Skip to content
2000
Volume 25, Issue 10
  • ISSN: 1871-5303
  • E-ISSN: 2212-3873
file format text download EPUB
file format pdf download PDF
side by side viewer icon HTML

Abstract

Background

Papillary Thyroid Carcinoma (PTC) is the most common thyroid cancer, with an etiology and progression that are not fully understood. Research suggests a link between cathepsins and PTC, but the causal nature of this link is unclear. This study uses Mendelian Randomization (MR) to investigate if cathepsins causally influence PTC risk.

Methods

We applied univariable and multivariable MR analyses using genetic variants as proxies for cathepsin levels. Genetic data for cathepsins were sourced from the INTERVAL study, while PTC data came from the Finnish Genome-Wide Association Study database. Our analysis employed several MR methods, including the Inverse Variance Weighted (IVW) approach, MR-Egger, and the Weighted Median method, to provide comprehensive insights and address possible pleiotropy.

Results

MR findings suggest a significant causal association between higher cathepsin levels and increased PTC risk. Notably, genetic variants indicating higher cathepsin Z expression were positively causal associated with PTC risk (OR:1.1190, 95% CI: 1.0029-1.2486), multivariable analysis confirmed significant carcinogenesis role of cathepsin Z in PTC (OR: 1.1593, 95% CI: 1.0137-1.3258), with results consistent across various tests, indicating a robust relationship.

Conclusion

This study established a causal link between cathepsin levels and PTC risk, emphasizing the roles of cathepsin Z in its progression. These insights could lead to new therapeutic strategies targeting these enzymes. Further research is necessary to understand the underlying biological mechanisms and their clinical implications.

© 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
Loading

Article metrics loading...

/content/journals/emiddt/10.2174/0118715303305715240912172648
2025-01-08
2025-08-13

  • From This Site

    /content/journals/emiddt/10.2174/0118715303305715240912172648
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
The full text of this item is not currently available.

