Generic placeholder image

Current Bioinformatics

Editor-in-Chief

ISSN (Print): 1574-8936
ISSN (Online): 2212-392X

Research Article

A NOD-Like Receptor Signaling-Based Gene Signature Identified as a Novel Prognostic Biomarker for Predicting Overall Survival of Colorectal Cancer Patients

Author(s): Xin Qi*, Jiachen Zuo, Donghui Yan, Guang Hu, Rui Wang, Jiajia Chen and Jiaolong Fu

Volume 17, Issue 1, 2022

Page: [77 - 88] Pages: 12

DOI: 10.2174/1574893616666211005122422

Price: $65

Abstract

Background: Colorectal Cancer (CRC) is the most frequently diagnosed gastrointestinal tract malignant tumor worldwide, which is closely associated with distant metastasis and poor prognosis. Due to high degree of heterogeneity, reliable prognostic biomarkers are urgently needed to guide the therapeutic intervention of CRC patients.

Objective: The present study aimed to develop a NOD-Like Receptors (NLRs) signaling-based gene signature that can successfully predict the overall survival of CRC patients.

Methods: Firstly, differentially expressed NLR signaling-related genes were identified between primary and metastatic human CRC samples. Genes with prognostic value were then screened through univariate Cox regression analysis. Next, the NLR signaling-based prognostic signature was constructed by LASSO-penalized Cox regression analysis, and its predictive ability was further confirmed in an independent cohort. Furthermore, functional studies including GO, GSEA, ssGSEA and chemotherapeutic response analyses were performed to explore the role of the NLR signaling-based signature in CRC pathogenesis and therapy.

Results: The established prognostic signature that consisted of 7 NLR signaling-related genes can effectively stratify the high-risk and low-risk CRC patients in both training and validation cohorts. Moreover, the signature proved to be an independent indicator of overall survival in CRC patients. Functional annotation and chemotherapeutic response analyses showed that the signature was closely associated with immune status and chemotherapeutic sensitivity of CRC patients.

Conclusion: The novel NLR signaling-based gene signature could serve as a potential tool for survival prediction and therapeutic evaluation, thereby contributing to the personalized prognostic management of CRC patients.

Keywords: Colorectal cancer, NLR signaling, prognostic signature, overall survival, immune status, chemotherapeutic response.

