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2000
Volume 32, Issue 40
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X
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Abstract

Introduction

Copine-3 (CPNE3) is a conservative calcium-dependent phospholipid-binding protein belonging to the copines protein family. CPNE3 has been implicated in the development and progression of several diseases, including cancer.

Methods

Herein, we investigated the molecular mechanisms through which CPNE3 regulates the migration of lung adenocarcinoma (LUAD) cells . Western blotting and immunohistochemical assays showed that CPNE3 is widely distributed in LUAD tissues and cell lines and that CPNE3 downregulation promotes the migration of human LUAD A549 cells.

Results

Stable isotope labelling with amino acids in cell culture, which is a quantitative proteomics approach coupled with bioinformatic analyses, revealed that CPNE3 regulates SQSTM1/p62 and vimentin expression, indicating that CPNE3 may mediate epithelial-mesenchymal transition (EMT). CPNE3 silencing by siRNA upregulated vimentin levels but downregulated E-cadherin levels in the A549 cells.

Conclusion

Furthermore, SQSTM1/p62 knockdown enhanced migratory ability and EMT progression in CPNE3-silenced A549 cells. Overall, CPNE3 knockdown was found to promote EMT by inhibiting SQSTM1/p62 signalling and facilitating cell migration. Our findings highlight the role of CPNE3 as a tumour suppressor, providing deeper insights into its tumour-suppressive roles in LUAD.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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References

