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Uridine-cytidine kinase 2 promotes metastasis of hepatocellular carcinoma cells via the Stat3 pathway

Authors Zhou Q, Jiang H, Zhang J, Yu W, Zhou Z, Huang P, Wang J, Xiao Z

Received 6 August 2018

Accepted for publication 24 September 2018

Published 26 November 2018 Volume 2018:10 Pages 6339—6355

DOI https://doi.org/10.2147/CMAR.S182859

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 3

Editor who approved publication: Dr Xueqiong Zhu


Qiming Zhou,1,2,* Hai Jiang,1–3,* Jianlong Zhang,1,2,* Wei Yu,1,2 Zhenyu Zhou,1,2 Pinbo Huang,1,2 Jie Wang,1,2 Zhiyu Xiao1,2

1Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; 2Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; 3Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China

*These authors contributed equally to this work

Introduction: Uridine-cytidine kinase 2 (Uck2) has been demonstrated to activate antitumor prodrugs and regulate chemosensitivity in cancer cells. However, the expression and function of Uck2 in hepatocellular carcinoma (HCC) remain unknown. In this study, we were the first to systematically elucidate the role of Uck2 in HCC.
Patients and methods: Uck2 gene expression was queried between normal liver tissues and HCC in a web-based data mining platform (www.oncomine.org). Uck2 gene expression in tissue microarray was determined by immunohistochemical staining. The clinical and prognostic significance of Uck2 expression was statistically analyzed. Stable cell lines with increased Uck2 expression were established using lentivirus-based vectors, and RNAi technology was used to transiently downregulate Uck2 expression. Cell migration and invasion were assessed by using wound-healing and transwell assays, respectively. mRNA and protein expression levels were determined using quantitative real-time PCR and Western blotting, respectively.
Results: We report the upregulation of Uck2 expression in HCC tissues. We explored the relationship between Uck2 levels and the clinicopathological features of HCC patients. High Uck2 notably correlated with early recurrence and poor prognosis in HCC patients. Uck2 expression in HCC cell lines regulated the cell migration and invasion capacities in vitro. The stable overexpression of Uck2 in Bel-7402 cells promoted their metastasis ability in vivo. Furthermore, the Uck2 upregulation increased the MMP2/9 expression and activated the Stat3 signaling pathway. In addition, WP1066, a Stat3 inhibitor, neutralized the effects of Uck2 on the MMP2/9 expression and the migration and invasion capacities of HCC cells.
Conclusion: Our data suggest that Uck2 promotes HCC cell migration and invasion via the Stat3 signaling pathway and might be a novel potential target in HCC therapy.

Keywords: uridine-cytidine kinase 2, metastasis, hepatocellular carcinoma, oncogene, signal transducer, activator of transcription 3

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