Abstract
Background
Chemoresistance is one of the major factors for treatment failure in OSCC. Identifying key resistance triggering molecules will be useful strategy for developing novel treatment methods.
Methods
To identify the causative factors of chemoresistance, we performed RNA sequencing and global proteomic profiling of human OSCC lines presenting with sensitive, early and late cisplatin-resistance patterns.
Results
From the common set of dysregulated genes from both the analysis, RRBP1 was identified to be upregulated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient sample indicates that RRBP1 expression is upregulated in chemotherapy-non-responder tumours as compared to chemotherapy-responder tumours. Genetic (knockout) or pharmacological (Radezolid, represses expression of RRBP1) inhibition of RRBP1 restores cisplatin-mediated cell death in chemo-resistant OSCC. Mechanistically, RRBP1 regulates Yes-associated protein1 (YAP1), a key protein in the Hippo pathway to induce chemoresistance. The PDC xenograft data suggests that knockout of RRBP1 induces cisplatin-mediated cell death and facilitates a significant reduction of tumour burden.
Conclusion
Overall, our data suggests that (I) RRBP1 is a major driver of cisplatin-resistance in OSCC, (II) RRBP1 regulates YAP1 expression to mediate cisplatin-resistance, (III) Radezolid represses RRBP1 expression and (IV) targeting RRBP1 reverses cisplatin-induced chemoresistance in advanced OSCC.
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Change history
07 May 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41416-021-01414-w
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Acknowledgements
O.S. is a UGC-SRF, S.M. is UGC-JRF, P.M. is CSIR SRF. S.R.K. and F.P. received fellowship from Department of Biotechnology. K.C.M. received institutional fellowship.
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O.S., S.M., R.A., P.M., S.R.K., F.P., S.K., P.P. and K.C.M. performed experiments, and analysed the data, under the direction of R.D. and R.K.N. R.R., D.K.M., A.D. and S.K.M. performed part of experiments. O.S. and R.D. designed experiments and supervised the study. O.S., R.D. and R.K.N. wrote the manuscript. All authors approved the final version.
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Ethics approval and consent to participate
This study was approved by Human Ethics committees (HEC) of Institute of Life Sciences, (84/HEC/18) and All India Institute of Medical Sciences (AIIMS), (T/EMF/Surg.Onco/19/03). The animal-related experiments were approved by Institutional Animal Ethics Committee of Institute of Life Sciences, (ILS/IAEC-147-AH/FEB-19).
Data availability
All the mass spectrometry data files (. raw and. mgf) with result files were deposited in the ProteomeXchange Consortium (PXD0016977) and all the RNA-seq data file were deposited in ArrayExpress (E-MTAB-9697).
Competing interests
The authors declare no competing interests.
Funding information
Grant support: This work is supported by Institute of Life Sciences, Bhubaneswar intramural support, ICMR (5/13/9/2019-NCD-III) and DBT BT/INF/22/SP28293/2018 (for imaging facility). Core support from International Centre for Genetic Engineering and Biotechnology to R.K.N. is highly acknowledged.
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The original online version of this article was revised: During the proof process the authors unfortunately removed of one the co-corresponding authors. The correct version should read: Correspondence: Rupesh Dash (rupesh.dash@gmail.com) or Ranjan K. Nanda (HYPERLINK “mailto:ranjan@icgeb.res.in” ranjan@icgeb.res.in).
Supplementary information
41416_2021_1336_MOESM3_ESM.tif
Supplementary figure 3: The confirmation of RRBP1 KO in OSCC Chemoresistance cell line done by using GeneArt®Genomic Cleavage Detection (GCD) Kit (Life technology) with PCR primers listed in supplem
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Shriwas, O., Arya, R., Mohanty, S. et al. RRBP1 rewires cisplatin resistance in oral squamous cell carcinoma by regulating Hippo pathway. Br J Cancer 124, 2004–2016 (2021). https://doi.org/10.1038/s41416-021-01336-7
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DOI: https://doi.org/10.1038/s41416-021-01336-7
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