  1. YangL. WangL. ZhangY. Immunotherapy for lung cancer: Advances and prospects.Am. J. Clin. Exp. Immunol.20165112027168951
     [Google Scholar]
  2. BrayF. FerlayJ. SoerjomataramI. SiegelR.L. TorreL.A. JemalA. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.201868639442410.3322/caac.2149230207593
     [Google Scholar]
  3. GuoT. DingY. ChenL. ZhuL. LinJ. ZhangJ. HuangY. LiW. LinR. PanX. Evaluation of pembrolizumab for the treatment of advanced non-small cell lung cancer: A retrospective, single-centre, single-arm study.J. Thorac. Dis.202113128229010.21037/jtd‑20‑341333569208
     [Google Scholar]
  4. AnsariJ. ShackelfordR.E. OstaE.H. Epigenetics in non-small cell lung cancer: From basics to therapeutics.Transl. Lung Cancer Res.20165215517110.21037/tlcr.2016.02.0227186511
     [Google Scholar]
  5. VallièresE. PetersS. HoutteV.P. DalalP. LimE. Therapeutic advances in non-small cell lung cancer.Thorax201267121097110110.1136/thoraxjnl‑2011‑20104322058187
     [Google Scholar]
  6. KenaanN. HannaG. SardiniM. IyounM.O. LaykaK. HannounehZ.A. AlshehabiZ. Advances in early detection of non-small cell lung cancer: A comprehensive review.Cancer Med.20241318e7015610.1002/cam4.7015639300939
     [Google Scholar]
  7. HoudaI. DickhoffC. GrootU.C.A. ReguartN. ProvencioM. LevyA. DziadziuszkoR. PompiliC. MaioD.M. ThomasM. BrunelliA. PopatS. SenanS. BahceI. New systemic treatment paradigms in resectable non-small cell lung cancer and variations in patient access across Europe.Lancet Reg. Health Eur.20243810084010.1016/j.lanepe.2024.10084038476748
     [Google Scholar]
  8. HendriksL.E. KerrK.M. MenisJ. MokT.S. NestleU. PassaroA. PetersS. PlanchardD. SmitE.F. SolomonB.J. VeronesiG. ReckM. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann. Oncol.202334433935710.1016/j.annonc.2022.12.00936872130
     [Google Scholar]
  9. CaudellE.G. CaudellJ.J. TangC.H. YuT.K. FrederickM.J. GrimmE.A. Characterization of human copine III as a phosphoprotein with associated kinase activity.Biochemistry20003942130341304310.1021/bi001250v11041869
     [Google Scholar]
  10. CowlandJ.B. CarterD. BjerregaardM.D. JohnsenA.H. BorregaardN. LollikeK. Tissue expression of copines and isolation of copines I and III from the cytosol of human neutrophils.J. Leukoc. Biol.200374337938810.1189/jlb.020308312949241
     [Google Scholar]
  11. HeinrichC. KellerC. BoulayA. VecchiM. BianchiM. SackR. LienhardS. DussS. HofsteengeJ. HynesN.E. Copine-III interacts with ERBB2 and promotes tumor cell migration.Oncogene201029111598161010.1038/onc.2009.45620010870
     [Google Scholar]
  12. ThomasG. JacobsK.B. YeagerM. KraftP. WacholderS. OrrN. YuK. ChatterjeeN. WelchR. HutchinsonA. CrenshawA. TassinC.G. StaatsB.J. WangZ. BosquetG.J. FangJ. DengX. BerndtS.I. CalleE.E. FeigelsonH.S. ThunM.J. RodriguezC. AlbanesD. VirtamoJ. WeinsteinS. SchumacherF.R. GiovannucciE. WillettW.C. CussenotO. ValeriA. AndrioleG.L. CrawfordE.D. TuckerM. GerhardD.S. FraumeniJ.F.Jr HooverR. HayesR.B. HunterD.J. ChanockS.J. Multiple loci identified in a genome-wide association study of prostate cancer.Nat. Genet.200840331031510.1038/ng.9118264096
     [Google Scholar]
  13. FuL. FuH. QiaoJ. PangY. XuK. ZhouL. WuQ. LiZ. KeX. XuK. ShiJ. High expression of CPNE 3 predicts adverse prognosis in acute myeloid leukemia.Cancer Sci.201710891850185710.1111/cas.1331128670859
     [Google Scholar]
  14. LinH. ZhangF. GengQ. YuT. CuiY. LiuX. LiJ. YanM. LiuL. HeX. LiJ. YaoM. Quantitative proteomic analysis identifies CPNE3 as a novel metastasis-promoting gene in NSCLC.J. Proteome Res.20131273423343310.1021/pr400273z23713811
     [Google Scholar]
  15. LinH. ZhangX. LiaoL. YuT. LiJ. PanH. LiuL. KongH. SunL. YanM. YaoM. CPNE3 promotes migration and invasion in non-small cell lung cancer by interacting with RACK1 via FAK signaling activation.J. Cancer20189224215422210.7150/jca.2587230519322
     [Google Scholar]
  16. GuptaG.P. MassaguéJ. Cancer metastasis: Building a framework.Cell2006127467969510.1016/j.cell.2006.11.00117110329
     [Google Scholar]
  17. VenningF.A. WullkopfL. ErlerJ.T. Targeting ECM disrupts cancer progression.Front. Oncol.2015522410.3389/fonc.2015.0022426539408
     [Google Scholar]
  18. JosephJ.P. HarishankarM.K. PillaiA.A. DeviA. Hypoxia induced EMT: A review on the mechanism of tumor progression and metastasis in OSCC.Oral Oncol.201880233210.1016/j.oraloncology.2018.03.00429706185
     [Google Scholar]
  19. MingH. LiB. ZhouL. GoelA. HuangC. Long non- coding RNAs and cancer metastasis: Molecular basis and therapeutic implications.Biochim. Biophys. Acta Rev. Cancer20211875218851910.1016/j.bbcan.2021.18851933548345
     [Google Scholar]
