Lu Guangxian, Li Jianhua, Ding Leyun, Wang Chenping, Tang Lian, Liu Xin, Xu Jinhui, Zhou Qin, Sun Jiantong, Wang Wenjuan, Ding Xinyuan
Department of Pharmacy, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
Front Oncol. 2021 Feb 24;11:629640. doi: 10.3389/fonc.2021.629640. eCollection 2021.
Ubiquitin C-terminal hydrolase L1 (UCHL1), which is a deubiquitinating enzyme, is known to play a role in chemoresistance in cancers. However, its potential roles and mechanisms in the chemoresistance of breast cancer (BC) remain unclear. In this study, we examined its expression in patients with BC and employed Kaplan-Meier analysis and the log-rank test for survival analyses. It was found that up-regulated UCHL1 expression was positively associated with both chemoresistance and poor prognosis, especially in patients with HER2+ BC. Moreover, UCHL1 expression was elevated in HER2+ BC cells (SK-BR-3 and BT474). Similarly, doxorubicin (DOX)-resistant BC cells (MCF-7/DOX) had higher UCHL1 levels than MCF-7 cells. CCK-8 assay showed that BC cells with higher UCHL1 levels were more resistant to DOX. Furthermore, by inhibiting UCHL1 in BC cells with elevated UCHL1 expression, we demonstrated that UCHL1 promoted DOX-resistance in BC. Mechanistically, UCHL1 probably promoted DOX-resistance of BC by up-regulating free fatty acid (FFA) synthesis, as exhibited by reduced FFA synthase expression and resurrected DOX-sensitivity upon UCHL1 inhibition. Overall, UCHL1 up-regulation is associated with DOX-resistance and poor prognosis in patients with HER2+ BC. UCHL1 induces DOX-resistance by up-regulating FFA synthesis in HER2+ BC cells. Thus, UCHL1 might be a potential clinical target for overcoming DOX resistance in patients with HER2+ BC.
泛素 C 末端水解酶 L1（UCHL1）是一种去泛素化酶，已知其在癌症的化疗耐药中发挥作用。然而，其在乳腺癌（BC）化疗耐药中的潜在作用和机制仍不清楚。在本研究中，我们检测了其在 BC 患者中的表达，并采用 Kaplan-Meier 分析和对数秩检验进行生存分析。结果发现，UCHL1 表达上调与化疗耐药和不良预后均呈正相关，尤其是在 HER2+ BC 患者中。此外，HER2+ BC 细胞（SK-BR-3 和 BT474）中 UCHL1 表达升高。同样，阿霉素（DOX）耐药的 BC 细胞（MCF-7/DOX）的 UCHL1 水平高于 MCF-7 细胞。CCK-8 检测表明，UCHL1 水平较高的 BC 细胞对 DOX 的耐药性更强。此外，通过抑制 UCHL1 表达升高的 BC 细胞中的 UCHL1，我们证明 UCHL1 促进了 BC 细胞对 DOX 的耐药性。机制上，UCHL1 可能通过上调游离脂肪酸（FFA）合成来促进 BC 细胞对 DOX 的耐药性，这表现为 FFA 合酶表达降低以及 UCHL1 抑制后 DOX 敏感性恢复。总体而言，UCHL1 上调与 HER2+ BC 患者的 DOX 耐药和不良预后相关。UCHL1 通过上调 HER2+ BC 细胞中的 FFA 合成诱导 DOX 耐药。因此，UCHL1 可能是克服 HER2+ BC 患者 DOX 耐药的潜在临床靶点。