References

  1. ChenD.W. LangB.H.H. McLeodD.S.A. NewboldK. HaymartM.R. Thyroid cancer.Lancet2023401103871531154410.1016/S0140‑6736(23)00020‑X37023783
     [Google Scholar]
  2. WangY. MeiJ. ZhangY. HeX. ZhengX. TanJ. JiaQ. LiN. LiD. WangY. MengZ. Cathepsin F genetic mutation is associated with familial papillary thyroid cancer.Am. J. Med. Sci.2022364441442410.1016/j.amjms.2022.03.01735447134
     [Google Scholar]
  3. TedelindS. PoliakovaK. ValetaA. HunegnawR. YemanaberhanE.L. HeldinN.E. KurebayashiJ. WeberE. Kopitar-JeralaN. TurkB. BogyoM. BrixK. Nuclear cysteine cathepsin variants in thyroid carcinoma cells.Biol. Chem.2010391892393510.1515/bc.2010.10920536394
     [Google Scholar]
  4. TanJ. QianX. SongB. AnX. CaiT. ZuoZ. DingD. LuY. LiH. Integrated bioinformatics analysis reveals that the expression of cathepsin S is associated with lymph node metastasis and poor prognosis in papillary thyroid cancer.Oncol. Rep.201840111112210.3892/or.2018.642829749483
     [Google Scholar]
  5. KimE.K. SongM.J. JangH.H. ChungY.S. Clinicopathologic analysis of cathepsin b as a prognostic marker of thyroid cancer.Int. J. Mol. Sci.20202124953710.3390/ijms2124953733333840
     [Google Scholar]
  6. KhaketT.P. KwonT.K. KangS.C. Cathepsins: Potent regulators in carcinogenesis.Pharmacol. Ther.201919811910.1016/j.pharmthera.2019.02.00330763594
     [Google Scholar]
  7. LindersD.G.J. BijlstraO.D. FallertL.C. HillingD.E. WalkerE. StraightB. MarchT.L. ValentijnA.R.P.M. PoolM. BurggraafJ. BasilionJ.P. VahrmeijerA.L. KuppenP.J.K. Cysteine cathepsins in breast cancer: Promising targets for fluorescence-guided surgery.Mol. Imaging Biol.2023251587310.1007/s11307‑022‑01768‑436002710
     [Google Scholar]
  8. ChenS. DongH. YangS. GuoH. Cathepsins in digestive cancers.Oncotarget2017825416904170010.18632/oncotarget.1667728402938
     [Google Scholar]
  9. BhattacharyyaC. ChakrabortyS. SenguptaR. NO news: S-(de)nitrosylation of cathepsins and their relationship with cancer.Anal. Biochem.202265511487210.1016/j.ab.2022.11487236027970
     [Google Scholar]
  10. MustafaA. ElkhamisyF. ArghianiN. Potential crosstalk between pericytes and cathepsins in the tumour microenvironment.Biomed. Pharmacother.202316411493210.1016/j.biopha.2023.114932
     [Google Scholar]
  11. MulitaF. IliopoulosF. TsilivigkosC. Cancer rate of Bethesda category II thyroid nodules Med. Glas. (Zenica)202216912110.17392/1413‑21
     [Google Scholar]
  12. MulitaF. PlachouriM.K. LiolisE. VailasM. PanagopoulosK. MaroulisI. Patient outcomes following surgical management of thyroid nodules classified as Bethesda category III (AUS/FLUS).Endokrynol. Pol.202172214314410.5603/EP.a2021.001833749812
     [Google Scholar]
  13. EmdinC.A. KheraA.V. KathiresanS. Mendelian randomization.JAMA2017318191925192610.1001/jama.2017.1721929164242
     [Google Scholar]
  14. Davey SmithG. HemaniG. Mendelian randomization: Genetic anchors for causal inference in epidemiological studies.Hum. Mol. Genet.201423R1R89R9810.1093/hmg/ddu32825064373
     [Google Scholar]
  15. BirneyE. Mendelian randomization.Cold Spring Harb. Perspect. Med.2021124a04130210.1101/cshperspect.a04130234872952
     [Google Scholar]
  16. BowdenJ. HolmesM.V. Meta-analysis and mendelian randomization: A review.Res. Synth. Methods201910448649610.1002/jrsm.134630861319
     [Google Scholar]
  17. SandersonE. Multivariable mendelian randomization and mediation.Cold Spring Harb. Perspect. Med.2021112a03898410.1101/cshperspect.a03898432341063
     [Google Scholar]
  18. SunB.B. MaranvilleJ.C. PetersJ.E. StaceyD. StaleyJ.R. BlackshawJ. BurgessS. JiangT. PaigeE. SurendranP. Oliver-WilliamsC. KamatM.A. PrinsB.P. WilcoxS.K. ZimmermanE.S. ChiA. BansalN. SpainS.L. WoodA.M. MorrellN.W. BradleyJ.R. JanjicN. RobertsD.J. OuwehandW.H. ToddJ.A. SoranzoN. SuhreK. PaulD.S. FoxC.S. PlengeR.M. DaneshJ. RunzH. ButterworthA.S. Genomic atlas of the human plasma proteome.Nature20185587708737910.1038/s41586‑018‑0175‑229875488
     [Google Scholar]
  19. KurkiM.I. KarjalainenJ. PaltaP. SipiläT.P. KristianssonK. DonnerK.M. ReeveM.P. LaivuoriH. AavikkoM. KaunistoM.A. LoukolaA. LahtelaE. MattssonH. LaihoP. Della Briotta ParoloP. LehistoA.A. KanaiM. MarsN. RämöJ. KiiskinenT. HeyneH.O. VeerapenK. RüegerS. LemmeläS. ZhouW. RuotsalainenS. PärnK. HiekkalinnaT. KoskelainenS. PaajanenT. LlorensV. Gracia-TabuencaJ. SiirtolaH. ReisK. ElnahasA.G. SunB. FoleyC.N. Aalto-SetäläK. AlasooK. ArvasM. AuroK. BiswasS. Bizaki-VallaskangasA. CarpenO. ChenC.Y. DadaO.A. DingZ. EhmM.G. EklundK. FärkkiläM. FinucaneH. GannaA. GhazalA. GrahamR.R. GreenE.M. HakanenA. HautalahtiM. HedmanÅ.K. HiltunenM. HinttalaR. HovattaI. HuX. Huertas-VazquezA. HuilajaL. HunkapillerJ. JacobH. JensenJ.N. JoensuuH. JohnS. JulkunenV. JungM. JunttilaJ. KaarnirantaK. KähönenM. KajanneR. KallioL. KälviäinenR. KaprioJ. KerimovN. KettunenJ. KilpeläinenE. KilpiT. KlingerK. KosmaV.M. KuopioT. KurraV. LaiskT. LaukkanenJ. LawlessN. LiuA. LongerichS. MägiR. MäkeläJ. MäkitieA. MalarstigA. MannermaaA. MaranvilleJ. MatakidouA. MeretojaT. MozaffariS.V. NiemiM.E.K. NiemiM. NiiranenT. O´DonnellC.J. ObeidatM. OkafoG. OllilaH.M. PalomäkiA. PalotieT. PartanenJ. PaulD.S. PelkonenM. PendergrassR.K. PetrovskiS. PitkärantaA. PlattA. PulfordD. PunkkaE. PussinenP. RaghavanN. RahimovF. RajpalD. RenaudN.A. Riley-GillisB. RodosthenousR. SaarentausE. SalminenA. SalminenE. SalomaaV. SchleutkerJ. SerpiR. ShenH. SiegelR. SilanderK. SiltanenS. SoiniS. SoininenH. SulJ.H. TachmazidouI. TasanenK. TienariP. Toppila-SalmiS. TukiainenT. TuomiT. TurunenJ.A. UlirschJ.C. VauraF. VirolainenP. WaringJ. WaterworthD. YangR. NelisM. ReigoA. MetspaluA. MilaniL. EskoT. FoxC. HavulinnaA.S. PerolaM. RipattiS. JalankoA. LaitinenT. MäkeläT.P. PlengeR. McCarthyM. RunzH. DalyM.J. PalotieA. FinnGen provides genetic insights from a well-phenotyped isolated population.Nature2023613794450851810.1038/s41586‑022‑05473‑836653562
     [Google Scholar]
  20. ZhangX. ZeY. SangJ. ShiX. BiY. ShenS. ZhangX. ZhuD. Risk factors and diagnostic prediction models for papillary thyroid carcinoma.Front. Endocrinol. (Lausanne)20221393800810.3389/fendo.2022.93800836133306
     [Google Scholar]
  21. MaoJ. ZhangQ. ZhangH. ZhengK. WangR. WangG. Risk factors for lymph node metastasis in papillary thyroid carcinoma: A systematic review and meta-analysis.Front. Endocrinol. (Lausanne)20201126510.3389/fendo.2020.0026532477264
     [Google Scholar]
  22. NietoH.R. ThorntonC.E.M. BrookesK. Nobre de MenezesA. FletcherA. AlshahraniM. KocbiyikM. SharmaN. BoelaertK. CazierJ.B. MehannaH. SmithV.E. ReadM.L. McCabeC.J. Recurrence of papillary thyroid cancer: A systematic appraisal of risk factors.J. Clin. Endocrinol. Metab.202210751392140610.1210/clinem/dgab83634791326
     [Google Scholar]
  23. FrolovaA.S. TikhomirovaN.K. KireevI.I. ZerniiE.Y. ParodiA. IvanovK.I. ZamyatninA.A.Jr Expression, intracellular localization, and maturation of cysteine cathepsins in renal embryonic and cancer cell lines.Biochemistry (Mosc.)20238871034104410.1134/S000629792307014337751872
     [Google Scholar]
  24. WeiS. LiuW. XuM. QinH. LiuC. ZhangR. ZhouS. LiE. LiuZ. WangQ. Cathepsin F and Fibulin-1 as novel diagnostic biomarkers for brain metastasis of non-small cell lung cancer.Br. J. Cancer2022126121795180510.1038/s41416‑022‑01744‑335217799
     [Google Scholar]
  25. ZhangF. LiangJ. LuY. TangY. LiuS. WuK. ZhangF. LuY. LiuZ. WangX. Macrophage-specific cathepsin as a marker correlated with prognosis and tumor microenvironmental characteristics of clear cell renal cell carcinoma.J. Inflamm. Res.2022156275629210.2147/JIR.S37525036386587
     [Google Scholar]
  26. Al-HashimiA. VenugopalanV. SereesongsaengN. TedelindS. PinzaruA.M. HeinZ. SpringerS. WeberE. FührerD. ScottC.J. BurdenR.E. BrixK. Significance of nuclear cathepsin V in normal thyroid epithelial and carcinoma cells.Biochim. Biophys. Acta Mol. Cell Res.202018671211884610.1016/j.bbamcr.2020.11884632910988
     [Google Scholar]
  27. WangJ. ChenL. LiY. GuanX.Y. Overexpression of cathepsin Z contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma.PLoS One201169e2496710.1371/journal.pone.002496721966391
     [Google Scholar]
  28. AkkariL. GochevaV. KesterJ.C. HunterK.E. QuickM.L. SevenichL. WangH.W. PetersC. TangL.H. KlimstraD.S. ReinheckelT. JoyceJ.A. Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix.Genes Dev.201428192134215010.1101/gad.249599.11425274726
     [Google Scholar]
  29. BatistaA.A.S. FrancoB.M. PerezM.M. PereiraE.G. RodriguesT. WroclawskiM.L. FonsecaF.L.A. SuarezE.R. Decreased levels of cathepsin Z mRNA expressed by immune blood cells: Diagnostic and prognostic implications in prostate cancer.Braz. J. Med. Biol. Res.20215410e1143910.1590/1414‑431x2021e1143934378678
     [Google Scholar]
  30. FangY. ZhangD. HuT. ZhaoH. ZhaoX. LouZ. HeY. QinW. XiaJ. ZhangX. YeL. KMT2A histone methyltransferase contributes to colorectal cancer development by promoting cathepsin Z transcriptional activation.Cancer Med.2019873544355210.1002/cam4.222631090199
     [Google Scholar]
  31. LinesK.E. ChelalaC. DmitrovicB. WijesuriyaN. KocherH.M. MarshallJ.F. Crnogorac-JurcevicT. S100P-binding protein, S100PBP, mediates adhesion through regulation of cathepsin Z in pancreatic cancer cells.Am. J. Pathol.201218041485149410.1016/j.ajpath.2011.12.03122330678
     [Google Scholar]
/content/journals/emiddt/10.2174/0118715303305715240912172648
Loading
Evaluating the Relationship between Cathepsins and Papillary Thyroid Carcinoma: A Mendelian Randomization Study
Endocr Metab Immune Disord Drug Targets 25, 811 (2025); https://doi.org/10.2174/0118715303305715240912172648
/content/journals/emiddt/10.2174/0118715303305715240912172648
/content/journals/emiddt/10.2174/0118715303305715240912172648
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): cathepsins; causal relationships; fineneedle aspiration; lysosomal proteases; mendelian randomization; Papillary thyroid carcinoma

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test