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Purpose: To characterize the phenotype and genotype of a Chinese family with autosomal‐dominant retinitis pigmentosa (RP) accompanied by iris coloboma. Methods: The proband, a 34‐year‐old male, was examined with his family by using fundus photography, optical coherence tomography (OCT), autofluorescence, and full‐field electroretinography (ffERG). Genetic analyses were conducted through whole‐exome sequencing (WES) to screen for variations. Results: Three members of this Chinese family were shown to be bilateral iris coloboma. The male proband and his mother exhibited typical RP feature. The proband's late grandfather had been documented manifestation of iris coloboma. The mode of inheritance was confirmed to be autosomal dominance. Through linkage analysis and WES, a heterozygous variation in the miR‐204 gene (n.37C>T), a noncoding RNA gene, was identified in these three members. Conclusions: In this third independent and the first Asian family, the existence of a miR‐204 variant associated with RP accompanied by iris coloboma was confirmed. Our findings reinforce the significance of miR‐204 as an important factor influencing visual function in the retina. When phenotypes like RP accompanied by iris coloboma in an autosomal‐dominant pattern, including in Chinese patients, miR‐204 aberrations should be considered. [ABSTRACT FROM AUTHOR]

Background and Purpose: Atherosclerosis induced by cyclosporine A (CsA), an inhibitor of the calcineurin/nuclear factor of activated T cells (NFAT) pathway, is a major concern after organ transplantation. However, the atherosclerotic mechanisms of CsA remain obscure. We previously demonstrated that calcineurin/NFAT signalling inhibition contributes to atherogenesis via suppressing microRNA‐204 (miR‐204) transcription. We therefore hypothesised that miR‐204 is involved in the development of CsA‐induced atherosclerosis. Experimental Approach: ApoE−/− mice with macrophage‐miR‐204 overexpression were generated to determine the effects of miR‐204 on CsA‐induced atherosclerosis. Luciferase reporter assays and chromatin immunoprecipitation sequencing were performed to explore the targets mediating miR‐204 effects. Key Results: CsA alone did not significantly affect atherosclerotic lesions or serum lipid levels. However, it exacerbated high‐fat diet‐induced atherosclerosis and hyperlipidemia in C57BL/6J and ApoE−/− mice, respectively. miR‐204 levels decreased in circulating monocytes and plaque lesions during CsA‐induced atherosclerosis. The upregulation of miR‐204 in macrophages inhibited CsA‐induced atherosclerotic plaque formation but did not affect serum lipid levels. miR‐204 limited the CsA‐induced foam cell formation by reducing the expression of the scavenger receptors SR‐BII and CD36. SR‐BII was post‐transcriptionally regulated by mature miR‐204‐5p via 3′‐UTR targeting. Additionally, nuclear‐localised miR‐204‐3p prevented the CsA‐induced binding of Ago2 to the CD36 promoter, suppressing CD36 transcription. SR‐BII or CD36 expression restoration dampened the beneficial effects of miR‐204 on CsA‐induced atherosclerosis. Conclusion and Implications: Macrophage miR‐204 ameliorates CsA‐induced atherosclerosis, suggesting that miR‐204 may be a potential target for the prevention and treatment of CsA‐related atherosclerotic side effects. [ABSTRACT FROM AUTHOR]

