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Soon after its discovery, microRNA-9 (miR-9) attracted the attention of neurobiologists, since it is one of the most highly expressed microRNAs in the developing and adult vertebrate brain. Functional analyses in different vertebrate species have revealed a prominent role of this microRNA in balancing proliferation in embryonic neural progenitor populations. Key transcriptional regulators such as FoxG1, Hes1 or Tlx, were identified as direct targets of miR-9, placing it at the core of the gene network controlling the progenitor state. Recent data also suggest that this function could extend to adult neural stem cells. Other studies point to a role of miR-9 in differentiated neurons. Moreover miR-9 has been implicated in human brain pathologies, either displaying a protective role, such as in Progeria, or participating in disease progression in brain cancers. Altogether functional studies highlight a prominent feature of this highly conserved microRNA, its functional versatility, both along its evolutionary history and across cellular contexts.

Childhood maltreatment (CM) is regarded as an important risk factor for major depressive disorder (MDD). However, the neural links corresponding to the process of early CM experience producing brain alterations and then leading to depression later remain unclear. To explore the neural basis of the effects of CM on MDD and the potential role of microRNA-9 (miR-9) in these processes, we recruited 40 unmedicated MDD patients and 34 healthy controls (HCs) to complete resting-state fMRI scans and peripheral blood miR-9 tests. The neural substrates of CM, miR-9, and depression, as well as their interactive effects on intrinsic amygdala functional connectivity (AFC) networks were investigated in MDD patients. Two-step mediation analysis was separately employed to explore whether AFC strength mediates the association among CM severity, miR-9 levels, and depression. A support vector classifier (SVC) model of machine learning was used to distinguish MDD patients from HCs. MDD patients showed higher miR-9 levels that were negatively correlated with CM scores and depressive severity. Overlapping effects of CM, miR-9, and depressive severity on bilateral AFC networks in MDD patients were primarily located in the prefrontal-striatum pathway and limbic system. The connection of amygdala to prefrontal-limbic circuits could mediate the effects of CM severity on the miR-9 levels, as well as the impacts of miR-9 levels on the severity of depression in MDD patients. Furthermore, the SVC model, which integrated miR-9 levels, CM severity, and AFC strength in prefrontal-limbic regions, had good power in differentiating MDD patients from HCs (accuracy 85.1%). MiR-9 may play a crucial role in the process of CM experience-produced brain changes targeting prefrontal-limbic regions and that subsequently leads to depression. The present neuroimaging-epigenetic results provide new insight into our understanding of MDD pathophysiology.

Curcumol has been reported to exert anti-tumor activity, but its intrinsic molecular mechanism in prostate cancer remains to be elucidated. The present study aimed to analyze the effect of curcumol on prostate cancer and identify its possible internal regulatory pathway using in vitro cell culture and in vivo tumor model experiments. The cytotoxicity of curcumol was detected using a Cell Counting Kit-8 assay and it was found that curcumol had no obvious toxicity or side effects on RWPE-1 cells. Wound healing, Transwell and flow cytometry assays demonstrated that curcumol could affect the activity of PC3 cells. The luciferase reporter assay also indicated that microRNA (miR)-9 could directly target pyruvate dehydrogenase kinase 1 (PDK1). After PC3 cells were transfected with miR-9 inhibitor or treated with curcumol, the expression levels of the PDK1/AKT/mTOR signaling pathway-related proteins [PDK1, phosphorylated (p)-AKT and p-mTOR] were increased or decreased, respectively. Next, the prostate cancer cell xenograft model was established. Tumor size and the expression levels of PDK1/AKT/mTOR signaling pathway-related factors were altered following treatment with curcumol. The in vitro and in vivo experiments collectively demonstrated that curcumol could inhibit the PDK1/AKT/mTOR signaling pathway by upregulating the expression level of miR-9. The present study found that curcumol regulates the PDK1/AKT/mTOR signaling pathway via miR-9 and affects the development of prostate cancer. These findings could provide a possible scientific insight for research into treatments for prostate cancer.

