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image of Unveiling the Power of Mitochondrial Fission and Fusion: A Five-Gene Signature for Personalized Prognosis in Gastric Cancer

Abstract

Background

Mitochondrial fission and fusion play important roles in tumorigenesis, progression and therapy. Dysregulation of these processes may lead to tumor progression, and regulation of these processes may provide novel strategies for cancer therapy. The involvement of genes related to mitochondrial fission and fusion (MD) in gastric cancer (GC) remains poorly understood.

Objective

The aim of this study was to establish an MD gene signature for GC patients and to investigate its association with prognosis, tumor microenvironment and treatment response in GC.

Methods

We use the TCGA-GC database as the cohort, focusing specifically on genes associated with MD. We conducted identification and consistency clustering analysis of differentially expressed genes in MD, conducted MD gene mutation and copy number variation analysis, as well as correlation and functional enrichment analysis between MD gene cluster classification and immune infiltration. TCGA-GC and GSE15459 were used to construct training and validation cohorts for the model. We used various statistical methods, including Cox and Lasso regression, to develop the model. We validated the model using bulk transcriptome and single-cell transcriptome datasets (GSE13861, GSE26901, GSE66229, and GSE13450). We used GSEA enrichment, CIBERSORT algorithm, ESTIMATE, and TIDE to gain insight into the annotation of MD signature and the characterization of the tumor microenvironment. OncoPredict was used to analyze the relationship between the PRG signature and the drug sensitivity. We validated the expression of several key genes in MD signature on GC cell lines using quantitative real-time PCR (qRT-PCR).

Results

These MDs-related subtypes exhibited different prognosis and immune filtration patterns. A five-gene signature, comprising AGT, HCFC1, KIFC3, NOX4, and RIN1, was developed. There was a clear distinction in overall survival between low- and high-risk patients. The analyses showed further confirmation of the independent prognostic value of the gene signature. There was a notable correlation between the MD signature, immune infiltration and drug susceptibility. The expression levels of AGT, HCFC1, KIFC3, NOX4 and RIN1 mRNA were all increased in these GC cells.

Conclusion

The MD signature has the capacity to significantly contribute to the prediction of personalized outcomes and the advancement of novel therapeutic strategies tailored for GC patients.

© 2024 Bentham Science Publishers
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2024-10-08
2024-11-26