  20. ChambersA.F. GroomA.C. MacDonaldI.C. Dissemination and growth of cancer cells in metastatic sites.Nat. Rev. Cancer20022856357210.1038/nrc86512154349
     [Google Scholar]
  21. ThieryJ.P. Epithelial–mesenchymal transitions in tumour progression.Nat. Rev. Cancer20022644245410.1038/nrc82212189386
     [Google Scholar]
  22. DemirkanB. The roles of epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in breast cancer bone metastasis: Potential targets for prevention and treatment.J. Clin. Med.20132426428210.3390/jcm204026426237148
     [Google Scholar]
  23. ZhangY. MunS.R. LinaresJ.F. TowersC.G. ThorburnA. MecoD.M.T. KwonY.T. KutateladzeT.G. Mechanistic insight into the regulation of SQSTM1/p62.Autophagy201915473573710.1080/15548627.2019.156993530653391
     [Google Scholar]
  24. ChenY. LiQ. LiQ. XingS. LiuY. LiuY. ChenY. LiuW. FengF. SunH. p62/SQSTM1, A central but unexploited target: Advances in its physiological/pathogenic functions and small molecular modulators.J. Med. Chem.20206318101351015710.1021/acs.jmedchem.9b0203832324396
     [Google Scholar]
  25. TroncosoC.C. GodoyV.M. BurgosP.V. Pro-tumoral functions of autophagy receptors in the modulation of cancer progression.Front. Oncol.20211061972710.3389/fonc.2020.61972733634029
     [Google Scholar]
  26. LuY. XiaoL. LiuY. WangH. LiH. ZhouQ. PanJ. LeiB. HuangA. QiS. MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation.Autophagy201511122213223210.1080/15548627.2015.110850726553592
     [Google Scholar]
  27. LiJ. YangB. ZhouQ. WuY. ShangD. GuoY. SongZ. ZhengQ. XiongJ. Autophagy promotes hepatocellular carcinoma cell invasion through activation of epithelial–mesenchymal transition.Carcinogenesis20133461343135110.1093/carcin/bgt06323430956
     [Google Scholar]
  28. LiuX. MengL. LiX. LiD. LiuQ. ChenY. LiX. BuW. SunH. Regulation of FN1 degradation by the p62/SQSTM1-dependent autophagy–lysosome pathway in HNSCC.Int. J. Oral Sci.20201213410.1038/s41368‑020‑00101‑533318468
     [Google Scholar]
  29. LvQ. HuaF. HuZ.W. DEDD, a novel tumor repressor, reverses epithelial-mesenchymal transition by activating selective autophagy.Autophagy20128111675167610.4161/auto.2143822874565
     [Google Scholar]
  30. BertrandM. PetitV. JainA. AmsellemR. JohansenT. LarueL. CodognoP. BeauI. SQSTM1/p62 regulates the expression of junctional proteins through epithelial-mesenchymal transition factors.Cell Cycle201514336437410.4161/15384101.2014.98761925496309
     [Google Scholar]
  31. QiangL. HeY.Y. Autophagy deficiency stabilizes TWIST1 to promote epithelial-mesenchymal transition.Autophagy201410101864186510.4161/auto.3217125126736
     [Google Scholar]
  32. Shelton, E.L.; Yutzey, K.E.; Twist1 function in endocardial cushion cell proliferation, migration, and differentiation during heart valve development.Dev. Biol.2008317128229510.1016/j.ydbio.2008.02.03718353304
     [Google Scholar]
  33. LuJ. LiuS.Y. ZhangJ. YangG.M. GaoG.B. YuN.N. LiY.P. LiY.X. MaZ.Q. WangY. LuC.H. Inhibition of BAG3 enhances the anticancer effect of shikonin in hepatocellular carcinoma.Am. J. Cancer Res.20211173575359334354861
     [Google Scholar]
  34. SzklarczykD. FranceschiniA. WyderS. ForslundK. HellerD. CepasH.J. SimonovicM. RothA. SantosA. TsafouK.P. KuhnM. BorkP. JensenL.J. Meringv.C. STRING v10: Protein–protein interaction networks, integrated over the tree of life.Nucleic Acids Res.201543D1D447D45210.1093/nar/gku100325352553
     [Google Scholar]
  35. TangH. PangP. QinZ. ZhaoZ. WuQ. SongS. LiF. The CPNE family and their role in cancers.Front. Genet.20211268909710.3389/fgene.2021.68909734367247
     [Google Scholar]
  36. LiJ. YeW. XuW. ChangT. ZhangL. MaJ. PeiR. HeM. ZhouJ. Activation of autophagy inhibits epithelial to mesenchymal transition process of human lens epithelial cells induced by high glucose conditions.Cell. Signal.20207510976810.1016/j.cellsig.2020.10976832896607
     [Google Scholar]
  37. WangY. XiongH. LiuD. HillC. ErtayA. LiJ. ZouY. MillerP. WhiteE. DownwardJ. GoldinR.D. YuanX. LuX. Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells.Autophagy201915588689910.1080/15548627.2019.156991230782064
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673340242250102104725
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SQSTM1/p62 Mediates the Effects of CPNE3 on the Epithelial- mesenchymal Transition and Migration Inhibition of Lung Adenocarcinoma Cells
Curr. Med. Chem. 32, 9212 (2025); https://doi.org/10.2174/0109298673340242250102104725
/content/journals/cmc/10.2174/0109298673340242250102104725
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  • Article Type:     Research Article
Keyword(s): CPNE3; EMT; lung adenocarcinoma; SILAC; SQSTM1/p62; systematic screening

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