Inflammasomes and Colorectal Cancer
Abstract
:1. Introduction
2. Inflammasomes and Inflammatory Bowel Disease
3. Inflammasomes Regulate Intestinal Inflammation
4. Inflammasomes Protect the Integrity of the Intestinal Epithelial Barrier
5. NLRP6 Inflammasomes Maintain the Microbiota Balance
6. Inflammasome and Intestinal Tumorigenesis
7. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Inflammasome Components Mice Model/Human | Suggested Mechanisms | Clinical Outcomes | References |
---|---|---|---|
NLRP3, ASC, Casp-1 and IL-18-deficient mice | -IL-18 levels ↓ -The production and activation of IFN-γ and tumor suppressor STAT1 ↓ | -Elevated susceptibility of DSS-induced colitis and colorectal cancer progression | [89] |
NLRP6-deficient mice | -Csnk1ε that stabilizes β-catenin↑ -SMARRC1↑ | -Enhanced susceptibility to experimental colitis and colorectal tumorigenesis -Develop relapsing colitis -Decreased regeneration of the colonic mucosa (Wound Healing) -Enhanced epithelial cell organization and proliferation upon Injury -Enhanced tissue injury with bleeding and ulcerations -Decrease of diseased colon length -Decreased body weight of mice | [116] |
NLRP6-deficient mice | IL-18↓, CCL5↑ | The intestinal hyperplasia, inflammatory cells migration, and increasing of the severity of DSS-induced colitis | [115] |
NLRP6 and ASC-deficient mice | IL-18, ↓ CCL5, IL-6↑ | Enhanced susceptibility to colorectal tumorigenesis | [118] |
NLRP3, NLRC4, Pycard and casp-1-deficient mice | Pycard and casp-1: IL-1β and IL-18 levels↓ | -Nlrp3, Pycard, and casp-1 deficiency: Enhanced acute and recurring colitis and colorectal cancer progression -NLRC4-deficient mice didn’t show significant differences in disease progression or outcome | [84] |
NLRP3, NLRC4 and Aim2-deficient mice | IL-18 ↓, FasL↓ | Colorectal cancer metastatic growth in the Liver | [125] |
Nlrp6-deficient mice | IL-18 ↓ proinflammatory cytokines (TNF, IL-6 and IL-1β) ↑ | -Elevated susceptibility to colitis and colitis-associated colon tumorigenesis -significant inflammation and injury within the colon -Prolonged epithelial cells proliferation | [92] |
Casp-1 and Casp-12-deficient mice | IL-18 ↓ Nf-kB ↑ | -Decrease of tissue repair -Increase of colitis, and colitis-associated tumorigenesis | [85] |
Casp-1 and NLRC4-deficient mice | Colonic epithelial cell proliferation and apoptosis ↑ | -Increase the colon tumorigenesis | [91] |
Aim-2-deficient mice | Aberrant Wnt signaling | -Elevated susceptibility to colon tumorigenesis | [126] |
Aim-2-deficient mice | DNA-PK and Akt activation ↑ | -Elevated susceptibility to colon tumorigenesis | [127] |
Aim-2-deficient mice | Aberrant Wnt signaling | -Elevated susceptibility to colon tumorigenesis | [128] |
HCT116 CRC cells | Blocking of cell cycle transition from G1 to S phase and suppressing the (PI3K)/protein kinase B (Akt) pathway | - As a tumor suppressor could apply as a potential therapeutic target for future improvement of AIM2-based gene therapy for human CRC | [129] |
Public CRC datasets/CRC patients | NLRC3, NLRC4, NLRP1, NLRP3 and AIM2 ↓NOD1/NOD2 ↑ | -NLRC3 and AIM-2 correlated to colorectal cancer progression | [130] |
Nude mice/ Colonic cancer patients, Cell culture of human colon cancer cell lines | -colonic cancer tissue: NALP-1 ↓ | Elevated susceptibility to colon tumorigenesis | [131] |
NLRP3-deficient C57BL/6 mice | IL-1 ↓ | -NLRP3 deficiency decreased cholesterol effects in progressing of colorectal tumor | [132] |
Cell culture of human colon cancer cell lines | vimentin, MMP9 and Snail1 ↓ E-cadherin ↑ | -Inflammasome-independent NLRP3 develop the TGF-β-induced EMT (epithelial–mesenchymal transition) in colorectal cancer | [134] |
NLRP-3 suppression | -Suppression of migration of CRC cells and metastatic ability | [135] | |
NLRP-3 suppression | -Caspase-1 activation and IL-1β maturation ↓ -Phagocytosis ↓ | -The attenuation of NLRP3-mediated colitis and inflammation-associated colon carcinogenesis | [136] |
