NLRC4, inflammation and colorectal cancer (Review)

Abstract

Chronic inflammation is recognized as a major risk factor for cancer and is involved in every phase of the disease. Inflammasomes are central to the inflammatory response and play a crucial role in cancer development. The present review summarizes the role of Nod‑like receptor C4 (NLRC4) in inflammation and colorectal cancer (CRC). Reviews of the literature were conducted using Web of Science, PubMed and CNKI, with search terms including 'NLRC4', 'colorectal cancer', 'auto‑inflammatory diseases' and 'prognosis'. Variants of NLRC4 can cause recessive immune dysregulation and autoinflammation or lead to ulcerative colitis as a heterozygous risk factor. Additionally, genetic mutations in inflammasome components may increase susceptibility to cancer. NLRC4 is considered a tumor suppressor in CRC. The role of NLRC4 in CRC signaling pathways is currently understood to involve five key aspects (caspase 1, NLRP3/IL‑8, IL‑1β/IL‑1, NAIP and p53). The mechanisms by which NLRC4 is involved in CRC are considered to be threefold (through pyroptosis, apoptosis, necroptosis and PANoptosis; regulating the immune response; and protecting intestinal epithelial cells to prevent CRC). However, the impact of NLRC4 mutations on CRC remains unclear. In conclusion, NLRC4 is a significant inflammasome that protects against CRC through various signaling pathways and mechanisms. The association between NLRC4 mutations and CRC warrants further investigation.

Keywords: Nod‑like receptor C4; colorectal cancer; mechanism of action; prognosis; signaling pathway.

Figure 1

Literature search process. CRC, colorectal cancer; IBD, inflammatory bowel disease; NLRC4, Nod-like receptor C4.

Figure 2

Schematic depiction of the architecture of NLRC4, showing the initial and terminal residues for each distinct domain of the protein (19). CARD, caspase-activating and recruitment domain; LRR, leucine-rich repeat; NLRC4, Nod-like receptor C4; NOD, nucleotide-binding oligomerization domain.

Figure 3

Inflammasome sensors have diverse roles in tumorigenesis. The NLRP1b, NLRP3 and NLRP6 inflammasomes facilitate the production of IL-18, which helps protect against colorectal cancer associated with colitis. IL-18 also triggers the anticancer activity of natural killer cells against metastatic colonic tumor cells, reduces the levels of IL-22BP and may prevent the establishment of colitis-inducing microbiota, potentially through its impact on MUC2 secretion by goblet cells. The NLRP3 inflammasome, along with the IL-1β/IL-1 receptor signaling pathway, drives a T-cell response against transplantable tumor cells. In mice, NAIP1-6 proteins regulate STAT3 phosphorylation and the transcription of genes involved in anti-apoptotic and cell proliferation mechanisms. NLRC4 inhibits melanoma growth by enhancing macrophage inflammation and increasing IFNγ production in T cells. AIM2 suppresses AKT and cMyc phosphorylation, limiting stem cell proliferation and preventing colonization by colitis-promoting microbiota (83). AIM2, absent in melanoma 2; IL-22BP, IL-22 binding protein; MUC2, mucin 2; NLRC4, Nod-like receptor C4; NOD, nucleotide-binding oligomerization domain; NLRP, NLR family pyrin domain containing.

Figure 4

Diagram of NLRC4 GOF mutations (120). CARD, caspase-activating and recruitment domain; GOF, gain-of-function; LRR, leucine-rich repeat; NBD, nucleotide-binding domain; NLRC4, Nod-like receptor C4.