Cell-autonomous redox-sensitive role of selenoprotein glutathione peroxidase-2 (Gpx2) in APC-driven colorectal carcinogenesis and stem cell function
Hematology, Oncology
Immunology
Final Report Abstract
Colorectal cancer (CRC) is a major health concern across the world, especially in the western countries as it is the third most common cause of cancer death in both men and women. The progression of CRC is influenced by various intrinsic and extrinsic factors such as diet rich in unsaturated fats, lifestyle with reduced physical activity, chronic gut inflammation as well as genetic predisposition. Chronic gut inflammation in inflammatory bowel disease patients increases their risk of developing colon cancer. Inflammation likely promotes tumor progression since resulting reactive oxygen species (ROS) can induce substantial oxidative alterations in the DNA nucleotides as well as in protein structure and function. Besides inflammation, epidemiological studies have linked a sub-optimal status of micronutrient selenium to an increased risk of CRC. Most of the CRC cases, which do not arise from IBD, can be classified into sporadic, familial and hereditary colon cancers. H2O2-scavenging glutathione peroxidase (GPx2) is expressed exclusively in the gastrointestinal (GI) system and is therefore also referred to as GI-GPx or GPx-GI. Its main role is thought to act as a protective barrier against oxidative stress, which might originate from food-derived hydroperoxides. Notably, GPx2 also co-localizes with Wnt pathway proteins within the intestinal crypt base, and hence, it has been speculated to play a prime role in gut mucosal homeostasis in normal and tumor cells. Findings from this study suggest that absence of GPx2 in the murine intestinal stem cell compartment impacts baseline epithelial morphology as well as differentiation. Furthermore, in human colon cancer cell lines GPx2 may play a role in tumor cell proliferation. In a murine APC-dependent intestinal cancer model, dose-dependent GPx2 expression impacts tumor multiplicity through, but not limited by, cellular apoptosis and its expression level significantly influences tumor dysplasia. Moreover, the function of GPx2 cannot be compensated by other epithelial selenoproteins. GPx2 influences proliferation of transformed epithelial cells in murine APC-dependent tumorigenesis and its absence makes tumor cells more susceptible to cell death postoxidative stress. Conclusion: GPx2 plays a unique as well as a complex role in the epithelial stem cell compartment. GPx2 loss modifies APC-dependent tumorigenesis in a dose-dependent manner; its role may be further shaped according to various epithelial-independent and -dependent factors.
