microRNA-539 suppresses tumor growth and tumorigenesis and overcomes arsenic trioxide resistance in hepatocellular carcinoma

Zhu, Congcong; Zhou, Ran; Zhou, Qing; Chang, Yue-wen; Jiang, Mawei

doi:10.1016/j.lfs.2016.10.002

Cited by 40 publications

(24 citation statements)

References 26 publications

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“…Muthusamy et al (48), profiling miRNAs in the failing heart, revealed miR-539 to be a regulator of O-GlcNAcase expression. Recently, miR-539 has been shown to inhibit migration, invasion, and epithelial-mesenchymal transition in several tumor types (50,51). To our knowledge, our present study represents the first comprehensive analysis of miR-539 in angiogenesis.…”

Section: Discussionmentioning

confidence: 75%

miR‐539‐5p inhibits experimental choroidal neovascularization by targeting CXCR7

et al. 2018

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Stromal cell-derived factor-1 (SDF-1) has been previously confirmed to participate in the formation of choroidal neovascularization (CNV) via its receptor, CXC chemokine receptor (CXCR) 4; CXCR7 is a recently identified receptor for SDF-1. The molecular mechanisms and therapeutic value of CXCR7 in CNV remain undefined. In this study, experimental CNV was induced by laser photocoagulation in Brown-Norway pigmented rats, and aberrant CXCR7 overexpression was detected in the retinal pigment epithelial/choroid/sclera tissues of laser-injured eyes. Blockade of CXCR7 activation via CXCR7 knockdown or neutralizing Ab administration inhibited SDF-1-induced cell survival and the tubular formation of human retinal microvascular endothelial cells (HRMECs) in vitro and reduced CNV leakage and lesion size in vivo. By using microRNA array screening and bioinformatic analyses, we identified miR-539-5p as a regulator of CXCR7. Transfection of HRMECs and choroid-retinal endothelial (RF/6A) cells with the miR-539-5p mimic inhibited their survival and tube formation, whereas CXCR7 overexpression rescued the suppressive effect of miR-539-5p. The antiangiogenic activities of the miR-539-5p mimic were additionally demonstrated in vivo by intravitreal injection. ERK1/2 and AKT signaling downstream of CXCR7 is involved in the miR-539-5p regulation of endothelial cell behaviors. These findings suggest that the manipulation of miR-539-5p/CXCR7 levels may have important therapeutic implications in CNV-associated diseases.-Feng, Y., Wang, J., Yuan, Y., Zhang, X., Shen, M., Yuan, F. miR-539-5p inhibits experimental choroidal neovascularization by targeting CXCR7.

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Section: Discussionmentioning

confidence: 75%

miR‐539‐5p inhibits experimental choroidal neovascularization by targeting CXCR7

et al. 2018

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“…Additionally, Zhu et al reported miR-539 was downregulated in HCC tissues and cells, and suppresses tumor growth and tumorigenesis in vitro and in vivo . miR-539 overcomes arsenic trioxide resistance in HCC (22). There may be different effects of miR-539 on different cellular processes involved in tumor development, so the roles of miR-539 are still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

miR-539 inhibits FSCN1 expression and suppresses hepatocellular carcinoma migration and invasion

et al. 2017

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Increasing evidence indicates that the dysregulation of miRNAs that act as tumor suppressors or oncogenes is involved in tumorigenesis. However, the role of miR-539 in hepatocellular carcinoma (HCC) has not been well investigated. Quantitative RT-PCR (qRT-PCR), proliferation assay, colony formation assay, migration and invasion assays, western blotting, and xenograft tumor growth models were performed to assess the expression levels and functions of miR-539 in HCC. Luciferase reporter assays, qRT-PCR, western blotting, and immunohistochemistry were used to identify and verify the targets of miR-539. miR-539 was significantly downregulated in HCC cell lines and tissue samples. Ectopic expression of miR-539 inhibited cell viability, proliferation, migration, and invasion in vitro and suppressed xenograft tumor growth in vivo. Fascin homologue 1 (FSCN1) was verified as a direct target of miR-539, and overexpression of FSCN1 promoted HCC cell migration and invasion. miR-539 acts as a novel tumor suppressor in the development and progression of HCC by targeting FSCN1, providing new insight into the mechanisms of HCC carcinogenesis and suggesting that miR-539 may be a therapeutic target.

