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Immunohistochemical expressions of EMT markers in pan-RAS–pERK1/2-positive tumors improve diagnosis and prognosis assessment of non-muscle invasive bladder cancer and muscle invasive bladder cancer patients

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Abstract

Mutation or overexpression renders pan-RAS (rat sarcoma) proteins insensitive to inactivation. Activated pan-RAS communicates signal from the cell surface receptor to activate RAS-MAPK/ERK (RAS-mitogen-activated protein kinases/extracellular signal regulated kinases) signaling and orchestrates epithelial-to-mesenchymal transition-activating transcription factors (EMT-ATFs) reprogramming to induce EMT. Owing to limited studies available in bladder cancer, the present study is taken up to examine the expressions of the EMT-associated markers in pan-RAS-pERK1/2 (pan-RAS-phosphoERK1/2)-positive well-characterized cohort of forty-two non-muscle invasive bladder cancer (NMIBC) and forty-five muscle invasive bladder cancer (MIBC) patients. Immunohistochemical staining was performed on paraffin embedded tissue sections to determine the immunolevels and cellular localization of marker proteins. Semi-quantitative expressions of pan-RAS, pERK1/2, and EMT markers (E-cadherin, Vimentin, N-cadherin, Snail, Slug Twist, and Zeb1) were statistically examined with clinicohistopathological profile of the patients using SPSS, version 20.0 software. The study documents the diagnostic relevance of immunohistochemical expressions of pan-RAS-pERK1/2/EMT-associated markers in order to stratify NMIBC and MIBC patients. Follow-up studies supported the role of altered EMT phenotype in pan-RAS-pERK1/2-activated positive tumors with disease aggressiveness. To the best of our knowledge, our study is the first concluding the impact of altered EMT phenotype via pan-RAS-pERK1/2 axis on the short survival outcome [short overall survival (OS) (p = 0.04), short progression-free survival (PFS) (p = 0.02) and short cancer-specific survival (CSS) (p = 0.03)] of muscle invasive bladder cancer patients.

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Acknowledgements

The Authors would like to thank Research and Development, Department of Higher Education, UP State Govt. [research grant no.-47/2021/606/70-4-2021-4 (56)/2020] for providing financial support to carry out research work. KT and NM are thankful to University Grants Commission (UGC), Govt. of India, for providing research fellowship.

Funding

University Grants Commission (UGC), Govt. of India,Research and Development, Department of Higher Education, UP State Govt., 47/2021/606/70-4-2021-4 (56)/2020

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Authors and Affiliations

  1. Department of Biochemistry, University of Lucknow, Lucknow, 226007, India

    Kiran Tripathi, Niharika Maurya & Minal Garg

  2. Department of Urology, King George’s Medical University, Lucknow, 226003, India

    Apul Goel

  3. Department of Pathology, King George’s Medical University, Lucknow, 226003, India

    Atin Singhai

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  1. Kiran Tripathi
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  2. Niharika Maurya
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Contributions

All authors contributed to the study conception and design. Manuscript preparation, data collection, and analysis were performed by KT, NM, and MG. The first draft of the manuscript was written by KT and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Minal Garg.

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Ethical clearance was obtained from Bioethics Cell, Institutional Ethics Committee (IEC), King George’s Medical University (Reference no.89th ECM II A/P8), Lucknow, India. Studies were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

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Tripathi, K., Maurya, N., Goel , A. et al. Immunohistochemical expressions of EMT markers in pan-RAS–pERK1/2-positive tumors improve diagnosis and prognosis assessment of non-muscle invasive bladder cancer and muscle invasive bladder cancer patients. Mol Cell Biochem 478, 1169–1190 (2023). https://doi.org/10.1007/s11010-022-04579-x

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