Project description:Human Ulcerative colitis (UC) is characterized by chronic colonic inflammation and has been associated with an increased risk of colorectal carcinoma. Gene and protein expression profiles of ABCB1/MDR1 have been shown to be dysregulated in UC and sporadic colorectal cancer. We demonstrated that in a murine model of colitis-associated tumorigenesis, MDR1A KO mice showed reduced tumor load when compared to wildtype (WT) mice. The aim of this study was to identify gene alterations in colitis-associated tumors in the context of MDR1A deficiency. We used microarrays to assess gene expression profiles of colitis-associated colonic tumors from WT or MDR1A KO mice.
Project description:MUC1 is a tumor-associated antigen that is aberrantly expressed in cancer and inflammatory bowel disease (IBD). Even though immune cells express low MUC1 levels, their modulations of MUC1 are important in tumor progression. Consistent with previous clinical data that show increased myeloid-derived suppressor cells (MDSCs) in IBD, we now show that down-regulation of MUC1 on hematopoietic cells increases MDSCs in IBD, similar to our data in tumor-bearing mice. We hypothesize that MDSC expansion in IBD is critical for tumor progression. In order to mechanistically confirm the linkage between Muc1 down-regulation and MDSC expansion, we generated chimeric mice that did not express Muc1 in the hematopoietic compartment (KO→WT). These mice were used in 2 models of colitis and colitis-associated cancer (CAC) and their responses were compared to wildtype chimeras (WT→WT). KO→WT mice show increased levels of MDSCs during colitis that was responsible for the larger colon tumors that eventually developed in these mice. Using microarray and qRT-PCR analysis, we observed increased pro-tumorigenic signaling in the colons of KO→WT mice during colitis as compared to WT→WT mice. Our RNA (microarray and qRT-PCR analysis) and protein analysis demonstrate increased up-regulation of metalloproteinases, collagenases, defensins, complements, growth factors, cytokines and chemokines in KO→WT mice as compared to WT→WT mice. Antibody-mediated depletion of MDSCs in mice during colitis reduced colon tumor formation during CAC. Development of CAC is a serious complication of colitis and our data highlight MDSCs as a targetable link between inflammation and cancer.
Project description:To explore the underlying mechanisms of NEDD4L in regulating colitis, colonic tissues from DSS-treated Nedd4lf/f VillinCre (IEC KO) mice and Nedd4lf/f (WT) littermates were subjected to RNA-sequencing analysis.
Project description:To explore the underlying mechanisms of NEDD4L in regulating colitis, colonic tissues from DSS-treated Nedd4lf/f VillinCre (IEC KO) mice and Nedd4lf/f (WT) littermates were subjected to RNA-sequencing analysis.
