Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Development and Validation of a Prognostic Model based on 11 E3-related Genes for Colon Cancer Patients

Author(s): Wanju JIang, Jiaxing Dong, Wenjia Zhang, Zhiye Huang, Taohua Guo, Kehui Zhang, Xiaohua Jiang* and Tao Du*

Volume 30, Issue 12, 2024

Published on: 15 March, 2024

Page: [935 - 951] Pages: 17

DOI: 10.2174/0113816128292398240306160051

Price: $65

Abstract

Background: Colon cancer is a common tumor in the gastrointestinal tract with a poor prognosis. According to research reports, ubiquitin-dependent modification systems have been found to play a crucial role in the development and advancement of different types of malignant tumors, including colon cancer. However, further investigation is required to fully understand the mechanism of ubiquitination in colon cancer.

Methods: We collected the RNA expression matrix of the E3 ubiquitin ligase-related genes (E3RGs) from the patients with colon adenocarcinoma (COAD) using The Cancer Genome Atlas program (TCGA). The “limma” package was used to obtain differentially expressed E3RGs between COAD and adjacent normal tissues. Then, univariate COX regression and least absolute shrinkage and selection operator (LASSO) analysis were performed to construct the prognostic signature and nomogram model. Afterward, we used the original copy number variation data of COAD to find potential somatic mutation and employed the “pRRophetic” package to investigate the disparity in the effectiveness of chemotherapy drugs between high and low-risk groups. The RT-qPCR was also implied to detect mRNA expression levels in tumor tissues.

Results: A total of 137 differentially expressed E3RG3 were screened and 11 genes (CORO2B, KCTD9, RNF32, BACH2, RBCK1, DPH7, WDR78, UCHL1, TRIM58, WDR72, and ZBTB18) were identified for the construction of prognostic signatures. The Kaplan-Meier curve showed a worse prognosis for patients with high risk both in the training and test cohorts (P = 1.037e-05, P = 5.704e-03), and the area under the curve (AUC) was 0.728 and 0.892 in the training and test cohorts, respectively. Based on the stratified analysis, this 11- E3RGs signature was a novel and attractive prognostic model independent of several clinicopathological parameters (age, sex, stage, TNM) in COAD. The DEGs were subjected to GO and KEGG analysis, which identified pathways associated with cancer progression. These pathways included the cAMP signaling pathway, calcium signaling pathway, Wnt signaling pathway, signaling pathways regulating stem cell pluripotency, and proteoglycans in cancer. Additionally, immune infiltration analysis revealed significant differences in the infiltration of macrophages M0, T cells follicular helper, and plasma cells between the two groups.

Conclusion: We developed a novel independent risk model consisting of 11 E3RGs and verified the effectiveness of this model in test cohorts, providing important insights into survival prediction in COAD and several promising targets for COAD therapy.