T cell acute lymphoblastic leukaemia (T‐ALL) is a highly aggressive haematological cancer of the bone marrow. The abnormal expression of microRNAs (miRNAs) is reportedly involved in T‐ALL development and progression. Thus, we aimed to decipher the involvement of miR‐204 silencing mediated by DNA methylation in the occurrence of T cell acute lymphoblastic leukaemia (T‐ALL). miR‐204 expression was determined in bone marrow and peripheral blood samples from T‐ALL patients by real‐time quantitative PCR (RT‐qPCR) with its effect on cell proliferation evaluated by functional assays. In addition, bisulphite sequencing PCR was employed to detect the DNA methylation level of the miR‐204 promoter region, and the binding site between miR‐204 and IRAK1 was detected by luciferase assay. We found that miR‐204 was down‐regulated in T cells of T‐ALL patients, which was caused by the increased DNA methylation in the promoter region of miR‐204. Moreover, overexpression of miR‐204 inhibited T‐ALL cell proliferation while enhancing their apoptosis through interleukin receptor‐associated kinase 1 (IRAK1), which enhanced the expression of matrix metalloproteinase‐2 (MMP‐2) and MMP‐9 through activation of p‐p65. Thus, miR‐204 modulated MMP‐2 and MMP‐9 through IRAK1/NF‐κB signalling pathway, which was confirmed by in vivo assay. Taken together, DNA methylation‐mediated miR‐204 silencing increased the transcription of IRAK1, thus activating the NF‐κB signalling pathway and up‐regulating the downstream targets MMP‐2/MMP‐9. [ABSTRACT FROM AUTHOR]

Acute myocardium infarction (AMI) is one of the main causes of cardiovascular death, and timely intervention and diagnosis are essential. Owing to the irreversible apoptosis and death of myocardial cells, which ultimately causes heart failure, the problem of myocardial repair after myocardial infarction needs to be urgently addressed. Exosomes can act as messengers between cells, delivering large amounts of proteins, RNA, and lipids to receptor cells, and regulating target cell functions. Studies have shown that exosomes can repair infarcted myocardium. We aimed to investigate the relationship between long non‐coding RNA NEAT1 in serum exosomes of patients and AMI and its underlying mechanism. Subjects were divided into control, UA, and STEMI groups. RNA was extracted from the serum exosomes, and the expressions of lncRNA NEAT1 and miR‐204 were detected by qRT‐PCR. MMP‐9 was detected by western blot, Spearman test was used to analyze the correlation among the three. Logistic regression and Receiver‐operating characteristic curve (ROC) were used to evaluate the prediction of acute myocardial infarction. The expressions of NEAT1 and MMP‐9 in serum exosomes of patients with acute ST‐segment elevation myocardial infarction were up‐regulated and positively correlated, miR‐204 expression was down‐regulated, there were no correlations between miR‐204 with NEAT1, or MMP‐9. Exosomal NEAT1, miR‐204, and MMP‐9 displayed potent biomarkers for diagnosis of acute ST‐segment elevation myocardial infarction. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is the most common ocular complication caused by diabetes mellitus and is the main cause of visual impairment in working‐age people. Reactive gliosis and pro‐inflammatory cytokine production by Müller cells contribute to the progression of DR. Melatonin is a strong anti‐inflammatory hormone, mediating the cytoprotective effect of a variety of retinal cells against hyperglycemia. In this study, melatonin inhibited the gliosis activation and inflammatory cytokine production of Müller cells in both in vitro and in vivo models of DR. The melatonin membrane blocker, Luzindole, invalidated the melatonin‐mediated protective effect on Müller cells. Furthermore, melatonin inhibited Müller cell activation and pro‐inflammatory cytokine production by upregulating the long noncoding RNA maternally expressed gene 3/miR‐204/sirtuin 1 axis. In conclusion, our study suggested that melatonin treatment could be a novel therapeutic strategy for DR. [ABSTRACT FROM AUTHOR]

Introduction: Acute myeloid leukemia (AML) is the most common acute leukemia in adults. There is growing evidence that microRNAs (miRNAs) provide prognostic information in AML. MiR‐204 has a tumor suppressor function, and several studies have proven its role in solid cancers. The aim of this work is to evaluate the level of expression of miR‐204 in adults newly diagnosed with AML with normal karyotype and to correlate its level of expression with disease outcome and different prognostic factors. Patients and methods: The study included 87 adult patients newly diagnosed with AML. Detection of miR‐204 was done using RT‐PCR in patients and seven age‐matched controls. Results: Acute myeloid leukemia patients showed significantly lower miR‐204 expression, compared to control group (P =.029). Low miR‐204 expression was significantly associated with positive CD34 (P =.017), with poor performance status (PS) (P =.009), and with the presence of diabetes mellitus (DM) (P =.014). Low expression of miR‐204 was also significantly associated with shorter overall survival (OS) (P =.020) and disease‐free survival (DFS) (P =.013). Low miR‐204 expression was identified as an independent prognostic factor for prediction of shorter OS (P =.034) and DFS (P =.027) in AML. Conclusion: To the best of our knowledge; this is the first time to prove the correlation between miR‐204 expression and CD34 expression. Further study of this correlation is needed to confirm the role of miR‐204 in CD34‐positive cells, including leukemic stem cells. This correlation may have therapeutic implications. MiR‐204 can be used as a biomarker for PS in AML patients. [ABSTRACT FROM AUTHOR]