MicroRNA (miR)‐9 plays different roles in different cancer types. Here, we investigated the role of miR‐9 in non‐small‐cell lung cancer (NSCLC) cell invasion and adhesion in vitro and explored whether miR‐9 was involved in transforming growth factor‐beta 1 (TGF‐β1)‐induced NSCLC cell invasion and adhesion by targeting SOX7. The expression of miR‐9 and SOX7 in human NSCLC tissues and cell lines was examined by reverse transcription‐quantitative polymerase chain reaction. Gain‐of‐function and loss‐of‐function experiments were performed on A549 and HCC827 cells to investigate the effect of miR‐9 and SOX7 on NSCLC cell invasion and adhesion in the presence or absence of TGF‐β1. Transwell–Matrigel assay and cell adhesion assay were used to examine cell invasion and adhesion abilities. Luciferase reporter assay was performed to determine whether SOX7 was a direct target of miR‐9. We found miR‐9 was up‐regulated and SOX7 was down‐regulated in human NSCLC tissues and cell lines. Moreover, SOX7 expression was negatively correlated with miR‐9 expression. miR‐9 knockdown or SOX7 overexpression could suppress TGF‐β1‐induced NSCLC cell invasion and adhesion. miR‐9 directly targets the 3′ untranslated region of SOX7, and SOX7 protein expression was down‐regulated by miR‐9. TGF‐β1 induced miR‐9 expression in NSCLC cells. miR‐9 up‐regulation led to enhanced NSCLC cell invasion and adhesion; however, these effects could be attenuated by SOX7 overexpression. We concluded that miR‐9 expression was negatively correlated with SOX7 expression in human NSCLC. miR‐9 was up‐regulated by TGF‐β1 and contributed to TGF‐β1‐induced NSCLC cell invasion and adhesion by directly targeting SOX7.

Aberrant expression of microRNAs (miRNAs) has been involved in the development and progression of malignancy. MicroRNA-9 (miR-9) has been confirmed to be underexpressed in many types of cancers. However, the relationship between miR-9 and the Wnt/β-catenin signaling pathway in oral squamous cell carcinoma (OSCC) remains largely unknown. Here we showed that the miR-9 was underexpressed in patients with OSCC and several OSCC cell lines. Lentivirus-mediated miR-9 overexpression in highly aggressive (Tca8113 and SCC-9) tumor cells significantly inhibited proliferation of the two cell lines in vitro and in vivo . Furthermore, we found that the CXC chemokine receptor 4 ( CXCR4 ) gene was a direct target of miR-9 . RNA interference silencing of CXCR4 proved that miR-9 underexpression led to constitutive activation of β-catenin through activation of CXCR4 expression in OSCC cells. Finally, we also analyzed the possible relationship between miR-9 and the genes downstream of the Wnt/β-catenin pathway in OSCC development and progression. These results provide new evidence of miR-9 as a promising tumor gene therapeutic target for OSCC patients.

Alzheimer's disease (AD) is the most serious neurodegenerative disease worldwide and is characterized by progressive cognitive impairment and multiple neurological changes, including neuronal loss in the brain. However, there are no available drugs to delay or cure this disease. Consequently, neuronal replacement therapy may be a strategy to treat AD. Osthole (Ost), a natural coumarin derivative, crosses the blood-brain barrier and exerts strong neuroprotective effects against AD and . Recently, microRNAs (miRNAs) have demonstrated a crucial role in pathological processes of AD, implying that targeting miRNAs could be a therapeutic approach to AD. In the present study, we investigated whether Ost could enhance cell viability and prevent cell death in amyloid precursor protein (APP)-expressing neural stem cells (NSCs) as well as promote APP-expressing NSCs differentiation into more neurons by upregulating microRNA (miR)-9 and inhibiting the Notch signaling pathway . In addition, Ost treatment in APP/PS1 double transgenic (Tg) mice markedly restored cognitive functions, reduced Aβ plague production and rescued functional impairment of hippocampal neurons. The results of the present study provides evidence of the neurogenesis effects and neurobiological mechanisms of Ost against AD, suggesting that Ost is a promising drug for treatment of AD or other neurodegenerative diseases.

In humans, optic nerve injuries and associated neurodegenerative diseases are often followed by perma- nent vision loss. Consequently, an important challenge is to develop safe and effective methods to replace retinal neurons and thereby restore neuronal functions and vision. Identifying cellular and molecular mechanisms allowing to replace damaged neurons is a major goal for basic and translational research in regenerative medicine. Contrary to mammals, the zebrafish has the capacity to fully regenerate entire parts of the nervous system, including retina. This regenerative process depends on endogenous retinal neural stem cells, the Miiller glial cells. Following injury, zebrafish Miiller cells go back into cell cycle to proliferate and generate new neurons, while mammalian Mtiller cells undergo reactive gliosis. Recently, transcription factors and microRNAs have been identified to control the formation of new neurons derived from ze- brafish and mammalian Mtiller cells, indicating that cellular reprogramming can be an efficient strategy to regenerate human retinal neurons. Here we discuss recent insights into the use of endogenous neural stem cell reprogramming for neuronal regeneration, differences between zebrafish and mammalian Mtiller cells, and the need to pursue the identification and characterization of new molecular factors with an instructive and potent function in order to develop theurapeutic strategies for eye diseases.