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References

  1. Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021 71 3 209 249 10.3322/caac.21660 33538338
    [Google Scholar]
  2. Jemal A. Bray F. Center M.M. Ferlay J. Ward E. Forman D. Global cancer statistics. CA Cancer J. Clin. 2011 61 2 69 90 10.3322/caac.20107 21296855
    [Google Scholar]
  3. Kolozsi P. Varga Z. Toth D. Indications and technical aspects of proximal gastrectomy. Front. Surg. 2023 10 1115139 10.3389/fsurg.2023.1115139 36874448
    [Google Scholar]
  4. Yoon J. Kim T.Y. Oh D.Y. Recent progress in immunotherapy for gastric cancer. J. Gastric Cancer 2023 23 1 207 223 10.5230/jgc.2023.23.e10 36751000
    [Google Scholar]
  5. Musicco C. Signorile A. Pesce V. Loguercio Polosa P. Cormio A. Mitochondria deregulations in cancer offer several potential targets of therapeutic interventions. Int. J. Mol. Sci. 2023 24 13 10420 10.3390/ijms241310420 37445598
    [Google Scholar]
  6. Cheng J. Sha Z. Zhang R. Ge J. Chen P. Kuang X. Chang J. Ren K. Luo X. Chen S. Gou X. L22 ribosomal protein is involved in dynamin-related protein 1-mediated gastric carcinoma progression. Bioengineered 2022 13 3 6650 6664 10.1080/21655979.2022.2045842 35230214
    [Google Scholar]
  7. Evans J.A. Carlotti E. Lin M.L. Hackett R.J. Haughey M.J. Passman A.M. Dunn L. Elia G. Porter R.J. McLean M.H. Hughes F. ChinAleong J. Woodland P. Preston S.L. Griffin S.M. Lovat L. Rodriguez-Justo M. Huang W. Wright N.A. Jansen M. McDonald S.A.C. Clonal transitions and phenotypic evolution in Barrett’s Esophagus. Gastroenterology 2022 162 4 1197 1209.e13 10.1053/j.gastro.2021.12.271 34973296
    [Google Scholar]
  8. Cormio A. Musicco C. Gasparre G. Cormio G. Pesce V. Sardanelli A.M. Gadaleta M.N. Increase in proteins involved in mitochondrial fission, mitophagy, proteolysis and antioxidant response in type I endometrial cancer as an adaptive response to respiratory complex I deficiency. Biochem. Biophys. Res. Commun. 2017 491 1 85 90 10.1016/j.bbrc.2017.07.047 28698145
    [Google Scholar]
  9. Courtois S. de Luxán-Delgado B. Penin-Peyta L. Royo-García A. Parejo-Alonso B. Jagust P. Alcalá S. Rubiolo J.A. Sánchez L. Sainz B. Jr Heeschen C. Sancho P. Inhibition of mitochondrial dynamics preferentially targets pancreatic cancer cells with enhanced tumorigenic and invasive potential. Cancers (Basel) 2021 13 4 698 10.3390/cancers13040698 33572276
    [Google Scholar]
  10. Zhang L. Sun L. Wang L. Wang J. Wang D. Jiang J. Zhang J. Zhou Q. Mitochondrial division inhibitor (mdivi-1) inhibits proliferation and epithelial-mesenchymal transition via the NF-κB pathway in thyroid cancer cells. Toxicol. In Vitro 2023 88 105552 10.1016/j.tiv.2023.105552 36621616
    [Google Scholar]
  11. Fu Y. Dong W. Xu Y. Li L. Yu X. Pang Y. Chan L. Deng Y. Qian C. Targeting mitochondrial dynamics by AZD5363 in triple-negative breast cancer MDA-MB-231 cell–derived spheres. Naunyn Schmiedebergs Arch. Pharmacol. 2023 396 10 2545 2553 10.1007/s00210‑023‑02477‑7 37093249
    [Google Scholar]
  12. Zhou A. Zhang D. Kang X. Brooks J.D. Identification of age‐ and immune‐related gene signatures for clinical outcome prediction in lung adenocarcinoma. Cancer Med. 2023 12 16 17475 17490 10.1002/cam4.6330 37434467
    [Google Scholar]
  13. Zhai X. Chen B. Hu H. Deng Y. Chen Y. Hong Y. Ren X. Jiang C. Identification of the molecular subtypes and signatures to predict the prognosis, biological functions, and therapeutic response based on the anoikis‐related genes in colorectal cancer. Cancer Med. 2024 13 10 e7315 10.1002/cam4.7315 38785271
