation and in cellular detoxification. Pathway analysis using Ingenuity Pathway Analysis (IPA) and gene set enrichment analysis (GSEA) confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2, another important regulator of intestinal homeostasis. To investigate the role of KCNQ1 in human colorectal cancer (CRC) we measured protein levels of KCNQ1 by immunohistochemistry in tissue microarrays containing samples from CRC patients with liver metastases who had undergone hepatic resection. Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival (OS). Our results indicate that both KCNQ1 and CFTR are potent tumor suppressor genes in GI cancer. Defining the mechanisms of action of KCNQ1 and CFTR, and elucidating the nature of their interactions in GI cancer can lead to their use as prognostic biomarkers and potential therapeutic targets for human cancers.