Song Wei, Zhang Heng, Lu Yi, Zhang Houliang, Ni Jinliang, Chang Lan, Gu Yongzhe, Wang Guangchun, Xu Tianyuan, Wu Zonglin, Wang Keyi
Department of Urology, Shanghai Shidong Hospital of Yangpu District, Shanghai, China.
Department of Urology, Shanghai Putuo District People's Hospital, Tongji University, Shanghai, China.
Front Pharmacol. 2024 Oct 8;15:1446920. doi: 10.3389/fphar.2024.1446920. eCollection 2024.
Patients diagnosed with papillary renal cell carcinoma (pRCC) exhibit a high rate of clinical metastasis; however, the underlying molecular mechanism is unclear. In this study, KH-type splicing regulatory protein (KHSRP) participated in pRCC progression and was associated with metastasis. It was positively correlated with the hallmark of epithelial-mesenchymal transition. KHSRP inhibition effectively alleviated the cellular function of migration and invasion. Additionally, KHSRP knockdown inhibited the proliferative ability of pRCC cells. A pharmaceutical screening was based on the KHSRP protein structure. Gemcitabine (Gem) decreased KHSRP expression. UIO-66@Gem@si-KHSRP (UGS) nanoparticles (NPs) were prepared for targeted delivery and applied in both and experiments to explore the clinical transition of KHSRP. UGS NPs exhibited better performance in inhibiting cellular proliferation, migration, and invasion than Gem. Additionally, the experiment results confirmed their therapeutic effects in inhibiting tumor metastasis with excellent biosafety. The silico analysis indicated that KHSRP knockdown increased cytotoxic cell infiltration in the tumor microenvironment to potentiate anti-tumor effects. Thus, KHSRP can promote pRCC progression as an oncogene and serve as a target in clinical transition through UGS NP-based therapy.
被诊断为乳头状肾细胞癌（pRCC）的患者临床转移率很高；然而，其潜在的分子机制尚不清楚。在本研究中，KH型剪接调节蛋白（KHSRP）参与了pRCC的进展并与转移相关。它与上皮-间质转化的标志呈正相关。抑制KHSRP可有效减轻细胞的迁移和侵袭功能。此外，敲低KHSRP可抑制pRCC细胞的增殖能力。基于KHSRP蛋白结构进行了药物筛选。吉西他滨（Gem）可降低KHSRP表达。制备了UIO-66@Gem@si-KHSRP（UGS）纳米颗粒（NPs）用于靶向递送，并应用于体内和体外实验以探索KHSRP的临床转化。UGS NPs在抑制细胞增殖、迁移和侵袭方面表现出比Gem更好的性能。此外，体内实验结果证实了它们在抑制肿瘤转移方面的治疗效果以及出色的生物安全性。计算机分析表明，敲低KHSRP可增加肿瘤微环境中细胞毒性细胞的浸润，从而增强抗肿瘤作用。因此，KHSRP作为一种癌基因可促进pRCC进展，并可通过基于UGS NPs的疗法成为临床转化的靶点。