    [Google Scholar]
  14. Li Z. Jin Y. Que T. Zhang X.A. Yi G. Zheng H. Yuan X. Wang X. Xu H. Nan J. Chen C. Wu Y. Huang G. Identification of necroptosis-related molecular subtypes and construction of necroptosis-related gene signature for glioblastoma multiforme. Curr. Med. Chem. 2023 31 33 5417 5431 37539935
    [Google Scholar]
  15. Yu Y. Li J. Li J. Zen X. Fu Q. Evidence from machine learning, diagnostic hub genes in sepsis and diagnostic models based on xgboost models, novel molecular models for the diagnosis of sepsis. Curr. Med. Chem. 2023 2023 7061448 37921181
    [Google Scholar]
  16. Zhang X. Jin L. Zhou C. Liu J. Jiang Q. Significance of aneuploidy in predicting prognosis and treatment response of uveal melanoma. Curr. Med. Chem. 2024 2024 38504568 38504568
    [Google Scholar]
  17. Ma Y. Li Z. Li D. Zheng B. Xue Y. G0 arrest gene patterns to predict the prognosis and drug sensitivity of patients with lung adenocarcinoma. PLoS One 2024 19 8 e0309076 10.1371/journal.pone.0309076 39159158
    [Google Scholar]
  18. Li N. Yu K. Huang D. Zhou H. Zeng D. Identifying a Novel Eight-NK Cell-related Gene Signature for Ovarian Cancer Prognosis Prediction. Curr. Med. Chem. 2024 31 12 1578 1594 10.2174/0929867331666230831101847 37650393
    [Google Scholar]
  19. Chang J. Wu H. Wu J. Liu M. Zhang W. Hu Y. Zhang X. Xu J. Li L. Yu P. Zhu J. Constructing a novel mitochondrial-related gene signature for evaluating the tumor immune microenvironment and predicting survival in stomach adenocarcinoma. J. Transl. Med. 2023 21 1 191 10.1186/s12967‑023‑04033‑6 36915111
    [Google Scholar]
  20. Yang J. Jin F. Li H. Shen Y. Shi W. Wang L. Zhong L. Wu G. Wu Q. Li Y. Identification of mitochondrial respiratory chain signature for predicting prognosis and immunotherapy response in stomach adenocarcinoma. Cancer Cell Int. 2023 23 1 69 10.1186/s12935‑023‑02913‑x 37062830
    [Google Scholar]
  21. Xiang P. Li F. Ma Z. Yue J. Lu C. You Y. Hou L. Yin B. Qiang B. Shu P. Peng X. HCF-1 promotes cell cycle progression by regulating the expression of CDC42. Cell Death Dis. 2020 11 10 907 10.1038/s41419‑020‑03094‑5 33097698
    [Google Scholar]
  22. Antonova A. Hummel B. Khavaran A. Redhaber D.M. Aprile-Garcia F. Rawat P. Gundel K. Schneck M. Hansen E.C. Mitschke J. Mittler G. Miething C. Sawarkar R. Heat-shock protein 90 controls the expression of cell-cycle genes by stabilizing metazoan-specific host-cell factor HCFC1. Cell Reports 2019 11 6 1645 1659.e9
    [Google Scholar]
  23. Du S. Zeng F. Sun H. Liu Y. Han P. Zhang B. Xue W. Deng G. Yin M. Cui B. Prognostic and therapeutic significance of a novel ferroptosis related signature in colorectal cancer patients. Bioengineered 2022 13 2 2498 2512 10.1080/21655979.2021.2017627 35067161
    [Google Scholar]
  24. Hancock M.L. Meyer R.C. Mistry M. Khetani R.S. Wagschal A. Shin T. Ho Sui S.J. Näär A.M. Flanagan J.G. Insulin receptor associates with promoters genome-wide and regulates gene expression. Cell 2019 177 3 722 736.e22 10.1016/j.cell.2019.02.030 30955890
    [Google Scholar]
  25. Zhu X. Yuan Z. Cheng S. Wang H. Liao Y. Zhou D. Wu Z. TIMM8A is associated with dysfunction of immune cell in BRCA and UCEC for predicting anti-PD-L1 therapy efficacy. World J. Surg. Oncol. 2022 20 1 336 10.1186/s12957‑022‑02736‑6 36207751
    [Google Scholar]
