Table 1.

Role of NOD proteins and their expression level in different types of cancer

		Role of NOD proteins and their expression level
Cancer	NOD protein	Protective (P)/ detrimental (D)		References
Colorectal	NOD1	P	NOD1 deficiency alone or together with a mutation in Apc (ApcMin/+) leads to increased risk of tumor formation in the AOM/DSS mouse model of colon cancer. Increased tumor formation is a consequence of increased intestinal epithelial apoptosis as well as intestinal permeability associated with enhanced inflammatory cytokine production and epithelial cell proliferation.	69
	NOD1	P	NOD1 deficiency in T cells increases risk of tumor formation in mice using AOM/DSS model of colon cancer. NOD1 deficiency in T cells is associated with impaired IFN‐γ production and STAT1 activation.	70
	NOD2	P	NOD2 (or RIPK2) deficiency results in increased susceptibility to tumor formation in AOM/DSS mouse model of colon cancer. Absence of NOD2 (or RIPK2) promotes pro‐inflammatory microenvironment in the intestines leading to enhanced epithelial dysplasia following chemically induced injury.	71
Gastric	NOD1	P	Decreased expression level of NOD1 in Helicobacter pylori‐positive GC patients. Stimulation of NOD1 by C12‐iE‐DAP before infection with Helicobacter pylori reduced risk of GC development in gerbils.	72
	NOD1/NOD2	D	Increased expression level of NOD1 in Helicobacter pylori‐positive and Helicobacter pylori‐negative GC patients. Increased expression level of NOD2 in Helicobacter pylori‐positive GC patients.	73, 74
Breast	NOD1	P	NOD1 deficiency leads to increased tumor growth in mouse model of breast cancer. Stimulation of NOD1 overexpressed breast cancer cells results in caspase 8–mediated apoptosis.	53, 54
Oral squamous cell carcinoma (OSCC)	NOD1	P	Decreased expression level of NOD1 in OSCC patients. NOD1 expression decreases along with OSCC progression.	75
	NOD1/NOD2	D	NOD1 and NOD2 are apparently expressed in YD‐10B and FaDu cell line. Stimulation of NOD1 and NOD2 in YD‐10B cells by Tri‐DAP and MDP, respectively, results in production of IL‐8 and MAPK activation. Stimulation of YD‐10B cells by MDP results in inhibition of the proliferation and induction of apoptosis.	76
Head and neck squamous cell carcinoma (HNSCC)	NOD1	D	Increased expression level of NOD1 in tumor biopsies, Detroit‐562 and FaDu cell line. Stimulation of NOD1 in HNSCC cells by iE‐DAP increases the production of β‐defensin 2, GM‐CSF, G‐CSF, and upregulates ICAM‐1. NOD1 activation by iE‐DAP increases the apoptosis and decreases the number of dead Detroit‐562 cells.	77
	NOD1	D	Increased expression level of NOD1 (as well as IL‐8 and RIPK2) in tumor biopsies. IL‐8 is a key factor in NOD1‐mediated RIPK2 activation and HNSCC progression.	78
Pancreatic	NOD1	D	Increased expression level of NOD1 in peripheral blood leukocytes of pancreatic cancer.	79

Abbreviations: AOM, azoxymethane; CSF, colony‐stimulating factor; DSS, dextran sulfate sodium; GC, gastric cancer; ICAM‐1, intercellular adhesion molecule‐1; iE‐DAP, d‐glutamyl‐meso‐diaminopimelic acid; IFN, interferon; IL, interleukin; MDP, muramyl dipeptide; NOD, nucleotide‐binding oligomerization domain; RIPK2, receptor‐interacting serine/threonine‐protein kinase 2; STAT1, signal transducer and activator of transcription 1; Tri‐DAP, l‐alanyl‐γ‐d‐glutamyl‐meso‐DAP.