VRK2 promotes HCC metastasis by enhancing autophagy-mediated degradation of ZO-1
4 affiliations
- 1Department of Thyroid Surgery, Second Affiliated Hospital School of Medicine, Zhejiang University
- 2Department of Interventional Radiology and Vascular Surgery, Ganzhou Key Laboratory of Interventional Medicine, Ganzhou Hospital-Nanfang Hospital, Southern Medical University (Ganzhou People’s Hospital)
- 3Center for Medical Research and Innovation in Digestive System Tumors, Minstry of Education
- 4Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine
Abstract
Background: Vaccinia-related kinase 2 (VRK2) is involved in multiple cancers, but its role in the metastasis of hepatocellular carcinoma (HCC) is largely unknown. The regulatory mechanisms underlying the abnormally low expression of the tight junction protein Zonula occludens-1 (ZO-1) in HCC also remain unclear. This study aimed to investigate the function of VRK2 in HCC metastasis and the underlying molecular mechanisms.
Methods: We examined VRK2 expression in HCC tissues using the GEPIA database, immunohistochemistry, western blotting and analyzed its correlation with patient prognosis. Gain- and loss-of-function approaches were employed to assess the effects of VRK2 on HCC cell invasion and metastasis in vitro and in vivo . Isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis, co-immunoprecipitation, phosphoproteomic mass spectrometry, and autophagic flux assays were performed to elucidate the molecular mechanisms.
Results: VRK2 was markedly overexpressed in HCC, and high VRK2 expression was associated with poor overall survival and disease-free survival. Silencing VRK2 decreased HCC cell invasion and metastasis in vitro and in vivo , whereas VRK2 overexpression increased them. Mechanistically, VRK2 directly phosphorylated Autophagy-related 5 (ATG5) at serine 106, enhancing its interaction with Ubiquitin-specific peptidase 13 (USP13) and protecting ATG5 from ubiquitin-dependent proteasomal degradation. The stabilization of ATG5 activated autophagy, which subsequently promoted the degradation of the tight junction protein ZO-1, leading to disruption of cell-cell adhesion and enhanced metastatic capacity. The VRK2-ATG5-autophagy-ZO-1 regulatory axis was validated in clinical HCC tissue specimens.
Conclusions: Our findings identify VRK2 as a novel promoter of HCC metastasis through phosphorylation-mediated stabilization of ATG5 and subsequent autophagy-dependent degradation of ZO-1. This study reveals VRK2 as a potential prognostic biomarker and therapeutic target for metastatic HCC.
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BibTeX
@article{ye2026vrk2,
title = {{VRK2 promotes HCC metastasis by enhancing autophagy-mediated degradation of ZO-1}},
author = {Mao Ye and Baoliang Zhong and Jingying Zhang and Binglong Bai and Hengqing Zhu and Jiangtao Li},
journal = {Frontiers in Oncology},
year = {2026},
month = nov,
doi = {10.3389/fonc.2026.1988374},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1988374/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - VRK2 promotes HCC metastasis by enhancing autophagy-mediated degradation of ZO-1
AU - Mao Ye
AU - Baoliang Zhong
AU - Jingying Zhang
AU - Binglong Bai
AU - Hengqing Zhu
AU - Jiangtao Li
PY - 2026
DA - 2026/11/04
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1988374
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1988374/full
AB - Background: Vaccinia-related kinase 2 (VRK2) is involved in multiple cancers, but its role in the metastasis of hepatocellular carcinoma (HCC) is largely unknown. The regulatory mechanisms underlying the abnormally low expression of the tight junction protein Zonula occludens-1 (ZO-1) in HCC also remain unclear. This study aimed to investigate the function of VRK2 in HCC metastasis and the underlying molecular mechanisms. Methods: We examined VRK2 expression in HCC tissues using the GEPIA database, immunohistochemistry, western blotting and analyzed its correlation with patient prognosis. Gain- and loss-of-function approaches were employed to assess the effects of VRK2 on HCC cell invasion and metastasis in vitro and in vivo . Isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis, co-immunoprecipitation, phosphoproteomic mass spectrometry, and autophagic flux assays were performed to elucidate the molecular mechanisms. Results: VRK2 was markedly overexpressed in HCC, and high VRK2 expression was associated with poor overall survival and disease-free survival. Silencing VRK2 decreased HCC cell invasion and metastasis in vitro and in vivo , whereas VRK2 overexpression increased them. Mechanistically, VRK2 directly phosphorylated Autophagy-related 5 (ATG5) at serine 106, enhancing its interaction with Ubiquitin-specific peptidase 13 (USP13) and protecting ATG5 from ubiquitin-dependent proteasomal degradation. The stabilization of ATG5 activated autophagy, which subsequently promoted the degradation of the tight junction protein ZO-1, leading to disruption of cell-cell adhesion and enhanced metastatic capacity. The VRK2-ATG5-autophagy-ZO-1 regulatory axis was validated in clinical HCC tissue specimens. Conclusions: Our findings identify VRK2 as a novel promoter of HCC metastasis through phosphorylation-mediated stabilization of ATG5 and subsequent autophagy-dependent degradation of ZO-1. This study reveals VRK2 as a potential prognostic biomarker and therapeutic target for metastatic HCC.
SN - 2234-943X
ER -