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Activation of the pattern recognition receptor NOD1 augments colon cancer metastasis.

ABSTRACT: While emerging data suggest nucleotide oligomerization domain receptor 1 (NOD1), a cytoplasmic pattern recognition receptor, may play an important and complementary role in the immune response to bacterial infection, its role in cancer metastasis is entirely unknown. Hence, we sought to determine the effects of NOD1 on metastasis. NOD1 expression in paired human primary colon cancer, human and murine colon cancer cells were determined using immunohistochemistry and immunoblotting (WB). Clinical significance of NOD1 was assessed using TCGA survival data. A series of in vitro and in vivo functional assays, including adhesion, migration, and metastasis, was conducted to assess the effect of NOD1. C12-iE-DAP, a highly selective NOD1 ligand derived from gram-negative bacteria, was used to activate NOD1. ML130, a specific NOD1 inhibitor, was used to block C12-iE-DAP stimulation. Stable knockdown (KD) of NOD1 in human colon cancer cells (HT29) was constructed with shRNA lentiviral transduction and the functional assays were thus repeated. Lastly, the predominant signaling pathway of NOD1-activation was identified using WB and functional assays in the presence of specific kinase inhibitors. Our data demonstrate that NOD1 is highly expressed in human colorectal cancer (CRC) and human and murine CRC cell lines. Clinically, we demonstrate that this increased NOD1 expression negatively impacts survival in patients with CRC. Subsequently, we identify NOD1 activation by C12-iE-DAP augments CRC cell adhesion, migration and metastasis. These effects are predominantly mediated via the p38 mitogen activated protein kinase (MAPK) pathway. This is the first study implicating NOD1 in cancer metastasis, and thus identifying this receptor as a putative therapeutic target.

SUBMITTER: Jiang HY

PROVIDER: S-EPMC7026222 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In 2011, J. Hoffman, and B. Beutler won the Nobel Prize of medicine for the fact that they discovered the pattern recognition receptors (PRRs) and meanwhile described their effect on cell activation from the innate and adaptive immune systems. There are more and more evidences that have proved the obvious effect of PRRs on tumorigenesis progression. Nevertheless, the overall impact of PRR genes on prognosis, tumor microenvironmental characteristics and treatment response in patients with colon adenocarcinoma (COAD) remains unclear. In this research, we systematically assessed 20 PRR genes and comprehensively identified the prognostic value and enrichment degree of PRRs. The unsupervised clustering approach was employed for dividing COAD into 4 PRR subtypes, namely cluster A, cluster B, cluster C and cluster D, which were significantly different in terms of the clinical features, the immune infiltrations, and the functions. Among them, cluster B has better immune activities and functions. Cox and LASSO regression analysis was further applied to identify a prognostic five-PRR-based risk signature. Such signature can well predict patients' overall survival (OS), together with a good robustness. Confounding parameters were controlled, with results indicating the ability of risk score to independently predict COAD patients' OS. Besides, a nomogram with a strong reliability was created for enhancing the viability exhibited by the risk score in clinical practice. Also, patients who were classified based on the risk score owned distinguishable immune status and tumor mutation status, response to immunotherapy, as well as sensitivity to chemotherapy. A low risk score, featuring increased tumor stemness index (TSI), human leukocyte antigen (HLA), immune checkpoints, and immune activation, demonstrated a superior immunotherapeutic response. According to the study results, the prognostic PRR-based risk signature could serve as a robust biomarker for predicting the clinical outcomes as well as evaluating therapeutic response for COAD patients.

Project description:BackgroundConstitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification.MethodsWe performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided.ResultsOur validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P = .07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P = .66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P = .27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P = .40).ConclusionIn this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.

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Activation of the pattern recognition receptor NOD1 augments colon cancer metastasis.

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