HEY2, a target of miR-137, indicates poor outcomes and promotes cell proliferation and migration in hepatocellular carcinoma

Wu, Donghai; Zhang, Meifang; Su, Shu-Guang; Fang, Heng-Ying; He, Dalin; Xie, Yuanyuan; Liu, Xuhui

doi:10.18632/oncotarget.9343

Cited by 21 publications

(24 citation statements)

References 31 publications

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“…Liang et al ( 12 ) reported that downregulation of miR-137 promoted cell proliferation in pediatric high-grade gliomas. Furthermore, the suppressive role of miR-137 in HCC has gradually been elucidated ( 13 ). Liu et al ( 14 ) reported that miR-137 suppresses tumor growth and metastasis in HCC by targeting AKT serine/threonine kinase 2.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-137 has a suppressive role in liver cancer via targeting EZH2

Cui

Sun

Liu

et al. 2017

Molecular Medicine Reports

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A variety of microRNAs (miRs) have been demonstrated to be associated with the development and malignant progression of human cancer; however, the regulatory mechanism of miR-137 underlying hepatocellular carcinoma (HCC) growth and metastasis still remains to be fully revealed. In the present study, reverse transcription-quantitative polymerase chain reaction and western blot were used to examine mRNA and protein expression. MTT assay, wound healing assay and Transwell assay were performed to determine cell proliferation, migration and invasion. Luciferase reporter assay was conducted to confirm the targeting relationship. miR-137 was significantly downregulated in HCC tissues compared to adjacent normal tissues. Low expression of miR-137 was significantly associated with lymph node metastasis, vein invasion, advanced clinical stage and poor prognosis in HCC. In addition, miR-137 was also downregulated in several liver cancer cell lines compared with normal liver epithelial cells. Overexpression of miR-137 led to a significant reduction in cell proliferation, migration and invasion of HepG2 cells. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) was further identified as a direct target gene of miR-137, and the protein expression of EZH2 was negatively regulated by miR-137 in HepG2 cells. Additionally, EZH2 was significantly upregulated in HCC tissues and liver cancer cell lines. Furthermore, overexpression of EZH2 significantly eliminated the inhibitory effects of miR-137 on the malignant phenotypes of HepG2 cells. Therefore, the findings suggest that miR-137 may have a suppressive role in HCC growth and metastasis via targeting EZH2.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-137 has a suppressive role in liver cancer via targeting EZH2

Cui

Sun

Liu

et al. 2017

Molecular Medicine Reports

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“…On the other hand, miR-34a was found to promote proliferation of human pulmonary artery smooth muscle cells by targeting platelet-derived growth factor alpha [ 15 ], and miR-181b activated the PI3K and MAPK signaling pathways, which subsequently promoted VSMCs proliferation [ 16 ]. Recently, miR-137 was found to play tumor-suppressive roles in the different types of cancers [ 17 – 20 ]. However, it is unclear whether miR-137 plays a role in the VSMCs proliferation and migration.…”

Section: Introductionmentioning

confidence: 99%

MiR-137 inhibited cell proliferation and migration of vascular smooth muscle cells via targeting IGFBP-5 and modulating the mTOR/STAT3 signaling

Jin

Huang

et al. 2017

PLoS ONE

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Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to the development of cardiovascular diseases. Studies have shown the great impact of microRNAs (miRNAs) on the cell proliferation of VSMCs. This study examined the effects of miR-137 on the cell proliferation and migration of VSMCs and also explored the underlying molecular mechanisms. The mRNA and protein expression levels were determined by qRT-PCR and western blot assays, respectively. The CCK-8 assay, wound healing assay and transwell migration assay were performed to measure cell proliferation and migration of VSMCs. The miR-137-targeted 3’untranslated region of insulin-like growth factor-binding protein-5 (IGFBP-5) was confirmed by luciferase reporter assay. Platelet-derived growth factor-bb (PDGF-bb) treatment enhanced cell proliferation and suppressed the expression of miR-137 in VSMCs. The gain-of-function and loss-of-function assays showed that overexpression of miR-137 suppressed the cell proliferation and migration, and also inhibited the expression of matrix genes of VSMCs; down-regulation of miR-137 had the opposite effects on VSMCs. Bioinformatics analysis and luciferase report assay results showed that IGFBP-5 was a direct target of miR-137, and miR-137 overexpression suppressed the IGFBP-5 expression and down-regulation of miR-137 increased the IGFBP-5 expression in VSMCs. PDGF-bb treatment also increased the IGFBP-5 mRNA expression. In addition, enforced expression of IGFBP-5 reversed the inhibitory effects of miR-137 on cell proliferation and migration of VSMCs. More importantly, overexpression of miR-137 also suppressed the activity of mTOR/STAT3 signaling in VSMCs. Taken together, the results suggest that miR-137 may suppress cell proliferation and migration of VSMCs via targeting IGFBP-5 and modulating mTOR/STAT3 signaling pathway.