NLRP-3 degredation | triggering autophagy after a small-molecule AMP-activated protein kinase activator (GL-V9) administration ↓ | -protection against colitis and tumorigenesis in colitis-associated colorectal cancer | [133] |
NAIP1-6-deficient mice | STAT-3 activation ↑ P53 activation ↓ | Elevated susceptibility to colon tumorigenesis | [100] |
NLRP12 | TRAF3 degradation, activation of NIK and p100 processing to p52 ↓ NF-KB pathway ↑ Cxcl13 and Cxcl12 ↑ | Enhanced susceptibility to experimental colitis and colorectal tumorigenesis | [137] |
CRC patients | -Epithelial protein expression of inflammasome components (NLRP1,3,6, ASC, AIM-2, caspase-1) and IL-1β and IL-18 -Epi IL-18 is correlated with higher lymphocyte infiltration within colorectal tumors | -NLRP6 and IL-18 expressions in epithelial tumor cells are strong predictors of patients’ outcomes -Epithelial expression of NLRP6 and IL-18 are correlated with tumor evolution -Re-establishing normal NLRP6 expression in tumor cells may present therapeutic advantages over preventing progress towards advanced CRC | [139] |
CRC patients | -NLRP3 expression in CRC↑ -The depth of tumor invasion, lymph node invasion, venous invasion and neural invasion in positive NLRP3 expression↑ | -The survival of patients with positive NLRP3 expression -Targeting NLRP3 may be promising for targeted therapy of CRC, especially for mTORC1-targeted resistant patients | [140] |
CRC patients | -TGF β, IL 1β, NF-κB, NLRP3 and caspase-1 protein and gene expression in CRC↑ -mRNA and protein levels of TGF-β, mature IL 1β, NF-κB and NLRP3 in patients with grade III ↑ -EMT markers N cadherin, vimentin and MMP 9 in CRC and also in grade III than grade I↑ -E-cadherin by the progression of CRC -NLRP3 protein level was inversely correlated with E-cadherin -NLRP3 protein level was positively correlated with IL 1β, active NF-κB, N cadherin, vimentin and MMP 9 | -NLRP3 inflammasome activation contributed to the progression of CRC and is correlated with the EMT process | [141] |
CRC cell lines and a subcutaneous tumor model | -NLRP3 in human CRC tissues↑ -Tumor size and invasion, lymph node metastasis, venous and neural invasion ↑ associated with NLRP-3 levels -knockdown of NLRP3 in CRC cells: CRC migration and growth in vitro ↓ and in vivo -knockdown of NLRP3 in CRC cells: Reversed EMT in vitro | -NLRP3 likely modulate CRC metastasis by EMT process activating -Potential therapeutic target | [142] |
CRC patients | -Activated and functional caspase-1/IL-18 axis in tumor cells↑ -Drive a Th1/Tc1 response elicited by TILs expressing IL-18Rα | -Caspase-1/IL-18 axis targeting can improve the antitumor immunity in subgroups of CRC | [143] |
Azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC mice | -Arctigenin administration: -NLRP3 inflammasome activation and fatty acid oxidation (FAO) metabolism in macrophages ↓ -The expression of carnitine palmitoyltransferase 1 (CPT1) ↓ -The acetylation of α-tubulin ↓ -NLRP3 complex formation ↓ | -NLRP3 inflammasome assembly inhibition in macrophages due to downregulation of to FAO associated to the preventative effect of arctigenin against CAC | [144] |
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Keshavarz Shahbaz, S.; Koushki, K.; Ayati, S.H.; Bland, A.R.; Bezsonov, E.E.; Sahebkar, A. Inflammasomes and Colorectal Cancer. Cells 2021, 10, 2172. https://doi.org/10.3390/cells10092172
Keshavarz Shahbaz S, Koushki K, Ayati SH, Bland AR, Bezsonov EE, Sahebkar A. Inflammasomes and Colorectal Cancer. Cells. 2021; 10(9):2172. https://doi.org/10.3390/cells10092172
Chicago/Turabian StyleKeshavarz Shahbaz, Sanaz, Khadijeh Koushki, Seyed Hassan Ayati, Abigail R. Bland, Evgeny E. Bezsonov, and Amirhossein Sahebkar. 2021. "Inflammasomes and Colorectal Cancer" Cells 10, no. 9: 2172. https://doi.org/10.3390/cells10092172
APA StyleKeshavarz Shahbaz, S., Koushki, K., Ayati, S. H., Bland, A. R., Bezsonov, E. E., & Sahebkar, A. (2021). Inflammasomes and Colorectal Cancer. Cells, 10(9), 2172. https://doi.org/10.3390/cells10092172