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Cellular Oncology

Open Access 14-04-2025 | Sorafenib | Research

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

Authors: 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

Published in: Cellular Oncology

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Abstract

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-129-5p-overexpressing MHCC97H cells combined with 25 mg/kg sorafenib to decrease HCC tumor size.

Conclusions

These results suggested that KCTD1 protects HIF-1α from degradation and activates the VEGF signaling cascade to enhance HCC progression. Therefore, KCTD1 may serve as a novel target of HCC and pave the way for an efficient combined therapy in advanced HCC.
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Metadata
Title
Exosomes delivering miR-129-5p combined with sorafenib ameliorate hepatocellular carcinoma progression via the KCTD1/HIF-1α/VEGF pathway
Authors
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
Publication date
14-04-2025
Publisher
Springer Netherlands
Published in
Cellular Oncology
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-025-01044-x

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