The long noncoding RNA urothelial carcinoma‐associated 1 (UCA1) has been reported to sustain the proliferation of acute myeloid leukemia (AML) cells through downregulating cell cycle regulators p27kip1. Yet, the foundational mechanism of UCA1 in AML pathologies remains unclear. Herein, we found an escalation of UCA1 expression and suppression of miR‐204 expression in pediatric AML patients and cells. UCA1 silencing suppressed cell proliferative abilities, promoted apoptotic rates, decreased Ki67, and increased cleaved caspase‐3 in AML cells. Moreover, UCA1 sponged miR‐204 and suppressed its expression. UCA1 overexpression inversed the miR‐204 suppressed proliferation and promoted apoptosis. UCA1 also boosted the expression of SIRT1, a miR‐204 target, via the sponging interaction. Furthermore, miR‐204 inhibited inducible nitric oxide synthase and cyclooxygenase‐2 expression, while UCA1 overexpression inversed the inhibitory effects in AML cells. Our findings concluded that UCA1 downregulation repressed cell proliferation and promoted apoptosis through inactivating SIRT1 signals by upregulating miR‐204 in pediatric AML. [ABSTRACT FROM AUTHOR]

Retinoblastoma (RB) is an aggressive eye cancer of infancy and childhood with high mortality. Studies have shown that long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) is closely related to the progression of multiple cancers. However, its role in RB remains unknown. This study aimed to investigate the role and underlying mechanism of NEAT1 in RB. We first detected the expression of NEAT1 in human RB tissues and cell lines. The effects of NEAT1 on the proliferation, migration, and apoptosis of RB cells were analyzed by loss‐of‐function. The underlying mechanism of NEAT1 in RB was mainly focused on the microRNA 204/C‐X‐C chemokine receptor type 4 (miR‐204/CXCR4) axis. In addition, the role and mechanism of NEAT1 in RB were further evaluated in a mouse xenograft tumor model. We found NEAT1 and CXCR4 expression levels were elevated, whereas miR‐204 expression was decreased in RB tissues and cells. Downregulation of NEAT1 significantly decreased the proliferation and migration but promoted the apoptosis of RB cells. NEAT1 functioned as a competing endogenous RNA for miR‐204 to regulate CXCR4 expression. Knockdown of NEAT1 suppressed the tumor volume, tumor weight, and CXCR4 expression, whereas increased miR‐204 expression in mice. In conclusion, NEAT1 promotes the development of RB via miR‐204/CXCR4 axis, which provides a new target for the treatment of RB disease. In this study, we found nuclear paraspeckle assembly transcript 1 (NEAT1) expression was elevated in retinoblastoma (RB) tissues and cells. It promoted the proliferation and migration, whereas decreased the apoptosis of RB cells. Further mechanism investigation demonstrated that NEAT1 functioned as a competing endogenous RNA for miR‐204 to elevate C‐X‐C chemokine receptor type 4 expression in RB. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is still the third most common cancer in the world with a limited prognosis due to the chemoresistance of CRC cells to 5‐fluorouracil (5‐FU)‐based chemotherapy. In our previous study, we revealed that miR‐204 overexpression could sensitize CRC cell to 5‐FU treatment through targeting HMGA2/PI3K signaling pathway; however, miR‐204 expression in CRC tissues is abnormally downregulated. Long non‐coding RNAs (lncRNAs) dysregulation has been reported in human diseases, including cancer. Also, lncRNA can regulate cancer cell