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.

Knockdown of RIPK2 Inhibits Proliferation and Migration, and Induces Apoptosis via the NF-κB Signaling Pathway in Gastric Cancer

“…NOD1 and NOD2 are sensors of different bacterial peptidoglycan components. It has been previously shown that the activation of NOD1 promotes colon cancer metastases ( Jiang et al, 2020 ); inhibition of RIPK2 can delay NOD signaling to decrease the production of inflammatory cytokine ( Nachbur et al, 2015 ), so RIPK2 could regulate the NOD signaling to control the occurrence and development of inflammation-related tumors. Collectively, these genes were predicted based on the neighborhood, co-expression, database, experiment data, co-occurrence, and text mining.…”

Nod1 promotes colorectal carcinogenesis by regulating the immunosuppressive functions of tumor-infiltrating myeloid cells

“…The potential contribution of Nod1 signaling in mediating the immunosuppressive activity of intra-tumoral myeloid cells is particularly interesting, as NOD1 expression is significantly elevated in human CRC tissue when compared to controls and increases with progressing stages of CRC (Liu et al, 2015b). Moreover, Nod1 activation has recently been implicated with increased CRC metastasis (Jiang et al, 2020), which further supports the concept that MPs can potentiate CRC by modulating the activity of intra-tumoral myeloid cells.…”

NOD1-Targeted Immunonutrition Approaches: On the Way from Disease to Health

“…The NOD1–cancer axis has been widely confirmed and it is quite relevant due to the high morbidity and mortality associated with these diseases [ 25 , 39 , 54 , 77 , 78 , 79 , 80 , 81 , 82 ]. For instance, a recent study has shown that activated NOD1 leads to the progression of colorectal carcinogenesis by modulating the immunosuppressive functions of tumor-infiltrating leukocytes via arginase-1 activity [ 77 ].…”

“…For instance, a recent study has shown that activated NOD1 leads to the progression of colorectal carcinogenesis by modulating the immunosuppressive functions of tumor-infiltrating leukocytes via arginase-1 activity [ 77 ]. Other previous studies have also linked NOD1 activities to colon cancer and metastasis [ 79 , 82 ] and carcinogenic responses to Helicobacter pylori pathogen [ 80 ]. Given the high impact of nutrition on the gastrointestinal tract and the microbiota content (also closely linked to NOD1) and the information provided by these studies, new immunonutrition strategies are required.…”

“…They are important posttranscriptional modulators of hematopoietic cell fate decisions, for example, or are involved in the regulation of gene expression associated with the immune response. However, the precise mechanisms involved in these biological and pathological processes are poorly defined in this still developing field [ 79 , 120 , 121 , 122 ]. An example of miRNAs in immune-related metabolic diseases is presented in a study in which miRNA-495 inhibited the inflammation caused by high glucose, the extracellular matrix accumulation, and the differentiation of cardiac fibroblasts by NOD1 downregulation [ 123 ].…”