MiR-9 has been found to be involved in the repair of spinal cord injury and regulates the proliferation and differentiation of mesenchymal stem cells. However, the role of miR-9 in repair of bone defects has not been well studied. The current study was designed to investigate its role and potential underlying mechanism in regulating osteoblast differentiation and angiogenesis. After treating the murine pre-osteoblast cell line MC3T3-E1 with BMP2, miR-9 expression was obviously down-regulated. Following transfection with miR-9 mimics, its overexpression enhanced the differentiation of MC3T3-E1 cells into osteoblasts as evidence that miR-9 up-regulated the mRNA levels of osteoblast differentiation-related protein, as well as increased differentiation and mineralization of osteoblasts. Further functional analysis has shown that miR-9 overexpression effectively increased human umbilical vein endothelial cell proliferation. Moreover, miR-9 up-regulation promoted cell migration, VEGF, and VE-cadherin concentrations, as well as tube formation in vitro. The mechanistic assay demonstrated that overexpression of miR-9-induced activation of the AMPK signaling pathway. Taken together, our findings suggested that miR-9 overexpression promoted osteoblast differentiation and angiogenesis via the AMPK signaling pathway, representing a novel and potential therapeutic target for the treatment of bone injury-related diseases.

The incidence of thyroid nodules has been increasing worldwide; however, there are currently no feasible and robust methods to differentiate malignant thyroid nodules from benign thyroid nodules. The present study aimed to establish a practical method to determine the malignancy of thyroid nodules. Reverse transcription-quantitative PCR and western blot analyses were performed to compare the levels of long non-coding RNA nuclear enriched abundant transcript 1 (NEAT1), microRNA (miR)-9, miR-124, PTEN and programmed cell death protein 6 (PDCD6) in the peripheral blood and thyroid tissue samples between patients with malignant and benign thyroid nodules. Additionally, a regulatory relationship between NEAT1, miR-124, miR-9, PTEN and PDCD6 was established in the present study. The diagnostic value of NEAT1, miR-124 and miR-9 was determined using a ROC analysis. The expression levels of NEAT1, PTEN and PDCD6 in peripheral blood and thyroid tissue samples collected from the benign group were higher compared with those in the malignant group, whereas the expression levels of miR-124 and miR-9 were lower in the benign group. In the peripheral blood, NEAT1 expression exhibited an area under the curve (AUC) value of 0.8546, whereas miR-124 and miR-9 expression had AUC values of 0.7657 and 0.7019, respectively. In the thyroid tissue, NEAT1, miR-124, and miR-9 had AUC values of 0.9304, 0.8221 and 0.7757, respectively. Additionally, miR-9 and miR-124 expression levels in BCPaP and SW579 cells was decreased after transfection with a NEAT1 expression vector compared with those in cells transfected with the control vector, whereas the expression of PTEN and PDCD6 was upregulated. By contrast, transfection with short hairpin RNA targeting NEAT1 notably increased the expression of miR-9 and miR-124 while downregulating the expression of PTEN and PDCD6 compared with that in the control cells. In conclusion, the results of the present study demonstrated that the dysregulation of NEAT1 expression may be used to differentiate benign and malignant thyroid nodules.

Metastasis is one of the hallmarks of cancer malignancy that usually causes more detrimental effects than a primary tumor. Many microRNAs were reported to be involved in the process of tumor metastasis. Hep11 and Hep12 cells were derived from primary and recurrence (intrahepatic metastatic) sites of hepatocellular carcinoma (HCC), respectively. Hep12 exhibited a higher invasive and migratory potential than Hep11. There was also a significantly higher expression of miR-9 in Hep12 cells than in Hep11 cells. Further studies in HCC cell lines demonstrated that miR-9 could promote tumor cell migration and invasion. In addition, miR-9 downregulated KLF17 protein expression by targeting the 3′UTR region of the KLF17 gene directly. As a transcription factor, KLF17 directly acted on the promoters of EMT-related genes (ZO-1, Vimentin and Fibronectin (FN)) in HCC cell lines. Therefore, we conclude that miR-9 may possibly promote HCC migration and invasion through regulation of KLF17. •miR-9 could promote migration and invasion in hepatocellular carcinoma.•miR-9 downregulate KLF17 protein expression by targeting 3′UTR region of KLF17 gene directly.•KLF17 could directly act on promoter of EMT related genes: ZO-1, Vimentin and Fibronectin (FN).