Molecular Mechanisms and Clinical Predictive Value of Colorectal Cancer Susceptibility Genes: WGCNA Analysis and Mendelian Randomization Study
DOI:
https://doi.org/10.53469/jcmp.2024.06(12).25Keywords:
CRC, WGCNA, CDC2, Mendelian randomization analysisAbstract
Background and objective: Colorectal cancer (CRC) is a highly heterogeneous disease, making treatment and prognosis prediction challenging. Early diagnosis of CRC and identification of gene expressions associated with its onset are crucial for prognosis, especially before clinical symptoms appear. This study aims to explore potential key genes involved in CRC and evaluate their clinical application in predicting the disease. Methods: This study utilizes differential expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA) to identify novel susceptibility modules and key genes associated with colorectal cancer (CRC). Through KEGG and GO analyses, we aim to investigate the potential functions of these key genes. Subsequently, we will construct a Nomogram model and assess its diagnostic value for CRC using ROC curves. Based on genome-wide association studies, a Mendelian randomization analysis will be conducted to determine the causal relationship between these key genes and CRC. Finally, we will explore the association between these key genes, which are causally linked to CRC risk factors, and immune cell infiltration. Results: A gene co-expression network was constructed using WGCNA, from which key modules related to colorectal cancer (CRC) were identified, along with 963 overlapping key genes derived from WGCNA. GO and KEGG pathway enrichment analyses revealed that these genes are involved in the biosynthesis of ribonucleoprotein complexes, rRNA metabolic processes, chromatin organization-regulated signaling pathways, as well as cell cycle, DNA replication, and ribosome-related pathways. Using Cytoscape software, we identified the top five highly expressed genes: CDC2, CCNB1, CCNA2, TOP2A, and CCNB2. We then developed a Nomogram model, which effectively predicts the risk of CRC. The performance of this model in CRC diagnosis was further validated through ROC curve analysis, showing promising diagnostic accuracy. Finally, we focused on CDC2 and observed a causal relationship between CDC2 and immune cell infiltration in CDAD. Through inverse variance-weighted analysis, we found that CDC2 significantly increased the risk of CDAD, with an OR of 1.0005 (95% CI = 1.0001-1.001, P = 0.01). Conclusion: We successfully identified the core genes associated with colorectal cancer (CRC). This finding provides important insights for further research into early diagnostic methods for CRC, while also contributing to the understanding of the molecular mechanisms underlying CRC risk genes.
References
Haggar, Fatima A, and Robin P Boushey. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors[J]. Clinics in colon and rectal surgery vol. 22,4 (2009): 191-7. doi:10.1055/s-0029-1242458.
He J, Pei L, Jiang H, et al. Chemoresistance of colorectal cancer to 5-fluorouracil is associated with silencing of the BNIP3 gene through aberrant methylation[J]. Journal of Cancer vol. 8,7 1187-1196. 9 Apr. 2017, doi:10.7150/jca.18171.
Marin JJ, Sanchez de Medina F, Castaño B, et al. Chemoprevention, chemotherapy, and chemoresistance in colorectal cancer[J]. Drug metabolism reviews vol. 44,2 (2012): 148-72. doi:10.3109/03602532.2011.638303.
Bertheloot D, Latz E, Franklin BS. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death[J]. Cellular & molecular immunology vol. 18,5 (2021): 1106-1121. doi:10.1038/s41423-020-00630-3.
Bhandari A, Woodhouse M, Gupta S. et al. Colorectal cancer is a leading cause of cancer incidence and mortality among adults younger than 50 years in the USA: a SEER-based analysis with comparison to other young-onset cancers[J]. Journal of investigative medicine: the official publication of the American Federation for Clinical Research vol. 65,2 (2017): 311-315. doi:10.1136/jim-2016-000229.
Benson AB 3rd, Venook AP, Cederquist L, et al. Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology[J]. Journal of the National Comprehensive Cancer Network: JNCCN vol. 15,3 (2017): 370-398. doi:10.6004/jnccn.2017.0036.