« Previous Next »
[1]
Hall AE, Pohl SÖG, Cammareri P, et al. RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer. Nat Commun 2022; 13(1): 2791.
[http://dx.doi.org/10.1038/s41467-022-30489-z] [PMID: 35589755]
[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]
Karimi F, Karimi-Maleh H, Rouhi J, et al. Revolutionizing cancer monitoring with carbon-based electrochemical biosensors. Environ Res 2023; 239(Pt 2): 117368.
[http://dx.doi.org/10.1016/j.envres.2023.117368] [PMID: 37827366]
[4]
Tao C, Rouhi J. A biosensor based on graphene oxide nanocomposite for determination of carcinoembryonic antigen in colorectal cancer biomarker. Environ Res 2023; 238(Pt 1): 117113.
[http://dx.doi.org/10.1016/j.envres.2023.117113] [PMID: 37696325]
[5]
Liu X, Zhang H, Lai L, et al. Ribonucleotide reductase small subunit M2 serves as a prognostic biomarker and predicts poor survival of colorectal cancers. Clin Sci 2013; 124(9): 567-79.
[http://dx.doi.org/10.1042/CS20120240] [PMID: 23113760]
[6]
Poturnajova M, Furielova T, Balintova S, Schmidtova S, Kucerova L, Matuskova M. Molecular features and gene expression signature of metastatic colorectal cancer (Review). Oncol Rep 2021; 45(4): 10.
[http://dx.doi.org/10.3892/or.2021.7961] [PMID: 33649827]
[7]
Höpfner D, Fauser J, Kaspers MS, Pett C, Hedberg C, Itzen A. Monoclonal Anti-AMP antibodies are sensitive and valuable tools for detecting patterns of AMPylation. iScience 2020; 23(12): 101800.
[http://dx.doi.org/10.1016/j.isci.2020.101800] [PMID: 33299971]
[8]
Wu M, Lu P, Yang Y, et al. LipoSVM: Prediction of lysine lipoylation in proteins based on the support vector machine. Curr Genomics 2019; 20(5): 362-70.
[http://dx.doi.org/10.2174/1389202919666191014092843] [PMID: 32476993]
[9]
Huang H, Zhang X, Li S, et al. Physiological levels of ATP negatively regulate proteasome function. Cell Res 2010; 20(12): 1372-85.
[http://dx.doi.org/10.1038/cr.2010.123] [PMID: 20805844]
[10]
Reyes-Turcu FE, Ventii KH, Wilkinson KD. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 2009; 78(1): 363-97.
[http://dx.doi.org/10.1146/annurev.biochem.78.082307.091526] [PMID: 19489724]
[11]
Stewart MD, Ritterhoff T, Klevit RE, Brzovic PS. E2 enzymes: More than just middle men. Cell Res 2016; 26(4): 423-40.
[http://dx.doi.org/10.1038/cr.2016.35] [PMID: 27002219]
[12]
Ye Y, Rape M. Building ubiquitin chains: E2 enzymes at work. Nat Rev Mol Cell Biol 2009; 10(11): 755-64.
[http://dx.doi.org/10.1038/nrm2780] [PMID: 19851334]
[13]
Shembade N, Harhaj EW. Regulation of NF-κB signaling by the A20 deubiquitinase. Cell Mol Immunol 2012; 9(2): 123-30.
[http://dx.doi.org/10.1038/cmi.2011.59] [PMID: 22343828]
[14]
Rossi M, Duan S, Jeong Y-T, Horn M, et al. Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase. Mol Cell 2013; 49(6): 1159-66.
[http://dx.doi.org/10.1016/j.molcel.2013.02.004]
[15]
Kleiger G, Mayor T. Perilous journey: A tour of the ubiquitin-proteasome system. Trends Cell Biol 2014; 24(6): 352-9.
[http://dx.doi.org/10.1016/j.tcb.2013.12.003] [PMID: 24457024]
[16]
Xiao Y, Liu R, Li N, Li Y, Huang X. Role of the ubiquitin-proteasome system on macrophages in the tumor microenvironment. J Cell Physiol 2024; 239(2): e31180.
[http://dx.doi.org/10.1002/jcp.31180] [PMID: 38219045]
[17]
Li W, Bengtson MH, Ulbrich A, et al. Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling. PLoS One 2008; 3(1): e1487.