« Previous
Graphical Abstract
[1]
Qu K, Gao F, Guo F, Zou Q. Taxonomy dimension reduction for colorectal cancer prediction. Comput Biol Chem 2019; 83107160
[http://dx.doi.org/10.1016/j.compbiolchem.2019.107160] [PMID: 31743831]
[2]
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209-49.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[3]
Chen L, Cao SQ, Lin ZM, He SJ, Zuo JP. NOD-like receptors in autoimmune diseases. Acta Pharmacol Sin 2021.
[PMID: 33589796]
[4]
Lupfer C, Kanneganti T-D. Unsolved mysteries in NLR biology. Front Immunol 2013; 4: 285.
[http://dx.doi.org/10.3389/fimmu.2013.00285] [PMID: 24062750]
[5]
Wilmanski JM, Petnicki-Ocwieja T, Kobayashi KS. NLR proteins: integral members of innate immunity and mediators of inflammatory diseases. J Leukoc Biol 2008; 83(1): 13-30.
[http://dx.doi.org/10.1189/jlb.0607402] [PMID: 17875812]
[6]
Liu P, Lu Z, Liu L, et al. NOD-like receptor signaling in inflammation-associated cancers: From functions to targeted therapies. Phytomedicine 2019; 64152925
[http://dx.doi.org/10.1016/j.phymed.2019.152925] [PMID: 31465982]
[7]
Karki R, Malireddi RKS, Zhu Q, Kanneganti T-D. NLRC3 regulates cellular proliferation and apoptosis to attenuate the development of colorectal cancer. Cell Cycle 2017; 16(13): 1243-51.
[http://dx.doi.org/10.1080/15384101.2017.1317414] [PMID: 28598238]
[8]
Liu R, Truax AD, Chen L, et al. Expression profile of innate immune receptors, NLRs and AIM2, in human colorectal cancer: correlation with cancer stages and inflammasome components. Oncotarget 2015; 6(32): 33456-69.
[http://dx.doi.org/10.18632/oncotarget.5587] [PMID: 26378020]
[9]
Dupaul-Chicoine J, Arabzadeh A, Dagenais M, et al. The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity 2015; 43(4): 751-63.
[http://dx.doi.org/10.1016/j.immuni.2015.08.013] [PMID: 26384545]
[10]
Cambui RAG, do Espírito Santo GF, Fernandes FP, et al. Double-edged sword of inflammasome genetics in colorectal cancer prognosis. Clin Immunol 2020; 213108373
[http://dx.doi.org/10.1016/j.clim.2020.108373] [PMID: 32135277]
[11]
Liang JY, Wang DS, Lin HC, et al. A Novel Ferroptosis-related Gene Signature for Overall Survival Prediction in Patients with Hepatocellular Carcinoma. Int J Biol Sci 2020; 16(13): 2430-41.
[http://dx.doi.org/10.7150/ijbs.45050] [PMID: 32760210]
[12]
Marisa L, de Reyniès A, Duval A, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med 2013; 10(5)e1001453
[http://dx.doi.org/10.1371/journal.pmed.1001453] [PMID: 23700391]
[13]
Phillips K, Parikh N, Kuwai T, Green T, Gallick G. Inhibition of colon tumor metastasis in an orthotopic nude mouse model with the dual selective Src/Abl kinase inhibitor, AZD0530. J Clin Oncol 2007; 25: 14032-2.
[http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14032]
[14]
Reddy SM, Kopetz S, Morris J, et al. Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer. Invest New Drugs 2015; 33(4): 977-84.
[http://dx.doi.org/10.1007/s10637-015-0257-z] [PMID: 26062928]
[15]
Wang H, Wang X, Xu L, Zhang J, Cao H. A molecular sub-cluster of colon cancer cells with low VDR expression is sensitive to chemotherapy, BRAF inhibitors and PI3K-mTOR inhibitors treatment. Aging (Albany NY) 2019; 11(19): 8587-603.
[http://dx.doi.org/10.18632/aging.102349] [PMID: 31596728]
[16]
Yu J, Liu D, Sun X, et al. CDX2 inhibits the proliferation and tumor formation of colon cancer cells by suppressing Wnt/β-catenin signaling via transactivation of GSK-3β and Axin2 expression. Cell Death Dis 2019; 10: 1-14.
[http://dx.doi.org/10.1038/s41419-018-1263-9]
[17]
Oh E-T, Kim CW, Kim HG, Lee J-S, Park HJ. Brusatol-mediated inhibition of c-Myc increases HIF-1α degradation and causes cell death in colorectal cancer under hypoxia. Theranostics 2017; 7(14): 3415-31.
[http://dx.doi.org/10.7150/thno.20861] [PMID: 28912885]
[18]
Ikehara N, Semba S, Sakashita M, Aoyama N, Kasuga M, Yokozaki H. BRAF mutation associated with dysregulation of apoptosis in human colorectal neoplasms. Int J Cancer 2005; 115(6): 943-50.
[http://dx.doi.org/10.1002/ijc.20957] [PMID: 15729718]
[19]
Bhattacharya S. Fabrication and characterization of chitosan-based polymeric nanoparticles of Imatinib for colorectal cancer targeting application. Int J Biol Macromol 2020; 151: 104-15.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.02.151] [PMID: 32070732]
[20]
Chargari C, Leteur C, Angevin E, et al. Preclinical assessment of JNJ-26854165 (Serdemetan), a novel tryptamine compound with radiosensitizing activity in vitro and in tumor xenografts. Cancer Lett 2011; 312(2): 209-18.
[http://dx.doi.org/10.1016/j.canlet.2011.08.011] [PMID: 21937165]
[21]
Jeitany M, Leroy C, Tosti P, et al. Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer. EMBO Mol Med 2018; 10(4)e7918
[http://dx.doi.org/10.15252/emmm.201707918] [PMID: 29438985]
[22]
Rohde S, Lindner T, Polei S, et al. Application of in vivo imaging techniques to monitor therapeutic efficiency of PLX4720 in an experimental model of microsatellite instable colorectal cancer. Oncotarget 2017; 8(41): 69756-67.
[http://dx.doi.org/10.18632/oncotarget.19263] [PMID: 29050239]
[23]
Shakoori A, Mai W, Miyashita K, et al. Inhibition of GSK-3 β activity attenuates proliferation of human colon cancer cells in rodents. Cancer Sci 2007; 98(9): 1388-93.
[http://dx.doi.org/10.1111/j.1349-7006.2007.00545.x] [PMID: 17640304]
[24]
Yuan L, Guo F, Wang L, Zou Q. Prediction of tumor metastasis from sequencing data in the era of genome sequencing. Brief Funct Genomics 2019; 18(6): 412-8.
[http://dx.doi.org/10.1093/bfgp/elz010] [PMID: 31204784]
[25]
Chen Y-T, Weng W-H, Pang S-T. Nod-like receptors family member-NLRC5 as a useful prognostic marker in renal cell carcinomas. AACR 2013.
[26]
Hu B, Ding G-Y, Fu P-Y, et al. NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells. J Hematol Oncol 2018; 11(1): 28.
[http://dx.doi.org/10.1186/s13045-018-0573-9] [PMID: 29482578]
[27]
Yuemaier M, Zhou Z, Zhou Y, et al. Identification of the Prognostic Value and Clinical Significance of Interferon Regulatory Factors (IRFs) in Colon Adenocarcinoma. Med Sci Monit 2020; 26: e927073-1.
[http://dx.doi.org/10.12659/MSM.927073] [PMID: 33161410]
[28]
Wu L-S, Liu Y, Wang XW, et al. LPS Enhances the Chemosensitivity of Oxaliplatin in HT29 Cells via GSDMD-Mediated Pyroptosis. Cancer Manag Res 2020; 12: 10397-409.
[http://dx.doi.org/10.2147/CMAR.S244374] [PMID: 33116894]
[29]
Huang Q, Li S, Cheng P, et al. High expression of anti-apoptotic protein Bcl-2 is a good prognostic factor in colorectal cancer: Result of a meta-analysis. World J Gastroenterol 2017; 23(27): 5018-33.
[http://dx.doi.org/10.3748/wjg.v23.i27.5018] [PMID: 28785155]
[30]
Lindner AU, Salvucci M, Morgan C, et al. BCL-2 system analysis identifies high-risk colorectal cancer patients. Gut 2017; 66(12): 2141-8.
[http://dx.doi.org/10.1136/gutjnl-2016-312287] [PMID: 27663504]
[31]
Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol 2019; 16(6): 361-75.
[http://dx.doi.org/10.1038/s41575-019-0126-x] [PMID: 30886395]
[32]
Braun MS, Seymour MT. Balancing the efficacy and toxicity of chemotherapy in colorectal cancer. Ther Adv Med Oncol 2011; 3(1): 43-52.
[http://dx.doi.org/10.1177/1758834010388342] [PMID: 21789155]
[33]
Lee J, Park D, Lee Y. Metformin synergistically potentiates the antitumor effects of imatinib in colorectal cancer cells. Dev Reprod 2017; 21(2): 139-50.
[http://dx.doi.org/10.12717/DR.2017.21.2.139] [PMID: 28785735]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy