Exosomes delivering miR-129-5p combined with sorafenib ameliorate hepatocellular carcinoma progression via the KCTD1/HIF-1α/VEGF pathway

作者：Xinyu Zhu, Zhiwei Li, Li Chen, Limin Li, Mi Ouyang, Hao Zhou, Kai Xiao, Ling Lin, Paul K. Chu, Chang Zhou, Chengfeng Xun, Liu Yang, Wenhuan Huang, Xiaofeng Ding · 发表于：Cellular Oncology · 年份：2025 · DOI：10.1007/s13402-025-01044-x · 被引用次数：8 · 研究领域：Ion channel regulation and function、MicroRNA in disease regulation、Extracellular vesicles in disease

BACKGROUND: Potassium channel tetramerization domain-containing 1 (KCTD1) plays a critical role in transcriptional regulation and adipogenesis, but its significance in hepatocellular cancer (HCC) has not been reported. METHODS: Immunohistochemistry, Western blotting and quantitative real-time PCR analysis were performed to assess the expression of KCTD1 and related genes in HCC cells. MTT assays, colony formation, cell migration, invasion and the in-vivo mouse models were utilized to evaluate the function of KCTD1 in HCC progression. Co-immunoprecipitation, chromatin immunoprecipitation and luciferase reporter assays were conducted to elucidate the molecular mechanisms of KCTD1 in HCC. RESULTS: KCTD1 expression was increased in human HCC tissues and closely associated with advanced tumor stages. KCTD1 overexpression enhanced growth, migration, and invasion of Huh7 and HepG2 cells both in vitro and in vivo, while KCTD1 knockdown reversed these effects in MHCC97H cells. Mechanistically, KCTD1 interacted with hypoxia-inducible factor 1 alpha (HIF-1α) and enhanced HIF-1α protein stability with the inhibited prolyl-hydroxylases (PHD)/Von Hippel-Lindau (VHL) pathway, consequently activating the Vascular Endothelial Growth Factor (VEGF)/VEGFR2 pathway in HCC cells. Sorafenib and KCTD1 knockdown synergistically inhibited intrahepatic tumor growth following in situ injection of MHCC97H cells. miR-129-5p downregulated KCTD1 by binding to KCTD1 3'UTR. Finally, 45 µg exosomes from miR-12...