[http://dx.doi.org/10.1371/journal.pone.0001487] [PMID: 18213395]
[18]
Arpalahti L, Haglund C, Holmberg CI. Proteostasis dysregulation in pancreatic cancer. Adv Exp Med Biol 2020; 1233: 101-15.
[http://dx.doi.org/10.1007/978-3-030-38266-7_4] [PMID: 32274754]
[19]
Cao Y, Zhou H, Chen X, et al. Recent insight into the role of RING-finger E3 ligases in glioma. Biochem Soc Trans 2021; 49(1): 519-29.
[http://dx.doi.org/10.1042/BST20201060] [PMID: 33544148]
[20]
Zhou Z, Zheng K, Zhou S, Yang Y, Chen J, Jin X. E3 ubiquitin ligases in nasopharyngeal carcinoma and implications for therapies. J Mol Med 2023; 101(12): 1543-65.
[http://dx.doi.org/10.1007/s00109-023-02376-7] [PMID: 37796337]
[21]
Tian B, Zhou J, Chen G, Jiang T, Li Q, Qin J. Downregulation of ZNF280A inhibits proliferation and tumorigenicity of colorectal cancer cells by promoting the ubiquitination and degradation of RPS14. Front Oncol 2022; 12: 906281.
[http://dx.doi.org/10.3389/fonc.2022.906281] [PMID: 36059657]
[22]
Zheng Y, Zhao Y, Jiang J, Zou B, Dong L. Transmembrane protein 100 inhibits the progression of colorectal cancer by promoting the ubiquitin/proteasome degradation of HIF-1α. Front Oncol 2022; 12: 899385.
[http://dx.doi.org/10.3389/fonc.2022.899385] [PMID: 35928881]
[23]
Schatoff EM, Leach BI, Dow LE. WNT signaling and colorectal cancer. Curr Colorectal Cancer Rep 2017; 13(2): 101-10.
[http://dx.doi.org/10.1007/s11888-017-0354-9] [PMID: 28413363]
[24]
Siraj AK, Bu R, Masoodi T, et al. Exome sequencing revealed comparable frequencies of RNF43 and BRAF mutations in Middle Eastern colorectal cancer. Sci Rep 2022; 12(1): 13098.
[http://dx.doi.org/10.1038/s41598-022-17449-9] [PMID: 35907983]
[25]
Guo Y, Zhou Y, Gu X, Xiang J. Tripartite motif 52 (TRIM52) promotes proliferation, migration, and regulation of colon cancer cells associated with the NF-κB signaling pathway. J Gastrointest Oncol 2022; 13(3): 1097-111.
[http://dx.doi.org/10.21037/jgo-22-317] [PMID: 35837156]
[26]
Zhuang Y, Liu P, Zhan Y, Kong D, Tian F, Zhao P. RING finger protein 128 (RNF128) regulates malignant biological behaviors of colorectal cancer cells via PI3K/AKT signaling pathway. Cell Biol Int 2022; 46(10): 1604-11.
[http://dx.doi.org/10.1002/cbin.11835] [PMID: 35723244]
[27]
Jiang T, Wang H, Liu L, et al. CircIL4R activates the PI3K/AKT signaling pathway via the miR-761/TRIM29/PHLPP1 axis and promotes proliferation and metastasis in colorectal cancer. Mol Cancer 2021; 20(1): 167.
[http://dx.doi.org/10.1186/s12943-021-01474-9] [PMID: 34922544]
[28]
Motakis E, Ivshina A, Kuznetsov V. Data-driven approach to predict survival of cancer patients. IEEE Eng Med Biol Mag 2009; 28(4): 58-66.
[http://dx.doi.org/10.1109/MEMB.2009.932937] [PMID: 19622426]
[29]
Niederer D, Schiller J, Groneberg DA, Behringer M, Wolfarth B, Gabrys L. Machine learning-based identification of determinants for rehabilitation success and future healthcare use prevention in patients with high-grade, chronic, nonspecific low back pain: An individual data 7-year follow-up analysis on 154,167 individuals. Pain 2022; pp. 10-97.
[http://dx.doi.org/10.1097/j.pain.0000000000003087] [PMID: 37856652]
[30]
Ding W, Ling Y, Shi Y, Zheng Z, Des A. DesA prognostic risk model of LncRNAs in patients with acute myeloid leukaemia based on TCGA data. Front Bioeng Biotechnol 2022; 10: 818905.