Barclay J, Clark AK, Ganju P et al. Role of the cysteine protease cathepsin S in neuropathic hyperalgesia[J]. Pain. 2007;130(3):225-234. doi:10.1016/j.pain.2006.11.017.
von Schack D, Agostino MJ, Murray BS, et al.Dynamic changes in the microRNA expression profile reveal multiple regulatory mechanisms in the spinal nerve ligation model of neuropathic pain[J]. PloS one vol. 6,3 e17670. 14 Mar. 2011, doi:10.1371/journal.pone.0017670.
Nangraj AS, Selvaraj G, Kaliamurthi S et al. Integrated PPI- and WGCNA-Retrieval of Hub Gene Signatures Shared Between Barrett's Esophagus and Esophageal Adenocarcinoma[J]. Frontiers in pharmacology vol. 11 881. 31 Jul. 2020, doi:10.3389/fphar.2020.00881
Benson AB 3rd, Venook AP, Cederquist L et al. Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology[J]. Journal of the National Comprehensive Cancer Network: JNCCN vol. 15,3 (2017): 370-398. doi:10.6004/jnccn.2017.0036
Jansen H, Samani NJ, Schunkert H. Mendelian randomization studies in coronary artery disease[J]. European heart journal vol. 35,29 (2014): 1917-24. doi:10.1093/eurheartj/ehu208.
Emdin CA, Khera AV, Kathiresan S. Mendelian Randomization. JAMA vol. 318,19 (2017): 1925-1926. doi:10.1001/jama.2017.17219
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis [J]. BMC bioinformatics vol. 9 559. 29 Dec. 2008, doi:10.1186/1471-2105-9-559.
Chen B, Khodadoust MS, Liu CL, et al. Profiling Tumor Infiltrating Immune Cells with CIBERSORT[J]. Methods in molecular biology (Clifton, N.J.) vol. 1711 (2018): 243-259. doi:10.1007/978-1-4939-7493-1_12
Emdin CA, Khera AV, Kathiresan S. Mendelian Randomization. JAMA vol. 318,19 (2017): 1925-1926. doi:10.1001/jama.2017.17219.
Dudbridge, Frank. Polygenic Mendelian Randomization[J]. Cold Spring Harbor perspectives in medicine vol. 11,2 a039586. 1 Feb. 2021, doi:10.1101/cshperspect.a039586
Franz M, Rodriguez H, Lopes C, et al. GeneMANIA update 2018[J]. Nucleic acids research vol. 46, W1 (2018): W60-W64. doi:10.1093/nar/gky311.
Thoma OM, Neurath MF, Waldner MJ. et al. Cyclin-Dependent Kinase Inhibitors and Their Therapeutic Potential in Colorectal Cancer Treatment [J]. Frontiers in pharmacology vol. 12 757120. 21 Dec. 2021, doi:10.3389/fphar.2021.757120.
Vu T, Datta A, Banister C et al. Serine-threonine Kinase Receptor-Associated Protein is a Critical Mediator of APC Mutation-Induced Intestinal Tumorigenesis Through a Feed-Forward Mechanism[J]. Gastroenterology vol. 162,1 (2022): 193-208. doi:10.1053/j.gastro.2021.09.010.
Solier S, Zhang YW, Ballestrero A, et al. DNA damage response pathways and cell cycle checkpoints in colorectal cancer: current concepts and future perspectives for targeted treatment[J]. Current cancer drug targets vol. 12,4 (2012): 356-71. doi:10.2174/156800912800190901.
Lu PH, Chen MB, Ji C, et al. Aqueous Oldenlandiadiffusa extracts inhibits colorectal cancer cells via activating AMP-activated protein kinase signalings [J]. Oncotarget vol. 7,29 (2016): 45889-45900. doi:10.18632/oncotarget.9969.
