Abstract
Introduction
In RCC, systematic procedures such as surgery, chemo-radiation therapy, and application of target-based inhibitors increase the risk of several comorbidities such as chronic kidney disease, hemorrhage, and cardiac arrest that may increase the mortality rate. Even though immune-based checkpoint inhibitor therapies have an overall good response rate, it is restricted to only 30–40% of patients. Hence, an in-depth study of tumor pathophysiology in RCC is needed to identify the new therapeutic target. In RCC, persisted hypoxia is an essential phenomenon for tumor growth and progression. KCMF1 is a newly identified ubiquitin ligase whose domain interacts with destabilized proteins and reprogrammed the ubiquitin coding for lysosome-mediated degradation and autophagy under hypoxic conditions/oxidative stress and maintaining cellular homeostasis. But in RCC, the functional role of KCMF1 remains undefined to date.
Method
We determined KCMF1 and its associated proteins RAD6 and UBR4 expression and their co-localization using confocal microscopy in tumor and non-tumor tissues samples. Further, immunofluorescence staining was performed to determine autophagy (LC3B, p62), hypoxia-inducible factor (HIF-1A) and ion channel markers (Kv1.3, KCNN4) in RCC patients (n−10). Inductively coupled plasma mass spectrophotometry (ICPMS) was performed to estimate the concentration of potassium (K+), sodium (Na+) and Zinc (zn2+) in tumor and non-tumor cells of RCC patients (n−20). Lastly, images were analyzed using ZEN3.1, and ImageJ software.
Result and conclusion
We observed a discrepancy in the formation of ubiquitin ligase, autophagosome via KCMF1, and ionic concentration in tumor cells, which might be one of the possible factors for cancer evolution. KCMF1-associated ubiquitin ligase system could be considered as a novel therapeutic target for RCC in the future.
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Data availability
The datasets generated and analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.
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Acknowledgements
We are grateful to Centralized Core Research Facility (CCRF) for providing confocal microscopy instrument facility to capture and analysis of the images using ZEN software.
Funding
This study received funding from the Council of Scientific & Industrial Research (CSIR-009/006(0480)/2018 EMR-I) (Project code C-2097).
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AS and AS designed the project and planned the experiments. AS performed all the experiments and generated the data. SDC helped in confocal microscopy and interpretation of the data. PS provides patient samples and clinical data. VVS and SNS contribute to the standardization of ICP-MS. AS and AS prepared the manuscript. All the authors provided critical review of the manuscript.
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Human sample was collected and used for experiments according to AIIMS ethics Committee guidelines (India). Approved human ethics file number is IECPG-413/27.06.2019.
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Singh, A., Choudhury, S.D., Singh, P. et al. KCMF1 regulates autophagy and ion channels’ function in renal cell carcinoma: a future therapeutic target. J Cancer Res Clin Oncol 149, 5617–5626 (2023). https://doi.org/10.1007/s00432-022-04507-y
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DOI: https://doi.org/10.1007/s00432-022-04507-y