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Many diseases, including cancer, afflict the intestines. This is in large part due to the continuous renewal of epithelial cells, and the exposure to toxins from the diet and to infectious agents. Inflammation also contributes to the genesis of cancer, as illustrated by the link between chronic and ulcerative colitis and colorectal cancer (CRC). Caspases, a family of cysteinyl peptidases, play a crucial role in both inflammation and cancer avoidance via cytokine productions and apoptosis (cell death), respectively. A growing body of evidence suggests that caspases play on all fronts to regulate inflammation and promote apoptosis whenever necessary. Recent studies showed that caspase-7, initially assigned to apoptosis, also contributes to inflammatory mechanisms. For instance, CASP7 gene ablation in mice causes resistance to endotoxic shock induced by bacterial lipopolysaccharides. This phenotype is recapitulated in animals carrying an amino acid substitution in the multifunctional enzyme poly(ADP ribose) polymerase 1 (PARP) gene that renders this protein resistant to caspase proteolysis. Moreover, a functional link between caspase-7, PARP and inflammation has been established. Thus, caspase-7 contributes to both inflammatory and apoptotic processes. Gene expression profiling revealed that caspase-7 mRNA levels are the highest in the intestines, but significantly diminished, or even abolished, in CRC compared to healthy tissue. These data suggest that caspase-7 could be a tumor suppressor, but this hypothesis must be verified. We propose studies that will determine the role of caspase-7 in the genesis and progression of CRC, and shed light on the underlying mechanisms. To this end, we propose three aims:
Aim 1: Analyze caspase-7 expression and activity in different model cell lines of CRC
We propose to compare the protein and gene expression of caspase-7 in non-immortalized intestinal epithelial cells and in a panel of human CRC cell lines that have distinct and well-defined tumorigenic and metastatic characteristics, as well as known genetic alterations. If detected, we will establish the functionality of the caspase in apoptosis induced by clinically relevant CRC chemotherapeutics.
Aim 2: Define the contribution of caspase-7 to CRC progression
We will evaluate the impact of the gain and the lost of function of caspase-7 on the phenotypes of cell lines identified in Aim 1. Caspase-7 expression will be restored by ectopic expression or ablated using shRNAs using lentiviruses. Proliferation, soft-agar and suspension growth assays, cellular migration, and cell invasion phenotypes will be assessed.
Aim 3: Analyze caspase-7, its regulators, and PARP expression in human CRC tumors
We will determine the expression of caspase-7 and key proteins in tumor and healthy colon samples from patients with CRC. These studies will help validate the mechanism of regulation and role of caspase-7 in CRC.
Conclusion: The high expression level of caspase-7 in the intestines is puzzling. The close relationship between caspase-7 and inflammation set the stage for novel and interesting discovery. This research will provide a solid ground to investigate the role of caspase-7 in CRC, and potentially lead to new treatment or diagnostic tools.
Francisco Nava Morales
Pharmacy / Pharmacology
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