proliferation, invasion, migration, as well as chemoresistance. LncRNA prostate cancer‐associated transcript 6 (PCAT6) acts as an oncogene in many cancers; herein, PCAT6 expression was abnormally upregulated in CRC tissues and cell lines, suggesting its potential role in CRC. Further, we assessed the specific function and mechanism of PCAT6 in CRC. Furthermore, we revealed that PCAT6 knockdown attenuated CRC chemoresistance to 5‐FU through miR‐204/HMGA2/PI3K; miR‐204 inhibition could partially reverse the effect of PCAT6 knockdown. Taken together, we demonstrate that the abnormal PCAT6 overexpression inhibits miR‐204 expression in CRC, thereby promoting HMGA2/PI3K signaling activity, ultimately enhancing the chemoresistance of CRC cells to 5‐FU; PCAT6 represents a promising target for dealing with CRC chemoresistance. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have been implicated in a wide range of biological processes including angiogenesis. MiR-204 was identified as a tumor suppressor in multiple cancer types, including lung adenocarcinoma. However, the function of miR-204 in lung tumor angiogenesis remains unknown. In this study, we found that the miR-204 expression was decreased in lung adenocarcinoma based on the cancer genome atlas (TCGA) analysis and gain-of-function experiment showed that miR-204 promoted cancer cell apoptosis and suppressed cell proliferation, migration in vitro and tumor growth in vivo. Functionally, both the tube formation and migration abilities of human umbilical vein endothelial cells (HUVECs) were suppressed by conditioned media from lung cancer A549 cells with miR-204 overexpression. Meanwhile, these conditioned media inhibited proliferation and promoted apoptosis in HUVECs. The key angiogenesis inducer hypoxia inducible factor-1α (HIF1α) and the pro-angiogenic mediators vascular endothelial growth factor and platelet-derived growth factor were decreased in A549 cells transfected with miR-204 mimics. Mechanistically, miR-204 could target Janus kinase 2 (JAK2) and further impaired signal transducer and activator of transcription 3 both in vitro and in vivo. Inhibition of JAK2 or signal transducer and activator of transcription 3 (STAT3) activity with small chemical inhibitors in A549 cells impaired lung adenocarcinoma angiogenesis in vitro. Meanwhile, conditional media from interleukin 6-treated lung normal epithelial cells significantly promoted tube formation of HUVEC, which was disturbed by miR-204 overexpression. Taken together, our findings demonstrate that miR-204 attenuates angiogenesis in lung adenocarcinoma potentially via JAK2-STAT3 pathway. Clinically, the miR-204/JAK2/STAT3 signaling pathway is a putative therapeutic target in lung adenocarcinoma. © 2017 IUBMB Life, 70(1):81-91, 2018 [ABSTRACT FROM AUTHOR]

Aberrant expression of miR-204 had been frequently reported in cancer studies; however, the mechanism of its function in retinoblastoma remained unknown. Here, we reported that miR-204 was frequently downregulated in retinoblastoma tissues and cell lines. Enforced expression of miR-204 inhibited retinoblastoma cells’ proliferation and invasion. In vivo study indicated that restoration of miR-204 inhibited tumor growth. CyclinD2 and MMP-9 were identified as potential targets of miR-204. In addition, a reverse correlation between miR-204 and CyclinD2 or MMP-9 expression was noted in retinoblastoma tissues. Taken together, our results identified a crucial tumor suppressive role of miR-204 in the progression of retinoblastoma. [ABSTRACT FROM AUTHOR]