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“…Although the role of this three miRNAs (miR-539, miR-376b and miR-18b) in GIST has not been reported yet, the following research supports our results. miRNA-539 overcomed arsenic trioxide resistance in hepatocellular carcinoma [33]. The decreased expression of miR-376 family might be related to the tumorigenesis of human glioma [34].…”

Section: Discussionmentioning

confidence: 98%

APOBEC3B and SPAG5, the Target Genes of miR-539, Involved into Imatinib-Resistant of Gastrointestinal Stromal Tumors

Zhang¹,

Liu²,

Li³

et al. 2020

Preprint

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Background: Although imatinib can effectively treat gastrointestinal stromal tumor (GIST), some patients are still resistant to it or cannot tolerate the adverse reactions of the drug. This study aimed to investigate potential miRNAs, mRNA and tumor-infiltrating lymphocytes (TILs) associated with the prognosis of imatinib-resistant GIST.Methods: mRNA, miRNA sequencing data and patient clinic traits of primary (imatinib-naive) and imatinib-resistant GIST were obtained from GEO (Gene Expression Omnibus) database. A systems biology approach combining Weighted co-expression network analysis (WGCNA) and differential expression analysis were utilized to detect the imatinib-resistant-related miRNA and gene modules and construct a miRNA-gene network. Tumor-infiltrating immune cells were analyzed by Estimating the Proportion of Immune and Cancer cells (EPIC) and Tumor-Immune System Interactions (TISIDB). miR-539 was measured by qRT-PCR. SPAG5 and APOBEC3B was measured by qRT-PCR and WB. Transforming growth factor (TGF)-β and interleukin (IL)-10 were assessed with enzyme-linked immunosorbent assay (ELISA). The proportions of CD4+ T cells, CD8+ T cells , NK cells and B cells in tumor-infiltrating lymphocyteswere analyzed via flow cytometry (FCM).Results: Two gene modules (brown and yellow) and one miRNA module were associated with the imatinib-resistant. Two hub genes (APOBEC3B and SPAG5) were associated with the imatinib-resistant. Three hub miRNAs were identified to be related to imatinib-resistant (miR-539, miR-376b and miR-18b). G1/S transition of mitotic cell cycle, G2/M transition of mitotic cell cycle, and cell proliferation were common pathways of the gene modules and miRNA module. apolipoprotein B mRNA editing catalytic polypeptide-like 3B (APOBEC3B) and Sperm-associated antigen 5 (SPAG5), which were both target genes of miR-539 was located at the core of miRNA–gene network. APOBEC3B (rho=0.509, p < 2.2e-16) and SPAG5 (rho=0.468, p < 2.2e-16) was positive correlated with the infiltration levels of activated CD4+ T cells. he proportions of CD4+ T cells, and the mRNA and protein relative expression of APOBEC3B and SPAG5 in imatinib-resistant tumor samples significantly increased as compared with tumor samples in imatinib-naive group. Imatinib-resistant tumor samples exhibited significantly downregulation of miR-539 and TGF-β1. Over-expression of miR-539 sensitized imatinib resistant GIST48 cells and increased the secretion of TGF-β1 by inhibiting APOBEC3B and SPAG5.Conclusion: APOBEC3B and SPAG5, the target genes of miR-539 may play as key factor for imatinib-resistant GIST by increasing the proportion of tumor-infiltrated activated CD4+ T cells via TGF-β1. These findings help to advance the understanding of imatinib-resistant GIST and provide potential therapeutic targets.

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microRNA-539 suppresses tumor growth and tumorigenesis and overcomes arsenic trioxide resistance in hepatocellular carcinoma

Cited by 40 publications

References 26 publications

miR‐539‐5p inhibits experimental choroidal neovascularization by targeting CXCR7

miR‐539‐5p inhibits experimental choroidal neovascularization by targeting CXCR7

miR-539 inhibits FSCN1 expression and suppresses hepatocellular carcinoma migration and invasion

APOBEC3B and SPAG5, the Target Genes of miR-539, Involved into Imatinib-Resistant of Gastrointestinal Stromal Tumors

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