  26. Teng F. Zhang J.X. Chen Y. Shen X.D. Su C. Guo Y.J. Wang P.H. Shi C. Lei M. Cao Y.O. Liu S.Q. LncRNA NKX2‐1‐AS1 promotes tumor progression and angiogenesis via upregulation of SERPINE1 expression and activation of the VEGFR‐2 signaling pathway in gastric cancer. Mol. Oncol. 2021 15 4 1234 1255 10.1002/1878‑0261.12911 33512745
    [Google Scholar]
  27. Li L. Zhu Z. Zhao Y. Zhang Q. Wu X. Miao B. Cao J. Fei S. FN1, SPARC, and SERPINE1 are highly expressed and significantly related to a poor prognosis of gastric adenocarcinoma revealed by microarray and bioinformatics. Sci. Rep. 2019 9 1 7827 10.1038/s41598‑019‑43924‑x 31127138
    [Google Scholar]
  28. Liao J. Peng B. Huang G. Diao C. Qin Y. Hong Y. Lin J. Lin Y. Jiang L. Tang N. Tang F. Liang J. Zhang J. Yan Y. Chen Q. Zhou Z. Shen C. Huang W. Huang K. Lan Q. Cui L. Zhong H. Xu F. Li M. Wei Y. Lu P. Zhang M. Inhibition of NOX4 with GLX351322 alleviates acute ocular hypertension-induced retinal inflammation and injury by suppressing ROS mediated redox-sensitive factors activation. Biomed Pharmacother. 2023 165 115052
    [Google Scholar]
  29. Espinosa-Sotelo R. Fusté N.P. Peñuelas-Haro I. Alay A. Pons G. Almodóvar X. Albaladejo J. Sánchez-Vera I. Bonilla-Amadeo R. Dituri F. Serino G. Ramos E. Serrano T. Calvo M. Martínez-Chantar M.L. Giannelli G. Bertran E. Fabregat I. Dissecting the role of the NADPH oxidase NOX4 in TGF-beta signaling in hepatocellular carcinoma. Redox Biol. 2023 65 102818 10.1016/j.redox.2023.102818 37463530
    [Google Scholar]
  30. Liu W.J. Wang L. Zhou F.M. Liu S.W. Wang W. Zhao E.J. Yao Q.J. Li W. Zhao Y.Q. Shi Z. Qiu J.G. Jiang B.H. Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC. Drug Resist. Updat. 2023 70 100987
    [Google Scholar]
  31. Garbarino O. Lambroia L. Basso G. Marrella V. Franceschini B. Soldani C. Pasqualini F. Giuliano D. Costa G. Peano C. Barbarossa D. Annarita D. Salvati A. Terracciano L. Torzilli G. Donadon M. Faggioli F. Spatial resolution of cellular senescence dynamics in human colorectal liver metastasis. Aging Cell 2023 22 7 e13853 10.1111/acel.13853 37157887
    [Google Scholar]
  32. Ting P.Y. Johnson C.W. Fang C. Cao X. Graeber T.G. Mattos C. Colicelli J. Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding. FASEB J. 2015 29 9 3750 3761 10.1096/fj.15‑271510 25999467
    [Google Scholar]
  33. Qiu Y. Wang Y. Chai Z. Ni D. Li X. Pu J. Chen J. Zhang J. Lu S. Lv C. Ji M. Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators. Acta Pharm. Sin. B 2021 11 11 3433 3446 10.1016/j.apsb.2021.02.014 34900528
    [Google Scholar]
  34. Wang Y. Zhang J. Zheng C.C. Huang Z.J. Zhang W.X. Long Y.L. Gao G.B. Sun Y. Xu W.W. Li B. He Q.Y. C20orf24 promotes colorectal cancer progression by recruiting Rin1 to activate Rab5‐mediated mitogen‑activated protein kinase/extracellular signal‐regulated kinase signalling. Clin. Transl. Med. 2022 12 4 e796 10.1002/ctm2.796 35389560
    [Google Scholar]
  35. Shimasaki N. Jain A. Campana D. NK cells for cancer immunotherapy. Nat. Rev. Drug Discov. 2020 19 3 200 218 10.1038/s41573‑019‑0052‑1 31907401
    [Google Scholar]
  36. Guo F. Zhang Y. Bai L. Cui J. Natural killer cell therapy targeting cancer stem cells: Old wine in a new bottle. Cancer Lett. 2023 570 216328 10.1016/j.canlet.2023.216328 37499742
    [Google Scholar]
  37. Xie G. Dong H. Liang Y. Ham J.D. Rizwan R. Chen J. CAR-NK cells: A promising cellular immunotherapy for cancer. EBioMedicine 2020 59 102975 10.1016/j.ebiom.2020.102975 32853984
    [Google Scholar]