Malki A, ElRuz RA, Gupta I, et al. Molecular Mechanisms of Colon Cancer Progression and Metastasis: Recent Insights and Advancements[J]. International journal of molecular sciences vol. 22,1 130. 24 Dec. 2020, doi:10.3390/ijms22010130.
Ladabaum U, Dominitz JA, Kahi C. Strategies for Colorectal Cancer Screening[J]. Gastroenterology vol. 158,2 (2020): 418-432. doi:10.1053/j.gastro. 2019.06. 043.
Siregar, Gontar Alamsyah, and Henry Sibarani. Comparison of Carcinoembryonic Antigen Levels Among Degree of Differentiation and Colorectal Cancer's Location in Medan[J]. Open access Macedonian journal of medical sciences vol. 7,20 3447-3450. 14 Oct. 2019, doi:10.3889/oamjms.2019. 442.
McKeown E, Nelson DW, Johnson EK, et al. Current approaches and challenges for monitoring treatment response in colon and rectal cancer[J]. Journal of Cancer vol. 5,1 31-43. 1 Jan. 2014, doi:10.7150/jca.7987.
Scherman P, Syk I, Holmberg E, et al. Influence of primary tumour and patient factors on survival in patients undergoing curative resection and treatment for liver metastases from colorectal cancer[J]. BJS open vol. 4,1 (2020): 118-132. doi:10.1002/bjs5.50237.
Li X, Guo D, Chu L, et al. Potential diagnostic value of combining inflammatory cell ratios with carcinoembryonic antigen for colorectal cancer[J]. Cancer Management and Research. 2019; Volume 11: 9631–9640. doi: 10.2147/CMAR.S222756.
He CZ, Zhang KH, Li Q, et al. Combined use of AFP, CEA, CA125 and CAl9-9 improves the sensitivity for the diagnosis of gastric cancer[J]. BMC Gastroenterology. 2013;13(1):p. 87. doi: 10.1186/1471-230X-13-87.
Wu CX, Wang XQ, Chok SH,et al. Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma[J]. Theranosticsvol. 8,14 3737-3750. 13 Jun. 2018, doi:10.7150/thno.25487.
Kvedaraite E, Ginhoux F. Human dendritic cells in cancer. Sci Immunol. 2022;7(70):eabm9409. doi:10.1126/sciimmunol.abm9409.
Huang J, Chen P, Liu K, et al. CDK1/2/5 inhibition overcomes IFNG-mediated adaptive immune resistance in pancreatic cancer[J]. Gut. 2021;70(5):890-899. doi:10.1136/gutjnl-2019-320441
Yuan J, Li X, Zhang G, et al. USP39 mediates p21-dependent proliferation and neoplasia of colon cancer cells by regulating the p53/p21/CDC2/cyclin B1 axis[J]. Mol Carcinog. 2021;60(4):265-278. doi:10.1002/mc.23290.
Wu WJ, Hu KS, Wang DS, et al. CDC20 overexpression predicts a poor prognosis for patients with colorectal cancer[J]. Transl Med. 2013;11:142. Published 2013 Jun 10. doi:10.1186/1479-5876-11-142.
Chigbrow M, Nelson M. Inhibition of mitotic cyclin B and cdc2 kinase activity by selenomethionine in synchronized colon cancer cells[J]. Anticancer Drugs. 2001;12(1):43-50. doi:10.1097/00001813-200101000-00006
Liu KC, Shih TY, Kuo CL, et al. Sulforaphane Induces Cell Death Through G2/M Phase Arrest and Triggers Apoptosis in HCT 116 Human Colon Cancer Cells[J]. Am J Chin Med. 2016;44(6):1289-1310. doi:10.1142/S0192415X16500725.
Zhang R, Xu J, Zhao J, et al.. Proliferation and invasion of colon cancer cells are suppressed by knockdown of TOP2A[J]. Cell Biochem. 2018;119(9):7256-7263. doi:10.1002/jcb.26916.
