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Targeting RPL23 restores chemosensitivity of cisplatin-resistant ovarian carcinoma by inhibiting EMT

Abstract

Chemoresistance is the inevitable outcome of chemotherapy for epithelial ovarian carcinoma (EOC), and its mechanism is still not fully understood. This study explored the role of ribosomal protein L23 (RPL23) in cisplatin resistance of EOC. WGCNA based on TCGA and GEO was used to screen and analyze target genes related to EOC chemotherapy sensitivity. Clinical samples of cisplatin resistance were collected to detect the expression of target genes. Cisplatin resistance was induced in EOC cell lines A2780 and SKOV3. The cell abilities of invasion, migration and adhesion were observed. Western blotting was used to detect protein expressions. Bioinformatics analysis showed that RPL23 may be related to EOC chemotherapy sensitivity, and was highly expressed in clinical samples and cell lines of cisplatin-resistant. After A2780 and SKOV3 were resistant to cisplatin, the inhibitory abilities of therapeutic dose of cisplatin on their invasion, migration and adhesion were significantly attenuated, and N-cadherin and vimentin were significantly up-regulated while E-cadherin was significantly down-regulated. However, above phenomena were significantly reversed after RPL23 knockdown. Taken together, the overexpressed RPL23 may lead to platinum resistance by inducing epithelial-mesenchymal transition (EMT) in EOC. Targeting knockdown RPL23 would restore the sensitivity of EOC cells to cisplatin by inhibiting EMT, suggesting that RPL23 is a potential therapeutic target for EOC after platinum resistance.

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All data generated or analyzed during this study are included in this published article, or available upon reasonable request from the corresponding author.

References

  • Ashrafizadeh M, Zarrabi A, Hushmandi K, Kalantari M, Mohammadinejad R, Javaheri T et al (2020) Association of the epithelial-mesenchymal transition (EMT) with cisplatin resistance. Int J Mol Sci 21:4002

    CAS  Article  Google Scholar 

  • Beckerman P, Qiu C, Park J, Ledo N, Ko Y-A, Park A-SD et al (2017) Human kidney tubule-specific gene expression based dissection of chronic kidney disease traits. EBioMedicine 24:267–276

    Article  Google Scholar 

  • Bozhkova DM, Poryazova-Markova EG (2019) The epithelial-mesenchymal transition, E-cadherin and tumor progression in ovarian serous tumors. Folia Med (plovdiv) 61:296–302

    CAS  Article  Google Scholar 

  • Bv Z, Tang D, Bowden NA (2018) Biomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment. Endocr Relat Cancer 25:R303–R318

    Article  Google Scholar 

  • Deng J, Bai X, Feng X, Ni J, Beretov J, Graham P et al (2019) Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression. BMC Cancer 19:618

    Article  Google Scholar 

  • Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong STC et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472–476

    CAS  Article  Google Scholar 

  • Freimund AE, Beach JA, Christie EL, Bowtell DDL (2018) Mechanisms of drug resistance in high-grade serous ovarian cancer. Hematol Oncol Clin N Am 32:983–996

    Article  Google Scholar 

  • Hassouni BE, Sarkisjan D, Vos JC, Giovannetti E, Peters GJ (2018) Targeting the ribosome biogenesis key molecule fibrillarin to avoid chemoresistance. Curr Med Chem 26:6020–6032

    Article  Google Scholar 

  • Kang H, Choi MC, Kim S, Jeong J-Y, Kwon A-Y, Kim T-H et al (2021a) USP19 and RPL23 as candidate prognostic markers for advanced-stage high-grade serous ovarian carcinoma. Cancers (basel) 13:3976

    CAS  Article  Google Scholar 

  • Kang J, Brajanovski N, Chan KT, Xuan J, Pearson RB, Sanij E (2021b) Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy. Signal Transduct Target Ther 6:323

    CAS  Article  Google Scholar 

  • Lheureux S, Gourley C, Vergote I, Oza AM (2019) Epithelial ovarian cancer. Lancet 393:1240–1253

    Article  Google Scholar 

  • Liu Y, Li Y, Wang R, Qin S, Liu J, Su F et al (2016) MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells. J Exp Clin Cancer Res 35:19

