Overexpression of Parkin in clear cell renal cell carcinoma decreases tumor aggressiveness by regulating CKS2 levels

Esser,Laura Kristin; Branchi,Vittorio; Shakeri,Farhad; Simon,Adrian Georg; Stephan,Carsten; Kristiansen,Glen; Buness,Andreas; Schorle,Hubert; Toma,Marieta Ioana

doi:10.3892/ijo.2022.5310

Overexpression of Parkin in clear cell renal cell carcinoma decreases tumor aggressiveness by regulating CKS2 levels

Authors:
- Laura Kristin Esser
- Vittorio Branchi
- Farhad Shakeri
- Adrian Georg Simon
- Carsten Stephan
- Glen Kristiansen
- Andreas Buness
- Hubert Schorle
- Marieta Ioana Toma
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Affiliations: Institute of Pathology, University Hospital Bonn, D-53127 Bonn, Germany, Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, D-53127 Bonn, Germany, Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, D-53127 Bonn, Germany, Department of Urology, Charité‑Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Berlin Institute for Urologic Research, D-10117 Berlin, Germany, Institute of Pathology, Department of Developmental Pathology, University Hospital Bonn, D-53127 Bonn, Germany
Published online on: January 18, 2022 https://doi.org/10.3892/ijo.2022.5310
Article Number: 20
Copyright: © Esser et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Low expression levels of the E3 ubiquitin‑protein ligase Parkin (PARK2) are exhibited in several cancer entities, including clear cell renal cell carcinoma (ccRCC), and are associated with poor prognosis; however, PARK2 can also function as a tumor suppressor gene. The aim of the present study was to thoroughly investigate the effects of PARK2 overexpression in ccRCC cell lines and to determine its effects on malignancy by conducting functional assays such as cell cycle analysis, apoptosis analysis, migration and invasion assays. Furthermore, liquid chromatography‑mass spectrometry was used to decipher potential targets of PARK2 that may influence the behavior of ccRCC tumor cells. In addition, ccRCC tumor tissues from a patient cohort were examined in tissue microarrays to find correlations between different clinical parameters. In the present study, it was demonstrated that the induction of PARK2 resulted in a less aggressive phenotype, as indicated by lower migration and invasion in ccRCC cell lines. Mass spectrometry revealed decreased levels of 29 proteins in cells with PARK2 overexpression, including CDC28 protein kinase regulatory subunit 2 (CKS2), which is highly expressed in numerous types of cancer. The link between the function of PARK2 as an E3 ubiquitin ligase and the low expression levels of CKS2 was investigated by mutating the catalytic domain of the PARK2 gene, and it was found that the effect of decreased migration was abolished in 786‑O and RCC‑MH ccRCC cell lines. CKS2 silencing decreased migratory ability of the cells. Furthermore, it was revealed that high CKS2 levels are associated with high tumor grading in patient samples and lower patient survival. In conclusion, the results from the present study indicated that PARK2 may signal via CKS2 to affect tumor behavior. In consequence, CKS2 may be a biomarker in ccRCC and may also serve as potential target for ccRCC therapy.

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