Zhao H, Ming T, Tang S, et al. Wnt signaling in colorectal cancer: pathogenic role and therapeutic target[J]. Molecular cancer vol. 21,1 144. 14 Jul. 2022, doi:10.1186/s12943-022-01616-7.
Rong Z, Luo Z, Fu Z,et al. The novel circSLC6A6/miR-1265/C2CD4A axis promotes colorectal cancer growth by suppressing p53 signaling pathway[J]. Journal of experimental & clinical cancer research: CR vol. 40,1 324. 16 Oct. 2021, doi:10.1186/s13046-021-02126-y.
Jafari M, Laraqui A, Baba W, et al. Prevalence and patterns of mutations in RAS/RAF/MEK/ERK/MAPK signaling pathway in colorectal cancer in North Africa [J]. BMC cancer vol. 22,1 1142. 7 Nov. 2022, doi:10.1186/s12885-022-10235-w.
Zhu H, Swami U, Preet R et al. Harnessing DNA Replication Stress for Novel Cancer Therapy[J]. Genes vol. 11,9 990. 25 Aug. 2020, doi:10.3390/ genes11090990.
Huang TT, Lampert EJ, Coots C et al. Targeting the PI3K pathway and DNA damage response as a therapeutic strategy in ovarian cancer [J]. Cancer treatment reviews vol. 86 (2020): 102021. doi:10.1016/ j.ctrv.2020.102021.
Feng ZY, Xu XH, Cen DZ, et al. miR-590-3p promotes colon cancer cell proliferation via Wnt/β-catenin signaling pathway by inhibiting WIF1 and DKK1[J]. European review for medical and pharmacological sciences vol. 21,21 (2017): 4844-4852.
Wu K, Zhao Z, Xiao Y, et al. Roles of mitochondrial transcription factor A and microRNA‑590‑3p in the development of colon cancer[J]. Molecular medicine reports vol. 14,6 (2016): 5475-5480. doi:10.3892/ mmr.2016.5955.
Wu H, Zhong W, Zhang R, et al. G-quadruplex-enhanced circular single-stranded DNA (G4-CSSD) adsorption of miRNA to inhibit colon cancer progression[J]. Cancer medicine vol. 12,8 (2023): 9774-9787. doi:10.1002/cam4.5721.
Uhr K, Prager-van der Smissen WJC, Heine AAJ,et al. MicroRNAs as possible indicators of drug sensitivity in breast cancer cell lines[J]. PloS one vol. 14,5 e0216400. 7 May. 2019, doi:10.1371/journal.pone.0216400.
Gao T, Zou M, Shen T, et al. Dysfunction of miR-802 in tumors[J]. Journal of clinical laboratory analysis vol. 35,11 (2021): e23989. doi:10.1002/jcla.23989.
Ge W, Goga A, He Y, et al. miR-802 Suppresses Acinar-to-Ductal Reprogramming During Early Pancreatitis and Pancreatic Carcinogenesis[J]. Gastroenterology vol. 162,1 (2022): 269-284. doi:10.1053/j.gastro.2021.09.029.
Jing X, Xie M, Ding K, et al. Exosome-transmitted miR-769-5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53[J]. Clinical and translational medicine vol. 12,5 (2022): e780. doi:10.1002/ctm2.780.
Luan PB, Jia XZ, Yao J. MiR-769-5p functions as an oncogene by down-regulating RYBP expression in gastric cancer[J]. European review for medical and pharmacological sciences vol. 24,12 (2020): 6699-6706. doi:10.26355/eurrev_202006_21657.
Lee, Daniel. miR-769-5p is associated with prostate cancer recurrence and modulates proliferation and apoptosis of cancer cells[J]. Experimental and therapeutic medicine vol. 21,4 (2021): 335. doi:10.3892/etm.2021.9766.
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Copyright (c) 2024 Dan Liu, Qinlang Liu, Lei Song, Linmei Sun
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