    Article  Google Scholar 

  • Liu Y, Li W, Luo J, Wu Y, Xu Y, Chen T et al (2021) Cysteine-rich intestinal protein 1 served as an epithelial ovarian cancer marker via promoting Wnt/ β-catenin-mediated EMT and tumour metastasis. Dis Markers 2021:3566749

    PubMed  PubMed Central  Google Scholar 

  • Loh C-Y, Chai JY, Tang TF, Wong WF, Sethi G, Shanmugam MK et al (2019) The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges. Cells 8:1118

    CAS  Article  Google Scholar 

  • Lu W, Kang Y (2019) Epithelial-mesenchymal plasticity in cancer progression and metastasis. Dev Cell 49:361–374

    CAS  Article  Google Scholar 

  • Meeren LE, Kluiver J, Rutgers B, Alsagoor Y, Kluin PM, Avd B et al (2019) A super-SILAC based proteomics analysis of diffuse large B-cell lymphoma-NOS patient samples to identify new proteins that discriminate GCB and non-GCB lymphomas. PLoS ONE 14:e0223260

    Article  Google Scholar 

  • Meng X, Tackmann NR, Liu S, Yang J, Dong J, Wu C et al (2016) RPL23 links oncogenic RAS signaling to p53-mediated tumor suppression. Cancer Res 76:5030–5039

    CAS  Article  Google Scholar 

  • Newton TR, Parsons PG, Lincoln DJ, Cummings MC, Wyld DK, Webb PM et al (2010) Expression profiling correlates with treatment response in women with advanced serous epithelial ovarian cancer. Int J Cancer 119:875–883

    Article  Google Scholar 

  • Qi Y, Li X, Chang C, Xu F, He Q, Zhao Y et al (2017) Ribosomal protein L23 negatively regulates cellular apoptosis via the RPL23/Miz-1/c-Myc circuit in higher-risk myelodysplastic syndrome. Rep 7:2323

    Google Scholar 

  • Rosen EY, Wexler EM, Versano R, Coppola G, Gao F, Winden KD et al (2011) Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling. Neuron 71:1030–1042

    CAS  Article  Google Scholar 

  • Shi O, Zhai H, Wang X, Han Z, Liu C, Lan M et al (2004) Ribosomal proteins S13 and L23 promote multidrug resistance in gastric cancer cells by suppressing drug-induced apoptosis. Exp Cell Res 296:337–346

    CAS  Article  Google Scholar 

  • Tang J, Kong D, Cui Q, Wang K, Zhang D, Gong Y et al (2018) Prognostic genes of breast cancer identified by gene co-expression network analysis. Front Oncol 8:374

    Article  Google Scholar 

  • Wu L, Li X, Xu F, Chang C, He Q, Zhang Z et al (2012) Over-expression of RPL23 in myelodysplastic syndromes is associated with apoptosis resistance of CD34+ cells and predicts poor prognosis and distinct response to CHG chemotherapy or decitabine. Ann Hematol 91:1547–1554

    CAS  Article  Google Scholar 

  • Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W et al (2013) Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 4:2612

    Article  Google Scholar 

  • Zhang F, Cui J-Y, Gao H-F, Yu H, Gao F-F, Chen J-L et al (2020) Cancer-associated fibroblasts induce epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer via CXCL12/CXCR4 axis. Future Oncol 16:2619–2633

    CAS  Article  Google Scholar 

  • Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H et al (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:525–530

    CAS  Article  Google Scholar 

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Correspondence to Yujuan Liu or Yan Jinlong.

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Liu, Y., Lai, S., He, J. et al. Targeting RPL23 restores chemosensitivity of cisplatin-resistant ovarian carcinoma by inhibiting EMT. Cytotechnology 74, 421–432 (2022). https://doi.org/10.1007/s10616-022-00535-1

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  • DOI: https://doi.org/10.1007/s10616-022-00535-1

Keywords

  • Epithelial ovarian carcinoma
  • Platinum resistance
  • RPL23
  • Epithelial-mesenchymal transition