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CEP55 Promotes Cell Motility via JAK2⁻STAT3⁻MMPs Cascade in Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common malignancies and has a poor prognosis. Novel diagnostic or prognostic biomarkers and potential therapeutic targets for HCC are thus urgently needed. CEP55 plays a crucial role in regulating physical cytokinesis. Whether, and how, CEP55 contributes to HCC development remains unclear. Herein, we demonstrate that CEP55 is abnormally upregulated in HCC tissue, and these high levels of CEP55 are closely related to the poor prognosis of HCC patients. Knockdown of CEP55 expression significantly inhibits HCC cell migration and invasion. We also demonstrate that CEP55 physiologically interacts with JAK2 and promotes its phosphorylation; thus, it is a novel regulator of JAK2⁻STAT3 signaling and its target genes MMP2/9. Finally, blocking JAK2 or STAT3 blunts the stimulation of migration and invasion due to CEP55 overexpression. In summary, our results suggest that CEP55, as an oncogene, promotes HCC cell migration and invasion through regulating JAK2⁻STAT3⁻MMPs signaling.

SUBMITTER: Li M

PROVIDER: S-EPMC6115913 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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CEP55 Promotes Cell Motility via JAK2⁻STAT3⁻MMPs Cascade in Hepatocellular Carcinoma.

Li Minjing M Gao Ju J Li Defang D Yin Yancun Y

Cells 20180808 8

Hepatocellular carcinoma (HCC) is one of the most common malignancies and has a poor prognosis. Novel diagnostic or prognostic biomarkers and potential therapeutic targets for HCC are thus urgently needed. CEP55 plays a crucial role in regulating physical cytokinesis. Whether, and how, CEP55 contributes to HCC development remains unclear. Herein, we demonstrate that CEP55 is abnormally upregulated in HCC tissue, and these high levels of CEP55 are closely related to the poor prognosis of HCC pati ...[more]

PMID: 30096813

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Project description:IntroductionHepatocellular carcinoma (HCC) accounts for 80% of all liver cancers and is the 2nd leading cause of cancer-related death in Taiwan. Various factors, including rapid cell growth, a high recurrence rate and drug resistance, make HCC difficult to cure. Moreover, the survival rate of advanced HCC patients treated with systemic chemotherapy remains unsatisfactory. Hence, the identification of novel molecular targets and the underlying mechanisms of chemoresistance in HCC and the development more effective therapeutic regimens are desperately needed.MethodsAn MTT assay was used to determine the cell viability after cisplatin or doxorubicin treatment. Western blotting, qRT‒PCR and immunohistochemistry were utilized to examine the protein tyrosine phosphatase IVA3 (PTP4A3) level and associated signaling pathways. ELISA was utilized to analyze the levels of the inflammatory cytokine IL-6 influenced by cisplatin, doxorubicin and PTP4A3 silencing.ResultsIn this study, we found that PTP4A3 in the cisplatin/doxorubicin-resistant microarray was closely associated with the overall and recurrence-free survival rates of HCC patients. Cisplatin or doxorubicin significantly reduced cell viability and decreased PTP4A3 expression in hepatoma cells. IL-6 secretion increased with cisplatin or doxorubicin treatment and after PTP4A3 silencing. Furthermore, PTP4A3 was highly expressed in tumor tissues versus adjacent normal tissues from HCC patients. In addition, we evaluated the IL-6-associated signaling pathway involving STAT3 and JAK2, and the levels of p-STAT3, p-JAK2, STAT3 and JAK2 were obviously reduced with cisplatin or doxorubicin treatment in HCC cells using Western blotting and were also decreased after silencing PTP4A3. Collectively, we suggest that cisplatin or doxorubicin decreases HCC cell viability via downregulation of PTP4A3 expression through the IL-6R-JAK2-STAT3 cascade.DiscussionTherefore, emerging evidence provides a deep understanding of the roles of PTP4A3 in HCC cisplatin/doxorubicin chemoresistance, which can be applied to develop early diagnosis strategies and reveal prognostic factors to establish novel targeted therapeutics to specifically treat HCC.

Project description:BackgroundUbiquitin-conjugating enzyme E2S (UBE2S), an E2 enzyme, is associated with the development of various tumors and exerts oncogenic activities. UBE2S is overexpressed in tumors, including hepatocellular carcinoma (HCC). However, the key molecular mechanisms of UBE2S in HCC still need additional research. The aim of this study was to explore the role of UBE2S in HCC.MethodsThe expression levels of UBE2S in HCC tissues and cells were detected by western blot analysis, quantitative real-time polymerase chain reaction analysis (qRT-PCR), and immunohistochemistry (IHC). A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, wound healing assay, colony formation assay transwell assay, and animal models were used to detect the proliferation and migration ability of HCC cells. Western blot analysis, qRT-PCR, immunofluorescence, small-interfering RNA (siRNA), and plasmid transfection and coimmunoprecipitation (Co-IP) assays were performed to detect the interaction among UBE2S, von Hippel-Lindau (VHL), hypoxia-inducible factor 1-alpha (HIF-1α), Janus kinase-2 (JAK2), and signal transducer and activator of transcription 3 (STAT3).ResultsIn this study, we found that high UBE2S expression was associated with poor prognosis in HCC patients. In addition, UBE2S expression was upregulated in HCC tissues and cell lines. Knockdown of UBE2S inhibited the proliferation and migration of HCC cells in vitro and in vivo by directly interacting with VHL to downregulate the HIF-1α and JAK2/STAT3 signaling pathways. Accordingly, overexpression of UBE2S significantly enhanced the proliferation and migration of HCC cells in vitro via VHL to upregulate HIF-1α and JAK2/STAT3 signaling pathways. Furthermore, we found that downregulation of UBE2S expression enhanced the sensitivity of HCC cells to sorafenib in vivo and in vitro.ConclusionUBE2S enhances malignant properties via the VHL/HIF-1α and VHL/JAK2/STAT3 signaling pathways and reduces sensitivity to sorafenib in HCC. The findings of this study may open a new approach for HCC diagnosis and provide a potential option for the treatment of HCC.

Dataset Information

CEP55 Promotes Cell Motility via JAK2⁻STAT3⁻MMPs Cascade in Hepatocellular Carcinoma.

Publications

CEP55 Promotes Cell Motility via JAK2⁻STAT3⁻MMPs Cascade in Hepatocellular Carcinoma.

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