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2000
Volume 25, Issue 2
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666

Abstract

Background

Resistance to chemotherapy is a major obstacle in the clinical management of gastric cancer, and the mechanisms underlying chemoresistance remain largely unknown.

Aims

This study aimed to investigate the involvement of ubiquitin-specific protease 5 (USP5), a deubiquitinating enzyme, in gastric cancer chemoresistance

Methods

USP5 expression was analyzed in fifty paired gastric cancer and adjacent normal tissues, chemo-sensitive and chemo-resistant gastric cancer lines using quantitative ELISA. The role of USP5 was determined using loss-of-function and gain-of-function methods. USP5-mediated downstream effectors were analyzed using biochemical methods focusing on p53.

Results

USP5 expression was comparable in tumors and normal in the majority of the cohort. Following chemotherapy treatment, USP5 expression significantly increased in gastric cancer cells, while p53 levels remained unaltered. Overexpression of USP5 amplified growth and migration while decreasing apoptosis induced by serum withdrawal across multiple gastric cancer cell lines. Conversely, USP5 knockdown effectively heightened gastric cancer sensitivity to paclitaxel and 5-FU treatments, particularly targeting chemo-resistant gastric cancer cells by inhibiting proliferation and migration and inducing apoptosis. Additionally, USP5 knockdown increased levels of p53 but not MDM2, increased p53 activity and increased transcription of p53 target genes. In contrast, USP5 overexpression decreased the level and activity of p53 and inhibited transcription of p53 target genes. The anti-proliferative, anti-migratory, and pro-apoptotic effects of USP5 were significantly diminished upon p53 depletion, highlighting the interplay between p53 and USP5 in regulating gastric cancer cell activities. Additionally, USP5 inhibition suppressed chemo-resistant gastric cancer cell migration suppressing epithelial-mesenchymal transition (EMT) and RhoA activity.

Conclusion

Targeting USP5 inhibition has emerged as a promising alternative therapeutic approach to overcoming chemoresistance in gastric cancer. Additionally, our study sheds light on the novel role of USP5 as a regulator of p53 in gastric cancer.

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2025-03-15
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References

