Wang Yu, Zhao Yun-Xia, Zhang Xiang-Wei, Jiang Yuan-Zhu, Ma Wei, Zhang Lin, Dong Wei
Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Department of Neurology, Shandong Provinacial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Front Mol Biosci. 2022 Jan 27;9:758968. doi: 10.3389/fmolb.2022.758968. eCollection 2022.
Lung cancer remains the leading cause of oncological death. There is an urgent need to discover new molecular targets and to develop new treatments. Our previous study showed that one of the UDP-glucuronosyltransferases (UGTs) family, UGT1A3, is an important prognostic factor for lung adenocarcinoma (LUAD), inhibiting UGT1A3 could significantly improve the efficacy of anti-tumor drugs. In this study, we aimed to explore the upstream transcriptional factor (USF1) of UGT1A3 and its way of playing a role in LUAD. The UGT1A3 promoter region was analyzed and dual-luciferase assay was involved to explore whether USF1 could bind to this region, and the possible regulation effects of USF1 to UGT1A3 was indicated by siRNA and recovery experiment. Then, the Cancer Genome Atlas database was used to analyze USF1 clinical features. The expression level of USF1 was detected by immunohistochemical assay and Western blotting. Cellular viability, proliferation, migration and invasion potential were also investigated. Meanwhile, the effect of USF1 in LUAD progression was detected in a mouse model. The downstream signaling pathway was analyzed by bioinformatic analysis and the expression of all related proteins was detected. UGT1A3 was transcriptionally regulated by USF1, which was highly expressed in all investigated samples including patients' tissues, studied cells lines, and mouse models. The knockdown of USF1 inhibited cells viability, proliferation, migration and invasion, and reduced the tumor volume. Moreover, USF1 promoted the progress of LUAD by regulating the neurotrophin signaling pathway. As an important transcriptional regulator of UGT1A3, USF1 was highly expressed in LUAD and promoted LUAD progression by regulating the neurotrophin signaling pathway. These findings provide a new theoretical data that could serve as a good foundation for the treatment of LUAD.
肺癌仍然是肿瘤死亡的主要原因。迫切需要发现新的分子靶点并开发新的治疗方法。我们之前的研究表明，尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）家族之一的UGT1A3是肺腺癌（LUAD）的一个重要预后因素，抑制UGT1A3可显著提高抗肿瘤药物的疗效。在本研究中，我们旨在探索UGT1A3的上游转录因子（USF1）及其在LUAD中的作用方式。对UGT1A3启动子区域进行了分析，并采用双荧光素酶测定法来探究USF1是否能结合该区域，siRNA和回复实验表明了USF1对UGT1A3可能的调控作用。然后，利用癌症基因组图谱数据库分析USF1的临床特征。通过免疫组织化学测定法和蛋白质印迹法检测USF1的表达水平。还研究了细胞活力、增殖、迁移和侵袭潜力。同时，在小鼠模型中检测USF1在LUAD进展中的作用。通过生物信息学分析下游信号通路，并检测所有相关蛋白的表达。UGT1A3受USF1转录调控，USF1在包括患者组织、研究的细胞系和小鼠模型在内的所有研究样本中均高表达。敲低USF1可抑制细胞活力、增殖、迁移和侵袭，并减小肿瘤体积。此外，USF1通过调节神经营养因子信号通路促进LUAD的进展。作为UGT1A3的重要转录调节因子，USF1在LUAD中高表达，并通过调节神经营养因子信号通路促进LUAD的进展。这些发现提供了新的理论数据，可为LUAD的治疗奠定良好基础。
