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RETRACTED ARTICLE: Differential operation of MLH1/MSH2 and FANCD2 crosstalk in chemotolerant bladder carcinoma: a clinical and therapeutic intervening study

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This article was retracted on 02 May 2024

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Abstract

We aimed to understand the crosstalk between mismatch repair (MMR) and FA-BRCA pathway in primary bladder carcinoma (BlCa) samples as well as in chemotolerant cell line. We analysed the genetic alterations of MLH1 and MSH2 (MMR-related genes) and after that we correlated it with the nuclear translocation of FANCD2 protein. Next, we evaluated this crosstalk in T24 BlCa cell line in response to doxorubicin treatment. In primary BlCa tumors, infrequent genetic deletion (17–20%) but frequent promoter methylation (28–55%) of MLH1 and MSH2 was observed, where MLH1 was significantly (p < 0.05) more methylated among the early staged samples (NMIBC). However, MSH2 was significantly more altered among the NMIBC samples, signifying the importance of MMR pathway during the early pathogenesis of the disease. Furthermore, BlCa samples with underexpressed MLH1/MSH2 protein possessed cytoplasmic FANCD2 protein; encouraging that inefficiency of MMR proteins might restrict FANCD2 nuclear translocation. Next, we analysed publicly available data in GEO2R tool where we observed that in response to chemotherapeutic drugs, expression of MLH1, MSH2 and FANCD2 were diminishing. Validating this result in doxorubicin tolerant T24 cells, we found that expression of MLH1 and MSH2 was gradually decreased with increasing dose of doxorubicin. Interestingly, FANCD2 mono-ubiquitination (L-form) was also reduced in chemotolerant T24 cells. The crosstalk between MMR and FA-BRCA pathway was substantiated in the primary BlCa tumors. Further, in response to doxorubicin, this crosstalk was found to be hampered due to under-expression of MLH1 and MSH2 gene, thereby rendering chemotolerance.

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References

  1. Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clinicians 68(6):394–424

    Google Scholar 

  2. Schabath MB, Spitz MR, Grossman HB et al (2003) Genetic instability in bladder cancer assessed by the comet assay. J Natl Cancer Inst 95(7):540–547

    Article  CAS  PubMed  Google Scholar 

  3. Yamamoto Y, Matsuyama H, Chochi Y et al (2007) Overexpression of BUBR1 is associated with chromosomal instability in bladder cancer. Cancer Genet Cytogenet 174(1):42–47

    Article  CAS  PubMed  Google Scholar 

  4. Knowles MA, Hurst CD (2015) Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 15(1):25–41

    Article  CAS  PubMed  Google Scholar 

  5. Sanguedolce F, Cormio A, Massenio P et al (2018) Altered expression of HER-2 and the mismatch repair genes MLH1 and MSH2 predicts the outcome of T1 high-grade bladder cancer. J Cancer Res Clin Oncol 144(4):637–644

    Article  CAS  PubMed  Google Scholar 

  6. Eichenauer T, Bannenberg DC, Wittmer MC et al (2020) 8p deletions in renal cell carcinoma are associated with unfavorable tumor features and poor overall survival. Urol Oncol 38(2):43

    Article  Google Scholar 

  7. Panneerselvam J, Park HW, Zhang J et al (2012) FAVL impairment of the fanconi anemia pathway promotes the development of human bladder cancer. Cell Cycle 11(15):2947–2955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Neveling K, Kalb R, Florl AR et al (2007) Disruption of the FA/BRCA pathway in bladder cancer. Cytogenet Genome Res 118(2–4):166–176

    Article  CAS  PubMed  Google Scholar 

  9. Zhang F, Fan Q, Ren K et al (2010) FANCJ/BRIP1 recruitment and regulation of FANCD2 in DNA damage responses. Chromosoma 119(6):637–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Basu M, Ghosh S, Roychowdhury A et al (2020) Integrative genomics and pathway analysis identified prevalent FA-BRCA pathway alterations in arsenic-associated urinary bladder carcinoma: chronic arsenic accumulation in cancer tissues hampers the FA-BRCA pathway. Genomics 112(6):5055–5065

    Article  CAS  PubMed  Google Scholar 

  11. Li J, Liu H, Yu J et al (2015) Chemoresistance to doxorubicin induces epithelial-mesenchymal transition via upregulation of transforming growth factor β signaling in HCT116 colon cancer cells. Mol Med Rep 12(1):192–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang Y, Wiltshire T, Senft J et al (2006) Fanconi anemia D2 protein confers chemoresistance in response to the anticancer agent, irofulven. Mol Cancer Ther 5(12):3153–3161

    Article  CAS  PubMed  Google Scholar 

  13. Nakashima S, Kobayashi S, Nagano H et al (2015) BRCA/fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer. Cancer Sci 106(5):584–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hashimoto T, Kurokawa Y, Takahashi T et al (2019) Predictive value of MLH1 and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer. Gastric Cancer 22(4):785–792

    Article  CAS  PubMed  Google Scholar 

  15. Basu M, Chatterjee A, Chakraborty B et al (2021) High nuclear expression of HIF1α, synergizing with inactivation of LIMD1 and VHL, portray worst prognosis among the bladder cancer patients: association with arsenic prevalence. J Cancer Res Clin Oncol 147(8):2309–2322

    Article  CAS  PubMed  Google Scholar 

  16. Dasgupta H, Islam S, Alam N et al (2019) Hypomethylation of mismatch repair genes MLH1 and MSH2 is associated with chemotolerance of breast carcinoma: clinical significance. J Surg Oncol 119(1):88–100