[http://dx.doi.org/10.3389/fbioe.2022.818905] [PMID: 35265597]
[31]
Du H, Li Y, Pang S, et al. Development and validation of a prognostic model based on RNA binding proteins in patients with esophageal cancer. J Thorac Dis 2023; 15(11): 6178-91.
[http://dx.doi.org/10.21037/jtd-23-1307] [PMID: 38090289]
[32]
Zhou L, Jiang Y, Liu X, et al. Promotion of tumor-associated macrophages infiltration by elevated neddylation pathway via NF-κB-CCL2 signaling in lung cancer. Oncogene 2019; 38(29): 5792-804.
[http://dx.doi.org/10.1038/s41388-019-0840-4] [PMID: 31243299]
[33]
Petroski MD, Deshaies RJ. Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 2005; 6(1): 9-20.
[http://dx.doi.org/10.1038/nrm1547] [PMID: 15688063]
[34]
Zhou L, Zhang W, Sun Y, Jia L. Protein neddylation and its alterations in human cancers for targeted therapy. Cell Signal 2018; 44: 92-102.
[http://dx.doi.org/10.1016/j.cellsig.2018.01.009] [PMID: 29331584]
[35]
Wu H, Lu XX, Wang JR, et al. TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/β- catenin degradation and is targeted for GSK3B/GSK3β-mediated phosphorylation and degradation. Autophagy 2019; 15(9): 1506-22.
[http://dx.doi.org/10.1080/15548627.2019.1586250] [PMID: 30806153]
[36]
Liang Q, Tang C, Tang M, Zhang Q, Gao Y, Ge Z. TRIM47 is up- regulated in colorectal cancer, promoting ubiquitination and degradation of SMAD4. J Exp Clin Cancer Res 2019; 38(1): 159.
[http://dx.doi.org/10.1186/s13046-019-1143-x] [PMID: 30979374]
[37]
Liu L, Zhang Y, Wong CC, et al. RNF6 promotes colorectal cancer by activating the Wnt/β-Catenin pathway via ubiquitination of TLE3. Cancer Res 2018; 78(8): 1958-71.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-2683] [PMID: 29374067]
[38]
Yao H, Ren D, Wang Y, et al. KCTD9 inhibits the Wnt/β-catenin pathway by decreasing the level of β-catenin in colorectal cancer. Cell Death Dis 2022; 13(9): 761.
[http://dx.doi.org/10.1038/s41419-022-05200-1] [PMID: 36055981]
[39]
Liu ML, Zang F, Zhang SJ. RBCK1 contributes to chemoresistance and stemness in colorectal cancer (CRC). Biomed Pharmacother 2019; 118: 109250.
[http://dx.doi.org/10.1016/j.biopha.2019.109250] [PMID: 31545242]
[40]
Merlos-Suárez A, Barriga FM, Jung P, et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 2011; 8(5): 511-24.
[http://dx.doi.org/10.1016/j.stem.2011.02.020] [PMID: 21419747]
[41]
Zhong J, Zhao M, Ma Y, et al. UCHL1 acts as a colorectal cancer oncogene via activation of the β-catenin/TCF pathway through its deubiquitinating activity. Int J Mol Med 2012; 30(2): 430-6.
[http://dx.doi.org/10.3892/ijmm.2012.1012] [PMID: 22641175]
[42]
Liu M, Zhang X, Cai J, et al. Downregulation of TRIM58 expression is associated with a poor patient outcome and enhances colorectal cancer cell invasion. Oncol Rep 2018; 40(3): 1251-60.
[http://dx.doi.org/10.3892/or.2018.6525] [PMID: 29956813]
[43]
Kawabata H, Azuma K, Ikeda K, et al. TRIM44 is a poor prognostic factor for breast cancer patients as a modulator of NF-κB signaling. Int J Mol Sci 2017; 18(9): 1931.
[http://dx.doi.org/10.3390/ijms18091931] [PMID: 28885545]
[44]
Yang J, Kim H, Shin K, et al. Molecular insights into the development of hepatic metastases in colorectal cancer: A metastasis prediction study. Eur Rev Med Pharmacol Sci 2020; 24(24): 12701-8.
[http://dx.doi.org/10.26355/eurrev_202012_24168] [PMID: 33378017]
[45]
