Wang Zhibin, Mao Jing, Zhang Yukun, Yang Wenyu, Sun Deliang, Lu Ziyin, Lu Xiuli, Gao Bing
Department of Biochemistry and Cell Biology, School of Life Sciences, Liaoning University, Shenyang, Liaoning 110036, P.R. China.
Department of Cell Biology and Genetics, School of Basic Medical Sciences, Shenyang Medical College, Shenyang, Liaoning 110034, P.R. China.
Oncol Lett. 2025 Jun 5;30(2):385. doi: 10.3892/ol.2025.15131. eCollection 2025 Aug.
There is a strong association between cholesterol reprogramming and cancer development. However, 3β-hydroxysteroid Δ24-reductase (DHCR24), the final enzyme in the cholesterol biosynthesis pathway, has been relatively understudied in cancer progression. The present study aimed to perform a comprehensive pan-cancer analysis of DHCR24 to elucidate its role across different malignancies. The interacting proteins of DHCR24 were identified by molecular docking node dynamics simulation. Duolink proximity ligation, cell viability and filipin staining assays were used to assess the function of DHCR24 in cancer cells and its underlying oncogenic mechanisms. The findings revealed that DHCR24 exhibits high expression in seven cancer types (bladder cancer, breast invasive carcinoma, liver hepatocellular carcinoma, prostate adenocarcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, uterine corpus endometrial carcinoma and stomach adenocarcinoma), and low expression in five others (glioblastoma multiforme, kidney chromophobe, kidney renal clear cell carcinoma, lung adenocarcinoma and lung squamous cell carcinoma), suggesting that DHCR24 serves distinct roles depending on the cancer type. Notably, it was demonstrated that DHCR24 expression consistently increases with tumor stage and serves as an independent prognostic factor in BLCA. Moreover, molecular docking and kinetic modeling identified HRAS as a key interacting protein of DHCR24. The Duolink assay further demonstrated that DHCR24 interacts with HRAS outside the nucleus in 5637 human BLCA cells. Filipin fluorescence staining and cell proliferation assays also revealed that this interaction promoted cholesterol synthesis, contributing to cancer cell proliferation in the 5637 cells. In conclusion, the results of the present study provide novel insights into the oncogenic role of DHCR24 in BLCA and demonstrates its interaction with HRAS for the first time to the best of our knowledge, highlighting a potential mechanism driving tumor progression.
胆固醇重编程与癌症发展之间存在密切关联。然而，3β - 羟基类固醇Δ24 - 还原酶（DHCR24）作为胆固醇生物合成途径中的终末酶，在癌症进展方面的研究相对较少。本研究旨在对DHCR24进行全面的泛癌分析，以阐明其在不同恶性肿瘤中的作用。通过分子对接节点动力学模拟鉴定了DHCR24的相互作用蛋白。采用Duolink邻近连接、细胞活力和 Filipin染色试验来评估DHCR24在癌细胞中的功能及其潜在的致癌机制。研究结果显示，DHCR24在七种癌症类型（膀胱癌、乳腺浸润性癌、肝细胞肝癌、前列腺腺癌、宫颈鳞状细胞癌和宫颈内膜腺癌、子宫内膜癌和胃腺癌）中高表达，而在其他五种癌症类型（多形性胶质母细胞瘤、肾嫌色细胞癌、肾透明细胞癌、肺腺癌和肺鳞状细胞癌）中低表达，这表明DHCR24在不同癌症类型中发挥着不同的作用。值得注意的是，研究表明DHCR24的表达随肿瘤分期持续增加，并作为膀胱癌的独立预后因素。此外，分子对接和动力学建模确定HRAS是DHCR24的关键相互作用蛋白。Duolink试验进一步证明，在5637人膀胱癌细胞中，DHCR24与HRAS在细胞核外相互作用。 Filipin荧光染色和细胞增殖试验还表明，这种相互作用促进了胆固醇合成，有助于5637细胞中的癌细胞增殖。总之，本研究结果为DHCR24在膀胱癌中的致癌作用提供了新的见解，并首次证明了其与HRAS的相互作用，突出了驱动肿瘤进展的潜在机制。
