Vaccinia-related kinase 1 promotes hepatocellular carcinoma by controlling the levels of cell cycle regulators associated with G1/S transition.

Namgyu Lee,Kyong-Tai Kim,Weiguang Xu,Sung Jin Park,Hoe-Yune Jung,Kwan Yong Choi,Seong-Hoon Kim,Jung-Hee Kwon,Hee Jung Wang,Young Bae Kim

doi:10.18632/oncotarget.4967

Namgyu Lee, Kyong-Tai Kim + Show 8 more

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https://doi.org/10.18632/oncotarget.4967

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Abstract

We identified the specific role of vaccinia-related kinase 1 (VRK1) in the progression of hepatocellular carcinoma (HCC) and evaluated its therapeutic and prognostic potential. VRK1 levels were significantly higher in HCC cell lines than a normal hepatic cell line, and were higher in HCC than non-tumor tissue. VRK1 knockdown inhibited the proliferation of SK-Hep1, SH-J1 and Hep3B cells; moreover, depletion of VRK1 suppressed HCC tumor growth in vivo. We also showed that VRK1 knockdown increased the number of G1 arrested cells by decreasing cyclin D1 and p-Rb while upregulating p21 and p27, and that VRK1 depletion downregulated phosphorylation of CREB, a transcription factor regulating CCND1. Additionally, we found that luteolin, a VRK1 inhibitor, suppressed HCC growth in vitro and in vivo, and that the aberrant VRK1 expression correlated with poor prognostic features of HCC. High levels of VRK1 were associated with shorter overall and disease-free survival and higher recurrence rates. Taken together, our findings suggest VRK1 may act as a tumor promoter by controlling the level of cell cycle regulators associated with G1/S transition and could potentially serve as a therapeutic target and/or prognostic biomarker for HCC.

Highlights

Liver cancer is the second leading cause of cancer-related death among males and the sixth most common cause of death among females, worldwide [1]
Our findings suggest that vaccinia-related kinase 1 (VRK1) enhances Hepatocellular carcinoma (HCC) cell proliferation by modulating the levels of regulators associated with G1/S transition and that VRK1 levels are much higher in HCC tissues than non-tumor tissues, and are associated with shorter overall and disease-free survival and a higher recurrence rate
To identify the role of VRK1 in liver cancer, VRK1 levels were examined in an immortalized hepatocyte cell line, THLE-2, and in six HCC cell lines, including SH-J1, SK-Hep1, Huh-7, Hep3B, HepG2 and SNU449

Summary

Introduction

Liver cancer is the second leading cause of cancer-related death among males and the sixth most common cause of death among females, worldwide [1]. The major reason for unsuccessful treatment of HCC is resistance to conventional chemotherapy [3], and surgical resection and liver transplantation have limited applicability due to frequent tumor recurrence [4]. A better understanding of the mechanisms underlying HCC progression is crucial for effective treatment of the disease. VRK1 www.impactjournals.com/oncotarget mediates p53 accumulation by increasing its stability through phosphorylation of Thr-18 within its mdm-2 binding site [10, 11]. VRK1 levels are downregulated by p53, forming autoregulatory loop [12]. This p53-induced downregulation of VRK1 is dependent on an autophagic pathway and protein degradation by lysosomes [13]

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