The involvement of miR-204 in lung cancer development is unclear. In our study, we analyzed the expression of miR-204 in tumor- and adjacent-tissue samples from 141 patients with non-small cell lung cancer (NSCLC). MiR-204 expression was decreased in tumor samples compared with non-cancerous tissue-derived controls. Moreover, miR-204 expression negatively correlated with homeobox protein SIX1 expression, tumor size and metastasis. MiR-204 silencing in miR-204-positive NSCLC cell lines promoted cell invasion and proliferation. Concomitantly, MiR-204 overexpression resulted in reduced cell proliferation and invasion, upregulated E-cadherin and downregulated N-cadherin and Vimentin expression. SIX1 was identified as a potential target of miR-204, and SIX1 silencing partially compromised the invasive and proliferative capacity of miR-204-deficient cells. Thus, miR-204 may be involved in the NSCLC development. [ABSTRACT FROM AUTHOR]

Highlights: [•] We found that miRNA-204 is down-regulated in NPC cell lines and patient tissues. [•] LMP-1 down-regulates miR-204 expression through activation of Stat-3. [•] Cell division cycle 42 protein (cdc42) is a direct target of miRNA-204. [•] miR-204 inhibits cell invasion and metastasis partly through targeting cdc42. [Copyright &y& Elsevier]

Regulation of adult neural stem cell (NSC) number is critical for lifelong neurogenesis. Here, we identified a post‐transcriptional control mechanism, centered around the microRNA 204 (miR‐204), to control the maintenance of quiescent (q)NSCs. miR‐204 regulates a spectrum of transcripts involved in cell cycle regulation, neuronal migration, and differentiation in qNSCs. Importantly, inhibition of miR‐204 function reduced the number of qNSCs in the subependymal zone (SEZ) by inducing pre‐mature activation and differentiation of NSCs without changing their neurogenic potential. Strikingly, we identified the choroid plexus of the mouse lateral ventricle as the major source of miR‐204 that is released into the cerebrospinal fluid to control number of NSCs within the SEZ. Taken together, our results describe a novel mechanism to maintain adult somatic stem cells by a niche‐specific miRNA repressing activation and differentiation of stem cells. Synopsis: Systemic niche control in adult neurogenesis remains incompletely understood. Here, miR‐204 is shown to be transferred from the choroid plexus to neural stem cells (NSC) to maintain their undifferentiated state, revealing a long‐distance, post‐transcriptional fate control mechanism. Quiescent NSCs of the subependymal zone exhibit high mRNA, but not protein, levels of neurogenic fate determinants.Translation of neurogenic mRNAs is controlled by miR‐204.Choroid plexus epithelium secretes miR‐204 within extracellular vesicles into the cerebrospinal fluid, regulating NSC maintenance. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is ranked as the second most common neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra. Micro(mi)RNAs are a class of small noncoding RNAs that regulate gene expression and aberrant expression of them is closely correlated with many neurodegenerative conditions including PD. Silent information regulator 1 (SIRT1) as a known deacetylase and B‐cell lymphoma‐2 (BCL2) as an antiapoptotic factor play vital roles in neural protection and survival. Methods: Differentiated PC12 cells exposed to MPP+ were served here as a known PD model. Cell viability was determined by MTS assay. Apoptotic cells and ROS levels were detected using flow cytometry. Gene selection and miRNA–mRNA interaction analysis were performed through in silico methods. Relative expression of miRNAs and genes was examined by RT‐qPCR. Results: MPP+ exposure markedly reduced cell viability, enhanced oxidative stress, and induced apoptosis in differentiated PC12 cells. Sirt1 and BCL2were shown to be markedly declined in response to MPP+, while miR‐200a and miR‐204 were significantly upregulated. Conclusion: The first novel finding of the current study is altered expression of miR‐200a and miR‐204 in differentiated PC12 cells in response to MPP+, suggesting that deregulation of them participate in MPP+ neurotoxicity mechanisms, possibly via affecting the expression of Sirt1 and BCL2 as potential targets. Altered expression of miR‐200a and miR‐204 in differentiated PC12 cells in response to MPP+, suggested that deregulation of them participates in MPP+ neurotoxicity mechanisms, possibly via affecting the expression of Sirt1 and BCL2 as potential targets. [ABSTRACT FROM AUTHOR]