Repaglinide restrains HCC development and progression by targeting FOXO3/lumican/p53 axis

作者：Yifei Tan, Yongjie Zhou, Wei Zhang, Zhenru Wu, Qing Xu, Qiong Wu, Jian Yang, Jian Yang, Tao Lv, Lvnan Yan, Hong Luo, Yujun Shi, Jiayin Yang, Jiayin Yang · 发表于：Cellular Oncology · 年份：2024 · DOI：10.1007/s13402-024-00919-9 · 被引用次数：5 · 研究领域：FOXO transcription factor regulation、Heat shock proteins research、Signaling Pathways in Disease

The recent focus on the roles of N-linked glycoproteins in carcinogenesis across various malignancies has prompted our exploration of aberrantly expressed glycoproteins responsible for HCC progression and potential therapeutic strategy. Mass spectrometry was applied to initially identify abnormally expressed glycoproteins in HCC, which was further assessed by immunohistochemistry (IHC) staining. The role of selected glycoprotein on HCC development and underlying mechanism was systematically investigated by colony formation, mouse xenograft, RNA-sequencing and western blot assays, etc. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to explore potential transcription factors (TFs) of selected glycoprotein. The regulation of repaglinide (RPG) on expression of lumican and downstream effectors was assessed by western blot and IHC, while its impact on malignant phenotypes of HCC was explored through in vitro and in vivo analyses, including a murine NASH-HCC model established using western diet and carbon tetrachloride (CCl 4 ). Lumican exhibited upregulation in both serum and tumor tissue, with elevated expression associated with an inferior prognosis in HCC patients. Knockdown of lumican resulted in significantly reduced growth of HCC in vitro and in vivo. Mechanically, lumican promoted HCC malignant phenotypes by inhibiting the p53/p21 signaling pathway. Forkhead Box O3 (FOXO3) was identified as the TF of lumican that transcriptionally enhanced its expr...