Wang J, Yu X, Ouyang N, et al. MicroRNA and mRNA interaction network regulates the malignant transformation of human bronchial epithelial cells induced by cigarette smoke. Front Oncol 2019; 9: 1029.
[http://dx.doi.org/10.3389/fonc.2019.01029] [PMID: 31649886]
[46]
Grant FM, Yang J, Nasrallah R, et al. BACH2 drives quiescence and maintenance of resting Treg cells to promote homeostasis and cancer immunosuppression. J Exp Med 2020; 217(9): e20190711.
[http://dx.doi.org/10.1084/jem.20190711] [PMID: 32515782]
[47]
Hoshino H, Kobayashi A, Yoshida M, et al. Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element. J Biol Chem 2000; 275(20): 15370-6.
[http://dx.doi.org/10.1074/jbc.275.20.15370] [PMID: 10809773]
[48]
Mares J, Szakacsova M, Soukup V, Duskova J, Horinek A, Babjuk M. Prediction of recurrence in low and intermediate risk non- muscle invasive bladder cancer by real-time quantitative PCR analysis: cDNA microarray results. Neoplasma 2013; 60(3): 295-301.
[http://dx.doi.org/10.4149/neo_2013_0391] [PMID: 23452234]
[49]
Okado H. Regulation of brain development and brain function by the transcriptional repressor RP58. Brain Res 2019; 1705: 15-23.
[http://dx.doi.org/10.1016/j.brainres.2018.02.042] [PMID: 29501651]
[50]
Xiang C, Baubet V, Pal S, et al. RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion. Cell Death Differ 2012; 19(4): 692-702.
[http://dx.doi.org/10.1038/cdd.2011.144] [PMID: 22095278]
[51]
Wang J, Che J. CircTP63 promotes hepatocellular carcinoma progression by sponging miR-155-5p and upregulating ZBTB18. Cancer Cell Int 2021; 21(1): 156.
[http://dx.doi.org/10.1186/s12935-021-01753-x] [PMID: 33685441]
[52]
Ben-Neriah Y, Karin M. Inflammation meets cancer, with NF-κB as the matchmaker. Nat Immunol 2011; 12(8): 715-23.
[http://dx.doi.org/10.1038/ni.2060] [PMID: 21772280]
[53]
Di Rosa M, Tibullo D, Cambria D, et al. Chitotriosidase expression during monocyte-derived dendritic cells differentiation and maturation. Inflammation 2015; 38(6): 2082-91.
[http://dx.doi.org/10.1007/s10753-015-0190-5] [PMID: 26026464]
[54]
Malaguarnera L, Imbesi R, Di Rosa M, et al. Action of prolactin, IFN-γ, TNF-α and LPS on heme oxygenase-1 expression and VEGF release in human monocytes/macrophages. Int Immunopharmacol 2005; 5(9): 1458-69.
[http://dx.doi.org/10.1016/j.intimp.2005.04.002] [PMID: 15953572]
[55]
Sica A, Mantovani A. Macrophage plasticity and polarization: In vivo veritas. J Clin Invest 2012; 122(3): 787-95.
[http://dx.doi.org/10.1172/JCI59643] [PMID: 22378047]
[56]
Chen X, Wang Y, Qu X, Bie F, Wang Y, Du J. TRIM58 is a prognostic biomarker remodeling the tumor microenvironment in KRAS-driven lung adenocarcinoma. Future Oncol 2021; 17(5): 565-79.
[http://dx.doi.org/10.2217/fon-2020-0645] [PMID: 33406903]
[57]
Xu W, Tao J, Zhu W, et al. Comprehensive multi-omics identification of interferon-γ response characteristics reveals that RBCK1 regulates the immunosuppressive microenvironment of renal cell carcinoma. Front Immunol 2021; 12: 734646.
[http://dx.doi.org/10.3389/fimmu.2021.734646] [PMID: 34795663]
[58]
Kaler P, Godasi BN, Augenlicht L, Klampfer L. The NF-κB/AKT-dependent induction of wnt signaling in colon cancer cells by macrophages and IL-1β. Cancer Microenviron 2009; 2(1): 69-80.
[http://dx.doi.org/10.1007/s12307-009-0030-y] [PMID: 19779850]

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