  1. ChenW. ZhengR. BaadeP.D. Cancer statistics in China, 2015.CA Cancer J. Clin.201666211513210.3322/caac.21338 26808342
    [Google Scholar]
  2. WagnerA.D. SynN.L. MoehlerM. Chemotherapy for advanced gastric cancer.Cochrane Database Syst. Rev.201788CD004064 28850174
    [Google Scholar]
  3. ObaK. PaolettiX. AlbertsS. Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: A meta-analysis.J. Natl. Cancer Inst.2013105211600160710.1093/jnci/djt270 24108812
    [Google Scholar]
  4. Fenoglio-PreiserC.M. WangJ. StemmermannG.N. NoffsingerA. TP53 and gastric carcinoma: A review.Hum. Mutat.200321325827010.1002/humu.10180 12619111
    [Google Scholar]
  5. RöckenC. Molecular classification of gastric cancer.Expert Rev. Mol. Diagn.201717329330110.1080/14737159.2017.1286985 28118758
    [Google Scholar]
  6. AdachiY. YasudaK. InomataM. SatoK. ShiraishiN. KitanoS. Pathology and prognosis of gastric carcinoma.Cancer20008971418142410.1002/1097‑0142(20001001)89:7<1418:AID‑CNCR2>3.0.CO;2‑A 11013353
    [Google Scholar]
  7. PeekR.M.Jr BlaserM.J. Helicobacter pylori and gastrointestinal tract adenocarcinomas.Nat. Rev. Cancer200221283710.1038/nrc703 11902583
    [Google Scholar]
  8. BiagioniA. SkalameraI. PeriS. Update on gastric cancer treatments and gene therapies.Cancer Metastasis Rev.201938353754810.1007/s10555‑019‑09803‑7 31486976
    [Google Scholar]
  9. ShiW.J. GaoJ.B. Molecular mechanisms of chemoresistance in gastric cancer.World J. Gastrointest. Oncol.20168967368110.4251/wjgo.v8.i9.673 27672425
    [Google Scholar]
  10. KitagawaH. HirakiM. NambaT. The oncological effect of mutant p53 on the metastatic phenotype of gastric cancer cells.Anticancer Res.202343114887489510.21873/anticanres.16686 37909947
    [Google Scholar]
  11. BusuttilR.A. ZapparoliG.V. HauptS. Role of p53 in the progression of gastric cancer.Oncotarget2014523120161202610.18632/oncotarget.2434 25427447
    [Google Scholar]
  12. BlanchetA. BourgmayerA. KurtzJ.E. MellitzerG. GaiddonC. Isoforms of the p53 family and gastric cancer: A ménage à trois for an unfinished affair.Cancers202113491610.3390/cancers13040916 33671606
    [Google Scholar]
  13. HuangY. LiangL. ZhaoY.X. RUNX2 Reverses p53-induced chemotherapy resistance in gastric cancer.Pharm. Genomics Pers. Med.20231625326110.2147/PGPM.S394393 37009416
    [Google Scholar]
  14. LiY. ReverterD. Molecular mechanisms of DUBs regulation in signaling and disease.Int. J. Mol. Sci.202122398610.3390/ijms22030986 33498168
    [Google Scholar]
  15. DayalS. SparksA. JacobJ. Allende-VegaN. LaneD.P. SavilleM.K. Suppression of the deubiquitinating enzyme USP5 causes the accumulation of unanchored polyubiquitin and the activation of p53.J. Biol. Chem.200928485030504110.1074/jbc.M805871200 19098288
    [Google Scholar]
  16. NakajimaS. LanL. WeiL. Ubiquitin-specific protease 5 is required for the efficient repair of DNA double-strand breaks.PLoS One201491e8489910.1371/journal.pone.0084899 24454762
    [Google Scholar]
  17. NingF. XinH. LiuJ. Structure and function of USP5: Insight into physiological and pathophysiological roles.Pharmacol. Res.202015710455710.1016/j.phrs.2019.104557 31756387
    [Google Scholar]
  18. LiX.Y. WuH.Y. MaoX.F. JiangL.X. WangY.X. USP5 promotes tumorigenesis and progression of pancreatic cancer by stabilizing FoxM1 protein.Biochem. Biophys. Res. Commun.20174921485410.1016/j.bbrc.2017.08.040 28807830
    [Google Scholar]
  19. MaX. QiW. PanH. YangF. DengJ. Overexpression of USP5 contributes to tumorigenesis in non-small cell lung cancer via the stabilization of β-catenin protein.Am. J. Cancer Res.201881122842295 30555744
    [Google Scholar]
  20. PotuH. PetersonL.F. PalA. Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway.Oncotarget20145145559556910.18632/oncotarget.2140 24980819
    [Google Scholar]
  21. QuK.Z. ZhangK. MaW. Ubiquitin‐proteasome profiling for enhanced detection of hepatocellular carcinoma in patients with chronic liver disease.J. Gastroenterol. Hepatol.201126475175810.1111/j.1440‑1746.2010.06491.x 21418304
    [Google Scholar]
  22. KurienB.T. ScofieldR.H. Western blotting: An introduction.Methods Mol. Biol.20151312173010.1007/978‑1‑4939‑2694‑7_5 26043986
    [Google Scholar]
  23. HouH. SunD. ZhangX. The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors.Cancer Cell Int.201919121610.1186/s12935‑019‑0937‑4 31440117
    [Google Scholar]
  24. FreedmanD.A. EpsteinC.B. RothJ.C. LevineA.J. A genetic approach to mapping the p53 binding site in the MDM2 protein.Mol. Med.19973424825910.1007/BF03401678 9131587
    [Google Scholar]
  25. XueS. WuW. WangZ. USP5 promotes metastasis in non-small cell lung cancer by inducing epithelial-mesenchymal transition via Wnt/β-catenin pathway.Front. Pharmacol.20201166810.3389/fphar.2020.00668 32477134
    [Google Scholar]
  26. LianJ. LiuC. GuanX. Ubiquitin specific peptidase 5 enhances STAT3 signaling and promotes migration and invasion in pancreatic cancer.J. Cancer202011236802681110.7150/jca.48536 33123271
    [Google Scholar]
  27. HuangW. LiuX. ZhangY. USP5 promotes breast cancer cell proliferation and metastasis by stabilizing HIF2α.J. Cell. Physiol.202223742211221910.1002/jcp.30686 35102545
    [Google Scholar]
  28. LawsonC.D. RidleyA.J. Rho GTPase signaling complexes in cell migration and invasion.J. Cell Biol.2018217244745710.1083/jcb.201612069 29233866
    [Google Scholar]
  29. TangZ. LiC. KangB. GaoG. LiC. ZhangZ. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses.Nucleic Acids Res.201745W1W98W10210.1093/nar/gkx247 28407145
    [Google Scholar]
  30. LiuY. WangW. ZouL. Ubiquitin specific peptidase 5 mediates Histidine‐rich protein Hpn induced cell apoptosis in hepatocellular carcinoma through P14‐P53 signaling.Proteomics20171712160035010.1002/pmic.201600350 28523650
    [Google Scholar]
  31. YoungM.J. HsuK.C. LinT.E. ChangW.C. HungJ.J. The role of ubiquitin-specific peptidases in cancer progression.J. Biomed. Sci.20192614210.1186/s12929‑019‑0522‑0 31133011
    [Google Scholar]
  32. CheungB.B. KleynhansA. MittraR. A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma.Oncogene202140132367238110.1038/s41388‑021‑01712‑w 33658627
    [Google Scholar]
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Supplementary material is available on the publisher’s website along with the published article.


  • Article Type:
    Research Article
Keyword(s): chemoresistance; EMT; gastric cancer; p53; Rho; USP5
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