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Abstract
Background
Sunitinib has emerged as the primary treatment for advanced or metastatic clear cell renal cell carcinoma (ccRCC) due to its significant improvement in patients’ average survival time. However, drug resistance and adverse effects of sunitinib pose challenges to its clinical benefits.
Methods
The differentially expressed genes (DEGs) associated with sunitinib sensitivity and resistance in ccRCC were investigated. Cell counting kit-8, plate colony formation, flow cytometry and subcutaneous xenograft tumor model assays were employed to explore the effects of PDZK1 on ccRCC. Further research on the molecular mechanism was conducted through western blot, co-immunoprecipitation, immunofluorescence co-localization and immunohistochemical staining.
Results
We elucidated that PDZK1 is significantly downregulated in sunitinib-resistant ccRCC specimens, and PDZK1 negatively regulates the phosphorylation of PDGFR-β and the activation of its downstream pathways through interaction with PDGFR-β. The dysregulated low levels of PDZK1 contribute to inadequate inhibition of cell proliferation, tumor growth, and insensitivity to sunitinib treatment. Notably, our preclinical investigations showed that miR-15b antagomirs enhance sunitinib cytotoxic effects against ccRCC cells by upregulating PDZK1 levels, suggesting their potential in overcoming sunitinib resistance.
Conclusions
Our findings establish the miR-15b/PDZK1/PDGFR-β axis as a promising therapeutic target and a novel predictor for ccRCC patients’ response to sunitinib treatment.
Details
; Zhang, Lijie 2 ; Liu, Hua 3 ; Yang, Yumeng 3
; Lu, Wenxiu 3
; Cao, Xuedi 3 ; Yang, Xiaomei 4 ; Qin, Qiong 4 ; Song, Ran 4 ; Feng, Duiping 5 ; Wang, Songlin 6 ; Bai, Tao 7
; He, Junqi 4
1 Capital Medical University, Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Beijing, People’s Republic of China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); Capital Medical University, Beijing Laboratory of Oral Health, Beijing, People’s Republic of China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); Capital Medical University, Laboratory for Clinical Medicine, Beijing, People’s Republic of China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X)
2 Beijing Luhe Hospital, Capital Medical University, Center for Endocrine Metabolism and Immune Diseases, Beijing, People’s Republic of China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X)
3 Capital Medical University, Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Beijing, People’s Republic of China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X)
4 Capital Medical University, Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Beijing, People’s Republic of China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); Capital Medical University, Laboratory for Clinical Medicine, Beijing, People’s Republic of China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X)
5 First Hospital of Shanxi Medical University, Department of Interventional Radiology, Taiyuan, People’s Republic of China (GRID:grid.452461.0) (ISNI:0000 0004 1762 8478)
6 Capital Medical University, Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Beijing, People’s Republic of China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); Capital Medical University, Beijing Laboratory of Oral Health, Beijing, People’s Republic of China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); Capital Medical University, Salivary Gland Disease Center and Molecular Laboratory for Gene Therapy and Tooth Regeneration, School of Stomatology, Beijing, People’s Republic of China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X)
7 First Hospital of Shanxi Medical University, Department of Pathology, Taiyuan, People’s Republic of China (GRID:grid.452461.0) (ISNI:0000 0004 1762 8478)