The members of myocyte Enhancer Factor 2 (MEF2) protein family was previously believed to function in the development of heart and muscle. Recent reports indicate that they are also closely associated with development and progression of many human diseases. Although their role in cancer biology is well established, the molecular mechanisms underlying their action is yet largely unknown. MEF2 family is closely associated with various signaling pathways, including Ca2+ signaling, MAP kinase signaling, Wnt signaling, PI3K/Akt signaling, etc. microRNAs also contribute to regulate the activities of MEF2. In this review, we summarize the known molecular mechanism by which MEF2 family contribute to human diseases.

/pdf/mef2-signaling-and-human-diseases-18xogaxwt3.pdf

MEF2 signaling and human diseases

MicroRNAs (miRNAs) are small non-coding RNAs that are key post-transcriptional regulators of gene expression. MicroRNA-214 (miR-214) and microRNA-218 (miR-218) have shown the function of tumor suppressors in various types of human cancers. However, the biological functions of miR-214 and miR-218 in breast cancer have not been elucidated completely. The present study evaluated the expression and biological function of miR-214 and miR-218 in human breast cancer. Our results revealed that the expression of miR-214 and miR-218 were significantly decreased in breast cancer tissues compared with adjacent tissues. The aberrant expression of miR-214 and miR-218 were negatively associated with Ki-67, and the miR-218 expression was positively associated with progesterone receptor (PR) in breast cancer tissues. In vitro, the cell proliferation and migration were decreased, cell apoptosis was induced, and cell cycle was also disturbed in miR-214 or miR-218 overexpressed breast cancer cells. Our results demonstrated that miR-214 and miR-218 function as tumor suppressors in breast cancer, and may become biomarkers and potential therapeutic targets in breast cancer.

https://www.spandidos-publications.com/10.3892/or.2016.4749/download

Tumor-suppressing roles of miR-214 and miR-218 in breast cancer

This study is performed to examine the impacts of microRNA-218 (miR-218) on cardiac microvascular endothelial cells (CMECs) injury induced by coronary artery disease (CAD). Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) was applied for detecting miR-218 expression in serum of patients with CAD and healthy controls, and the correlation between miR-218 expression and the clinical indexes such as creatine kinase, creatine kinase-myocardial band, cardiac troponin I, and coronary Gensini score was analyzed. CMECs were coincubated with homocysteine for 24 hr for CMECs injury, and the cells were transfected with miR-218 mimics or miR-218 inhibitors. Besides, we used oxidized low density lipoprotein as an inducer to incubate with CMECs for 24 hr, and the model of CMECs injury was established to be transfected with miR-218 mimics. RT-qPCR and western blot analysis were used to detect miR-218 and HMGB1 expression in CMECs. A series of experiments were used to determine cell proliferation, apoptosis, migration, and angiogenesis ability of CMECs. Vascular endothelial growth factor expression and inflammatory factor contents were measured. The obtained results suggested that miR-218 expression in peripheral blood of patients with CAD descended substantially versus that of healthy controls. Low miR-218 expression was found in CAD-induced CMECs injury. Overexpressed miR-218 promoted the proliferation, migration, angiogenesis ability, induced apoptosis, and alleviated the inflammatory injury of CAD-induced CMECs. miR-218 may negatively regulate the expression of HMGB1 in CAD. This study demonstrates that upregulation of miR-218 reduces CMECs injury induced by CAD through the inhibition of HMGB1.

Upregulation of microRNA-218 reduces cardiac microvascular endothelial cells injury induced by coronary artery disease through the inhibition of HMGB1.

Myocyte enhancer factor (MEF)-2 plays a critical role in proliferation, differentiation, and development of various cell types in a tissue specific manner. Four isoforms of MEF-2 (A-D) differentially participate in controlling the cell fate during the developmental phases of cardiac, muscle, vascular, immune and skeletal systems. Through their associations with various cellular factors MEF-2 isoforms can trigger alterations in complex protein networks and modulate various stages of cellular differentiation, proliferation, survival and apoptosis. The role of the MEF-2 family of transcription factors in the development has been investigated in various cell types, and the evolving alterations in this family of transcription factors have resulted in a diverse and wide spectrum of disease phenotypes, ranging from cancer to infection. This review provides a comprehensive account on MEF-2 isoforms (A-D) from their respective localization, signaling, role in development and tumorigenesis as well as their association with histone deacetylases (HDACs), which can be exploited for therapeutic intervention.