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“…Liu et al found that miR-98 was upregulated in rabbit brains during the progression of AD-like pathology, consistent with previous reports that miR-98 was upregulated in AD mouse models ( 38 ). Furthermore, during zebrafish arteriovenous differentiation, Sox18 and Sox7 induced HEY2 ortholog gridlock, and a high expression of HEY2 has been found in other diseases, indicating that HEY2 may inhibit cell differentiation ( 21 ). However, miR-98 contributed to inhibition of the expression of HEY2 and the Notch signaling pathway in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Notch signals are transferred among adjacent cells through Notch receptors and their ligands that regulate differentiation, proliferation and apoptosis in several cell types, including stem cells ( 20 ). Hairy and enhancer of split (Hes)-related with YRPW motif protein 2 (HEY2), a hairy-related transcription factor family of Notch-downstream transcriptional repressors, has indispensable and complementary functions for the development of blood vessels ( 21 , 22 ). MicroRNAs (miRs) are small non-coding RNAs that regulate protein output post-transcriptionally, and each biological process is associated with miRNA-dependent regulation ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-98 reduces amyloid β-protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer's disease mice

2018

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Alzheimer’s disease (AD) is a chronic neurodegenerative disease that often occurs at a slow pace yet deteriorates with time. MicroRNAs (miRs) have been demonstrated to offer novel therapeutic hope for disease treatment. The aim of the present study was to investigate the effect of miR-98 on amyloid β (Aβ)-protein production, oxidative stress and mitochondrial dysfunction through the Notch signaling pathway by targeting hairy and enhancer of split (Hes)-related with YRPW motif protein 2 (HEY2) in mice with AD. A total of 70 Kunming mice were obtained and subjected to behavioral assessment. The levels of oxidative stress-related proteins glutathione peroxidase, reduced glutathione, super-oxide dismutase, malondialdehyde, acetylcholinesterase and Na+-K+-ATP were measured. Morphological changes in brain tissue, HEY2-positivity levels, neuronal apoptotic index (AI) and neuron mitochondrial DNA (mtDNA) levels were also determined. Subsequently, the levels of miR-98 and the mRNA and protein levels of HEY2, Jagged1, Notch1, Hes1, Hes5, β-amyloid precursor protein, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein in tissues and hippocampal neurons were determined by reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. Finally, hippocampal neuron viability and apoptosis were determined using an MTT assay and flow cytometry, respectively. The levels of miR-98-targeted HEY2 and miR-98 were low and the levels of HEY2 were high in the AD mice. The AD mice exhibited poorer learning and memory abilities, oxidative stress function, and morphological changes of pyramidal cells in the hippocampal CA1 region. Furthermore, the AD mice exhibited increased protein levels of HEY2 and AI in the CA1 region of brain tissues with reduced mtDNA levels and dysfunctional neuronal mitochondria. miR-98 suppressed hippocampal neuron apoptosis and promoted hippocampal neuron viability by inactivating the Notch signaling pathway via the inhibition of HEY2. In conclusion, the results demonstrated that miR-98 reduced the production of Aβ and improved oxidative stress and mitochondrial dysfunction through activation of the Notch signaling pathway by binding to HEY2 in AD mice.

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HEY2, a target of miR-137, indicates poor outcomes and promotes cell proliferation and migration in hepatocellular carcinoma

Cited by 21 publications

References 31 publications

MicroRNA-137 has a suppressive role in liver cancer via targeting EZH2

MicroRNA-137 has a suppressive role in liver cancer via targeting EZH2

MiR-137 inhibited cell proliferation and migration of vascular smooth muscle cells via targeting IGFBP-5 and modulating the mTOR/STAT3 signaling

MicroRNA-98 reduces amyloid β-protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer's disease mice

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