  38. Wen M. Li Y. Qin X. Qin B. Wang Q. Insight into Cancer Immunity: MHCs, Immune Cells and Commensal Microbiota. Cells 2023 12 14 1882 10.3390/cells12141882 37508545
    [Google Scholar]
  39. Gutiérrez-Melo N. Baumjohann D. T follicular helper cells in cancer. Trends Cancer 2023 9 4 309 325 10.1016/j.trecan.2022.12.007 36642575
    [Google Scholar]
  40. Mintz M.A. Cyster J.G. T follicular helper cells in germinal center B cell selection and lymphomagenesis. Immunol. Rev. 2020 296 1 48 61 10.1111/imr.12860 32412663
    [Google Scholar]
  41. Komi D.E.A. Redegeld F.A. Role of mast cells in shaping the tumor microenvironment. Clin. Rev. Allergy Immunol. 2020 58 3 313 325 10.1007/s12016‑019‑08753‑w 31256327
    [Google Scholar]
  42. Derakhshani A. Vahidian F. Alihasanzadeh M. Mokhtarzadeh A. Lotfi Nezhad P. Baradaran B. Mast cells: A double-edged sword in cancer. Immunol. Lett. 2019 209 28 35 10.1016/j.imlet.2019.03.011 30905824
    [Google Scholar]
  43. Lichterman J.N. Reddy S.M. Mast cells: A new frontier for cancer immunotherapy. Cells 2021 10 6 1270 10.3390/cells10061270 34063789
    [Google Scholar]
  44. Franceschi S. Corsinovi D. Lessi F. Tantillo E. Aretini P. Menicagli M. Scopelliti C. Civita P. Pasqualetti F. Naccarato A.G. Ori M. Mazzanti C.M. Mitochondrial enzyme GLUD2 plays a critical role in glioblastoma progression. EBioMedicine 2018 37 56 67 10.1016/j.ebiom.2018.10.008 30314897
    [Google Scholar]
  45. Gao S.C. Wu M.D. Zhang X.X. Liu Y.F. Wang C.L. Identification of prognostic melatonin-related lncRNA signature in tumor immune microenvironment and drug resistance for breast cancer. Asian J. Surg. 2023 46 9 3529 3541 10.1016/j.asjsur.2023.05.174 37330302
    [Google Scholar]
  46. Wenzel U. Herzog A. Kuntz S. Daniel H. Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. Proteomics 2004 4 7 2160 2174 10.1002/pmic.200300726 15221776
    [Google Scholar]
  47. Tang S.M. Deng X.T. Zhou J. Li Q.P. Ge X.X. Miao L. Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects. Biomed Pharmacother. 2020 121 109604
    [Google Scholar]
  48. Deepika Maurya P.K. Health benefits of quercetin in age-related diseases. Molecules 2022 27 8 2498 10.3390/molecules27082498 35458696
    [Google Scholar]
  49. Röcken C. Predictive biomarkers in gastric cancer. J. Cancer Res. Clin. Oncol. 2023 149 1 467 481 10.1007/s00432‑022‑04408‑0 36260159
    [Google Scholar]
  50. Ji J. Wang Z. Sun W. Li Z. Cai H. Zhao E. Cui H. Effects of cynaroside on cell proliferation, apoptosis, migration and invasion though the MET/AKT/mTOR axis in gastric cancer. Int. J. Mol. Sci. 2021 22 22 12125 10.3390/ijms222212125 34830011
    [Google Scholar]
  51. Jørgensen J.T. Mollerup J. Companion diagnostics and predictive biomarkers for MET-targeted therapy in NSCLC. Cancers (Basel) 2022 14 9 2150 10.3390/cancers14092150 35565287
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673339515240930053412
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Unveiling the Power of Mitochondrial Fission and Fusion: A Five-Gene Signature for Personalized Prognosis in Gastric Cancer
Bentham Science Publishers ; https://doi.org/10.2174/0109298673339515240930053412
/content/journals/cmc/10.2174/0109298673339515240930053412
/content/journals/cmc/10.2174/0109298673339515240930053412
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  • Article Type:     Research Article
Keywords: signature ; mitochondrial fission and fusion ; drug sensitivity ; prognosis ; tumor microenvironment ; Gastric cancer

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