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

ABSTRACT: 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.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC6267774 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Zhou Qiming Q Jiang Hai H Zhang Jianlong J Yu Wei W Zhou Zhenyu Z Huang Pinbo P Wang Jie J Xiao Zhiyu Z

Cancer management and research 20181126

<h4>Introduction</h4>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.<h4>Patients and methods</h4>Uck2 gene expression was queried between normal liver tissues and HCC in a web-based data mining platform (www.oncomine.org). Uck2 gene e ...[more]

PMID: 30568496

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Project description:BackgroundmiR-500a-3p has been demonstrated to be involved in the development, progression and metastasis in several human cancers. Constitutive activation of JAK/STAT3 signaling pathway has been reported to play an important role in the development and progression of hepatocellular carcinoma (HCC).The purpose of this study was to determine the biological roles and clinical significance of miR-500a-3p in HCC and to identify whether miR-500a-3p has an effect on the activity of JAK/STAT3 signaling in HCC.MethodsmiR-500a-3p expression was examined by real-time PCR in 8 paired HCC tissues and individual 120 HCC tissues respectively. Statistical analysis was performed to explore the clinical correlation between miR-500a-3p expression and clinicopathological features and overall and relapse-free survival in HCC patients. In vitro and in vivo assays were performed to investigate the biological roles of miR-500a-3p in HCC. The bioinformatics analysis, real-time PCR, western blot and luciferase reporter assay were performed to discern and examine the relationship between miR-500a-3p and its potential targets. Clinical correlation of miR-500a-3p with its targets was examined in HCC tissues.ResultsmiR-500a-3p is dramatically elevated in HCC tissues and cells and high expression of miR-500a-3p correlates with poor overall and relapse-free survival in HCC patients. Upregulating miR-500a-3p enhances, while silencing miR-500a-3p suppresses, the spheroid formation ability, fraction of side population and expression of cancer stem cell factors in vitro and tumorigenicity in vivo in HCC cells. Our findings further reveal miR-500a-3p promotes the cancer stem cell characteristics via targeting multiple negative regulators of JAK/STAT3 signaling pathway, including SOCS2, SOCS4 and PTPN11, leading to constitutive activation of STAT3 signaling. Moreover, the inhibitory effects of anti-miR-500a-3p on cancer stem cell phenotypes and activity of STAT3 signaling were reversed by silencing SOCS2, SOCS4 and PTPN11 in miR-500a-3p-downexpressing cells, respectively. Clinical correlation of miR-500a-3p with the targets was examined in human HCC tissues.Conclusionour results uncover a novel mechanism by which miR-500a-3p promotes the stemness maintenance of cancer stem cell in HCC, suggesting that silencing miR-500a-3p may serve as a new therapeutic strategy in the treatment of hepatocellular carcinoma.

Project description:Hepatocellular carcinoma (HCC) is a malignant tumor with a high metastatic rate. Recent studies have shown that the mitosis‑associated spindle‑assembly checkpoint regulatory protein spindle pole body component 25 homolog (SPC25) promotes HCC progression, although the underlying mechanism has yet to be fully elucidated. The aim of the present study was to investigate the mechanism through which SPC25 may promote HCC progression in greater detail. First, the expression of SPC25 was analyzed in publicly available databases to explore the association between SPC25 and HCC metastasis. Western blotting was subsequently performed to examine the level of SPC25 expression in different HCC cell lines. SPC25 was then silenced in HCCLM3 and Huh7 cells, and the effects of SPC25 silencing were investigated using cell proliferation, wound‑healing, Transwell migration assays and an in vivo mouse model. Finally, the mechanism of SPC25 action with respect to the promotion of HCC metastasis was explored using microarray analysis and rescue experiments. The results obtained demonstrated that SPC25 is highly expressed in HCC, and this high level of expression is associated with poor prognosis and metastasis. Moreover, SPC25 silencing led to a marked inhibition of the invasion and migration of HCC cells both in vitro and in vivo. The gene‑expression profiling and mechanistic experiments suggest that SPC25 preferentially influences the expression of genes associated with extracellular matrix (ECM)‑integrin interactions, including integrin subunit β4 (ITGB4), an upstream element of the integrin pathway. ITGB4 upregulation partly reversed the decline in cell invasion and migration capacities that resulted from SPC25 silencing. Furthermore, deleting both SPC25 and ITGB4 caused a decrease in the phosphorylation of focal adhesion kinase (FAK), phosphoinositide 3‑kinase (PI3K) and AKT, which are downstream elements of the integrin pathway. Taken together, the results of the present study demonstrated the important role of SPC25 as a prognostic indicator and as a promoter of metastasis in HCC, and the underlying mechanism of its action has been partially elucidated, suggesting that SPC25 could be used as a biomarker and as a target for therapeutic intervention in the treatment of HCC.

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

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

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