    Article  CAS  PubMed  Google Scholar 

  17. Roy R, Mandal S, Chakrabarti J et al (2021) Downregulation of hyaluronic acid-CD44 signaling pathway in cervical cancer cell by natural polyphenols plumbagin pongapin and karanjin. Mol Cell Biochem 476(10):3701–3709

    Article  CAS  PubMed  Google Scholar 

  18. Islam S, Dasgupta H, Basu M et al (2020) Downregulation of beta-catenin in chemo-tolerant TNBC through changes in receptor and antagonist profiles of the WNT pathway: clinical and prognostic implications. Cell Oncol 43(4):725–741

    Article  CAS  Google Scholar 

  19. Ling YH, el-Naggar AK, Priebe W et al (1996) Cell cycle-dependent cytotoxicity, G2/M phase arrest, and disruption of p34cdc2/cyclin B1 activity induced by doxorubicin in synchronized P388 cells. Mol Pharmacol 49(5):832–841

    CAS  PubMed  Google Scholar 

  20. Hayashi T, Fujita K, Hayashi Y et al (2020) Mutational landscape and environmental effects in bladder cancer. Int J Mol Sci 21(17):6072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wojtczyk-Miaskowska A, Presler M, Michajlowski J et al (2017) Gene expression DNA methylation and prognostic significance of DNA repair genes in human bladder cancer. Cell Physiol Biochem 42(6):2404–2417

    Article  CAS  PubMed  Google Scholar 

  22. Friedrich MG, Chandrasoma S, Siegmund KD et al (2005) Prognostic relevance of methylation markers in patients with non-muscle invasive bladder carcinoma. Int J Cancer 41(17):2769–2778

    CAS  Google Scholar 

  23. Seah KS, Loha JY, TrangNguyen TT et al (2018) SAHA and cisplatin sensitize gastric cancer cells to doxorubicin by induction of DNA damage, apoptosis and perturbation of AMPK-mTOR signalling. Exp Cell Res 370(2):283–291

    Article  CAS  PubMed  Google Scholar 

  24. Galluzzi L, Senovilla L, Vitale I et al (2012) Molecular mechanisms of cisplatin resistance. Oncogene 31:1869–1883

    Article  CAS  PubMed  Google Scholar 

  25. Montazeri V, Ghahremani MH, Montazeri H et al (2020) A preliminary study of NER and MMR pathways involved in chemotherapy response in bladder transitional cell carcinoma: impact on progression-free survival. Iran J Pharm Res 19(1):355–365

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Burgos-Molina AM, Mercado-Sáenz S, Cárdenas C et al (2021) Identification of new proteins related with cisplatin resistance in Saccharomyces cerevisiae. Appl Microbiol Biotechnol 105:1965–1977

    Article  CAS  PubMed  Google Scholar 

  27. Stark AM, Doukas A, Hugo HH et al (2015) Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma. Neuro Res 37(2):1–11

    Google Scholar 

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Funding

This work was supported by University Grants Commission-National Eligibility Test Fellowship grant [Sr. No. 2061430780, Ref No.: 22/06/2014(i)EU-V to M.B.], Department of Biotechnology- West Bengal [923/(Sanc.)-BT (Estt.) RD 13/13F to C.K.P. and A.G.], Department of Science and Technology (Govt. of India), Kiran Division (SR/WOS-A/LS-278/2016 to D.M.) and NASI Senior Scientist Platinum Jubilee Fellowship (2020) to C.K.P.

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Authors and Affiliations

  1. Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37 SPMukherjee Road, Kolkata, West Bengal, 700026, India

    Mukta Basu, Debalina Mukhopadhyay, Balarko Chakraborty & Chinmay Kumar Panda

  2. Department of Life Science, Presidency University, 86/1, College Street, Kolkata, 700073, India

    Sabnam Ghosh & Amlan Ghosh

  3. Department of Urology, IPGMER, SSKM, 244 A.J.C. Bose Road, Kolkata, 700020, India

    Dilip Kumar Pal

  4. Department of Medical Oncology, Cedars Sinai Medical Center, Los Angeles, United States

    Mukta Basu

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  1. Mukta Basu
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  2. Debalina Mukhopadhyay
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  4. Sabnam Ghosh
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  7. Chinmay Kumar Panda
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Contributions

CKP, AG, DKP designed the study and brought funding from Department of Biotechnology, West Bengal. MB performed the experiments in the primary tumor samples and cell line. DKP provided the tumor samples and confirmed the histological stages of the tumor samples. MB and SG analyzed the results and did the statistical analysis. MB and CKP drafted the manuscript. DM and BC helped in the revision of the manuscript. The whole study was supervised by CKP and AG.

Corresponding author

Correspondence to Chinmay Kumar Panda.

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The authors declare no potential conflict of interest.

Ethical approval

The study was done with appropriate approval of the Institutional Ethical Committee and have been performed in accordance with the ethical standards as laid down in the 1964 (Declaration of Helsinki).

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The study was done with informed consent from the patients and have been performed in accordance with the ethical standards as laid down in the 1964 (Declaration of Helsinki).

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A proper written consent for publication has been taken from either the patient or their guardian.

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This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1007/s11010-024-05021-0

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11010_2022_4616_MOESM4_ESM.tif

Supplementary file4 (TIF 449 KB) Fig. S1 Kaplan-Meier survival curve in patients with a MLH1 deletion b MSH2 deletion c MLH1 methylation

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Basu, M., Mukhopadhyay, D., Chakraborty, B. et al. RETRACTED ARTICLE: Differential operation of MLH1/MSH2 and FANCD2 crosstalk in chemotolerant bladder carcinoma: a clinical and therapeutic intervening study. Mol Cell Biochem 478, 1599–1610 (2023). https://doi.org/10.1007/s11010-022-04616-9

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  • DOI: https://doi.org/10.1007/s11010-022-04616-9

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