Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, People's Republic of China.
Beijing Laboratory of Oral Health, Capital Medical University, Beijing, People's Republic of China.
Br J Cancer. 2024 Jul;131(2):347-360. doi: 10.1038/s41416-024-02725-4. Epub 2024 May 31.
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.
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.
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.
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.
舒尼替尼已成为晚期或转移性透明细胞肾细胞癌（ccRCC）的主要治疗药物，因为它显著延长了患者的平均生存时间。然而，舒尼替尼的耐药性和不良反应对其临床获益构成了挑战。
研究了与 ccRCC 中舒尼替尼敏感性和耐药性相关的差异表达基因（DEGs）。采用细胞计数试剂盒-8、平板集落形成、流式细胞术和皮下异种移植肿瘤模型实验来探讨 PDZK1 对 ccRCC 的影响。通过 Western blot、共免疫沉淀、免疫荧光共定位和免疫组织化学染色进一步研究了分子机制。
我们阐明了 PDZK1 在舒尼替尼耐药的 ccRCC 标本中显著下调，并且 PDZK1 通过与 PDGFR-β 相互作用负调控 PDGFR-β 的磷酸化和下游途径的激活。失调的低水平 PDZK1 导致细胞增殖、肿瘤生长的抑制不足以及对舒尼替尼治疗的不敏感。值得注意的是，我们的临床前研究表明，miR-15b 拮抗剂通过上调 PDZK1 水平增强了舒尼替尼对 ccRCC 细胞的细胞毒性作用，提示其在克服舒尼替尼耐药方面的潜力。
我们的研究结果确立了 miR-15b/PDZK1/PDGFR-β 轴作为一种有前途的治疗靶点和预测 ccRCC 患者对舒尼替尼治疗反应的新标志物。
