Abstract
NLRs (nucleotide-binding domain leucine-rich repeat proteins or NOD-like receptors) are regulators of inflammation and immunity. A subgroup of NLRs and the innate immune receptor, AIM2 (absent-in-melanoma 2), can induce the assembly of a large caspase-1 activating complex called the inflammasome. Other NLRs regulate key signaling pathways such as NF-kB and MAPK. Since inflammation is a central component of colorectal cancer (CRC), this work was undertaken to analyze NLR and AIM2 expression in human CRC by combining bioinformatics analysis and experimental verification using clinical tissue samples. Additional experiments analyzed the association of (i) gene expression and cancer staging, and (ii) gene expression among inflammasome components.Ten public CRC datasets from the Oncomine® Platform were analyzed. Genes analyzed include NLRP1, NLRP3, NLRP6, NLRP12, NLRC3, NLRC4, NLRC5, NOD1, NOD2 and AIM2. Additionally, forty case-matched cancer samples and adjacent healthy control tissues isolated from a cohort of Chinese CRC patients were profiled.Three patterns of gene expression in CRC are shown. The expression of NLRC3, a checkpoint of inflammation, and the inflammasome components NLRP1, NLRP3, NLRC4 and AIM2 were reduced in CRC. NOD1 and NOD2 expression was increased in CRC, while NLRC5, NLRP6 and NLRP12 showed little difference compared to controls. Reduced expression of NLRC3 in CRC was verified in all available databases analyzed and confirmed with our patient cohort. Furthermore, the extent of NLRC3 and AIM2 gene reduction was correlated with cancer progression. This report reveals the potential value of NLR and AIM2 genes as biomarkers of CRC and cancer progression.
Highlights
Inflammation is one of the hallmarks of cancer
Expression levels of NOD-like receptors (NLR) and AIM2 in colorectal cancer culled from the Oncomine® Platform
The main function of NLRC5 is regulating class I Major Histocompatibility Complex (MHC) genes [12], while NOD1/NOD2 proteins are primarily required for the positive regulation of NF-κB and MAPK [13]
Summary
Inflammation is one of the hallmarks of cancer. Whereas acute inflammation protects against infectious pathogens, chronic inflammation is associated with DNA and tissue damage, including genetic and epigenetic changes leading to cancer. A common feature of gastrointestinal inflammatory diseases that leads to www.impactjournals.com/oncotarget colorectal cancer (CRC) is the exaggerated production of cytokines by resident innate immune cells. These proinflammatory mediators stimulate the secretion of molecules that damage the intestinal epithelium and further amplify the response by recruiting and activating additional immune cells [1]. The majority of studies assessing PRR signaling in cancer have focused on members of the TLR family. New and emerging findings in murine models have revealed a significant role for members of the NLR family in contributing to a variety of hallmarks associated with cancer including inflammation, cell death, tumor growth, angiogenesis, invasion, and metastasis [2]
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