Browsing by Subject "Colon Cancer"

Now showing 1 - 4 of 4
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    Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis
    (American Association for Cancer Research, 2017-07-01) Maiuri, Ashley R.; Peng, Michael; Sriramkumar, Shruthi; Kamplain, Caitlin M.; DeStefano Shields, Christina E.; Sears, Cynthia L.; O’Hagan, Heather M.; Medicine, School of Medicine
    Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared with normal epithelium and noninflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hypermethylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis.
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    p53 protein regulates Hsp90 ATPase activity and thereby Wnt signaling by modulating Aha1 expression
    (ASBMB, 2014-01-22) Okayama, Sachiyo; Kopelovich, Levy; Balmus, Gabriel; Weiss, Robert S.; Herbert, Brittney-Shea; Dannenberg, Kotha; Department of Medical & Molecular Genetics, IU School of Medicine
    The p53 tumor suppressor gene encodes a homotetrameric transcription factor which is activated in response to a variety of cellular stressors, including DNA damage and oncogene activation. p53 mutations occur in >50% of human cancers. Although p53 has been shown to regulate Wnt signaling, the underlying mechanisms are not well understood. Here we show that silencing p53 in colon cancer cells led to increased expression of Aha1, a co-chaperone of Hsp90. Heat shock factor-1 was important for mediating the changes in Aha1 levels. Increased Aha1 levels were associated with enhanced interactions with Hsp90, resulting in increased Hsp90 ATPase activity. Moreover, increased Hsp90 ATPase activity resulted in increased phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β), leading to enhanced expression of Wnt target genes. Significantly, levels of Aha1, Hsp90 ATPase activity, Akt, and GSK3β phosphorylation and expression of Wnt target genes were increased in the colons of p53-null as compared with p53 wild type mice. Using p53 heterozygous mutant epithelial cells from Li-Fraumeni syndrome patients, we show that a monoallelic mutation of p53 was sufficient to activate the Aha1/Hsp90 ATPase axis leading to stimulation of Wnt signaling and increased expression of Wnt target genes. Pharmacologic intervention with CP-31398, a p53 rescue agent, inhibited recruitment of Aha1 to Hsp90 and suppressed Wnt-mediated gene expression in colon cancer cells. Taken together, this study provides new insights into the mechanism by which p53 regulates Wnt signaling and raises the intriguing possibility that p53 status may affect the efficacy of anticancer therapies targeting Hsp90 ATPase.
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    Perspectives on Colon Cancer Screening—A Physician Panel Discussion for Preclinical Medical Students
    (Association of American Medical Colleges, 2020-10) Dilly, Christen K.; Craven, Hannah J.; Molleston, Jean P.; Medicine, School of Medicine
    Introduction Colon cancer is the third most common cancer in the US, and the survival rate improves drastically with early detection. It is important for medical students to understand screening options, and to be able to effectively discuss these options with their patients. While basic information about colon cancer screening is ubiquitous in US medical school curricula, no published curricula describe teaching students the nuances of negotiating this discussion with patients and tailoring screening to individual patients' needs. Methods We developed a 90-minute session for second-year medical students as part of a gastroenterology and nutrition course. We provided a short lecture on colon cancer screening. We then had a panel of practicing gastroenterologists and a primary care physician discuss their approaches to six hypothetical cases. The students reflected in writing on what they learned from the session and on their opinions of the session format. Results Of second-year medical students, 139 attended the session and 110 submitted written reflections on the session (79% response rate). The students perceived significant gains in knowledge, communication skills, and attitudes around the discussions. Discussion This expert panel session taught medical students knowledge and communication skills related to colon cancer screening. The session could be easily implemented at any medical school, either at the preclinical or clinical level.
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    Validation-based insertional mutagenesis (VBIM) technology identifies adenomatous polypossis coli (APC) like protein (ALP) as a novel negative regulator of NF-κB
    (2015-01) Mundade, Rasika S.; Lu, Tao; Sullivan, William J., Jr.; Safa, Ahmad R.
    Colorectal cancer (CRC) is the third leading cause of cancer related deaths in the United States. The nuclear factor κB (NF-κB) is an important family of transcription factors whose aberrant activation has been found in many types of cancer, including CRC. Therefore, understanding the regulation of NF-κB is of ultimate importance for cancer therapy. Using a novel validation-based insertional mutagenesis (VBIM) strategy, our lab has identified the novel adenomatous polyposis coli (APC) like protein (ALP) gene as a negative regulator of NF-κB. Preliminary studies from our lab demonstrated that overexpression of ALP led to decreased NF-κB activity by κB reporter assay and electrophoresis mobility gel shift assay (EMSA). The current project aims to further evaluate the role of ALP in the regulation of NF-κB signaling in CRC cells. We found that overexpression of ALP in human CRC HT29 cells greatly reduced both the number and the size of colonies that were formed in a soft agar assay. ALP overexpression also decreased the cell growth rate and cell migration ability, while shRNA mediated knockdown of ALP showed opposite effects, confirming that ALP is a tumor suppressor in CRC HT29 cells. Overexpression of ALP led to decreased NF-κB activity by κB reporter assay and condition media assay in CRC HT29 cells. Furthermore, immunohistochemical analysis with human colon vii tissues revealed that there is a gradual loss of ALP protein with tumor progression. We also found that ALP predominantly localizes in the cytoplasm, and binds to the p65 subunit of NF-κB, and might be functioning downstream of IκB kinase (IKK). In summary, in this study, we provide evidence regarding the tumor suppressor role of ALP in CRC by functioning as novel negative regulator of NF-κB. This discovery could lead to the establishment of ALP as a potential biomarker and therapeutic target in CRC.