/pdf/mef-2-isoforms-a-d-roles-in-development-and-tumorigenesis-1gfu9qnlcm.pdf

MEF-2 isoforms' (A-D) roles in development and tumorigenesis.

// Zhi-Qin Hu 1, 2, * , Jian-Fang Luo 1, 2, * , Xue-Ju Yu 1, 2, * , Jie-Ning Zhu 1, 2 , Lei Huang 3 , Jing Yang 1, 4 , Yong-Heng Fu 1, 2 , Tao Li 2 , Yu-Mei Xue 1, 2 , Ying-Qing Feng 1, 2 and Zhi-Xin Shan 1, 2 1 Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangzhou, China 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China 3 Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China 4 School of Medicine, South China University of Technology, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Ying-Qing Feng, email: fyq1819@163.com Zhi-Xin Shan, email: zhixinshan@aliyun.com Keywords: microRNA-92b-3p, cardiac hypertrophy, cardiomyocyte, MEF2D Received: June 10, 2017      Accepted: July 30, 2017      Published: September 08, 2017 ABSTRACT The role of microRNA-92b-3p (miR-92b-3p) in cardiac hypertrophy was not well illustrated. The present study aimed to investigate the expression and potential target of miR-92b-3p in angiotensin II (Ang-II)-induced mouse cardiac hypertrophy. MiR-92b-3p was markedly decreased in the myocardium of Ang-II-infused mice and of patients with cardiac hypertrophy. However, miR-92b-3p expression was revealed increased in Ang-II-induced neonatal mouse cardiomyocytes. Cardiac hypertrophy was shown attenuated in Ang-II-infused mice received tail vein injection of miR-92b-3p mimic. Moreover, miR-92b-3p inhibited the expression of atrial natriuretic peptide (ANP), skeletal muscle α-actin (ACTA1) and β-myosin heavy chain (MHC) in Ang-II-induced mouse cardiomyocytes in vitro . Myocyte-specific enhancer factor 2D (MEF2D), which was increased in Ang-II-induced mouse hypertrophic myocardium and cardiomyocytes, was identified as a target gene of miR-92b-3p. Functionally, miR-92b-3p mimic, consistent with MEF2D siRNA, inhibited cell size increase and protein expression of ANP, ACTA1 and β-MHC in Ang-II-treated mouse cardiomyocytes. Taken together, we demonstrated that MEF2D is a novel target of miR-92b-3p, and attenuation of miR-92b-3p expression may contribute to the increase of MEF2D in cardiac hypertrophy.

Targeting myocyte-specific enhancer factor 2D contributes to the suppression of cardiac hypertrophic growth by miR-92b-3p in mice.

Cardiac myxoma is the most common type of human heart tumor, yet the molecular mechanism is still poorly understood. In the present study, we found that the level of myocyte enhancer factor 2D (MEF2D), a key regulatory protein for cardiac development, was elevated in specimens of cardiac myxoma, and was positively associated with the proliferation of myxoma cells. MEF2D suppression reduced the proliferation of myxoma cells and its tumorigenicity. Cell cycle progression was also inhibited by MEF2D suppression. miR-218, which is downregulated in myxoma, suppressed MEF2D expression by targeting its mRNA 3'UTR. Altogether, we found that miR-218/MEF2D may be an effective target for myxoma treatment.

/pdf/mir-218-suppresses-cardiac-myxoma-proliferation-by-targeting-rv1na6qjhv.pdf

miR-218 suppresses cardiac myxoma proliferation by targeting myocyte enhancer factor 2D

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miR-218 suppresses cardiac myxoma proliferation by targeting myocyte enhancer factor 2D