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Myocardial infarction (MI) is defined as the irreversible death of heart muscle that occurs secondary to prolonged lack of oxygen supply, which has resulted in millions of death worldwide. This study was conducted with aims of investigating how microRNA-212 (miR-212) and the inhibition of aquaporin-9 (AQP9) through the activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway plays a role in the prevention of MI. The relationship between miR-212 and AQP9 was determined with the use of bioinformatics combined with the dual luciferase reporter gene assay. Next, the MI model was established and the cardiomyocytes were transfected with different mimic, inhibitor and siRNAs to investigate the specific activity of miR-212, AQP9 and the PI3K/Akt signaling pathway in MI. The expression of miR-212, AQP9, PI3K, Akt, VEGF, Bax, and B cell lymphoma 2 (Bcl-2), along with cell apoptosis were determined using reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot analysis and flow cytometry. Based on the results, AQP9 was verified as the direct target gene of miR-212. MI led to a decrease in miR-212 expression and an increase in AQP9 expression. It was also found that miR-212 activated the PI3K/Akt signaling pathway in MI through the inhibition of AQP9 expression. The overexpression of miR-212 or silencing AQP9 decreased cardiomyocytes apoptosis. These findings indicated that the overexpression of miR-212 inhibited AQP9 by activating the PI3K/Akt signaling pathway, thus decreasing cardiomyocytes apoptosis, promoting vascular regeneration and alleviating ventricular remodeling in rats with MI. [ABSTRACT FROM AUTHOR]

Abstract: Neuregulins are growth factors that signal via the ErbB3 and ErbB4 receptors. Here we show using immunohistochemistry that they are often expressed in the nucleus of a range of tumour types including soft tissue and breast. The Neuregulin 1 type I-β3 (NRG1-β3) isoform localises to two sub-nuclear compartments in animal cells, nucleoli and spliceosomes. We used NRG1-β3 tagged with photoactivatable GFP and demonstrated that this re-localised from nucleoli to spliceosomes over 90min. Tyrosine kinase activity was not required for retaining the NRG1-β3 within the nucleus. Mutation of the lysines 14 and 16 or 15 and 16 together prevented nucleolar uptake while four positively charged residues were identified which were required for spliceosome uptake. Molecular modelling suggests that three of these may form a binding site. We showed using a kinome array that NRG1-β3 and a mutant exclusively localising to spliceosomes increased phosphorylation and/or expression of the HER4 and HER2 receptors. Using a transcriptomic analysis the same two constructs induced expression of several messenger RNAs and we confirmed the increased expression at the protein level of the most highly induced, Heat Shock Protein 70B′. These results suggest that Neuregulin activates receptor signalling in spliceosomes leading to altered gene expression. [ABSTRACT FROM AUTHOR]

IκBα protein plays an important role in NFκB signaling pathway regulation. The dysfunction of IκBα is tightly related to various diseases, including cancers. However, the molecular mechanisms by which IκBα loses its normal functions are diverse and complex. Here, we reported a novel cleavage of IκBα protein occurred in AML cells. Compared with the full-length IκBα protein, the truncated IκBα fragment exhibited a dramatically weak binding ability to NFκB complex and showed a significant decreased inhibition on NFκB transactivation. Knockdown of PR3, a serine protease mainly expressed in myeloid cells, could inhibit such IκBα cleavage and enhance the sensitivities of AML cells to the differentiation inducers. In addition, we showed that the level of PR3 mRNA was relatively higher in newly diagnosed AML patients than in those patients with complete remission, suggesting that PR3 expression and its involvement in IκBα cleavage might be closely associated with AML. Our studies revealed for the first time a PR3-involved IκBα cleavage in AML cells, providing some new evidences for further understanding the mechanisms underlying the deregulation of NFκB pathway in AML. Finally, we also suggested a potential clinical application value of PR3 protein in the treatment and prognosis surveillance for leukemia. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignant disease with a poor prognosis. We previously found that p62 presented a marked nuclear-cytoplasmic translocation in ESCC cells as compared that in normal esophageal epithelial cells, but its effects on ESCC cells remain unclear. This study aims to clarify the impacts of different cellular localization of p62 on the function of ESCC cells and the underlying molecular mechanisms. We here demonstrated that cytoplasmic p62 enhances the migration and invasion abilities of esophageal cancer cells, whereas nuclear p62 has no effect. We further explored the interaction protein of p62 by using GST pull-down experiment and identified EPLIN as a potential protein interacting with p62. In addition, reducing EPLIN expression significantly inhibited the migration and invasion of ESCC cells, which were rescued when EPLIN expression was restored after the p62 knockdown. At a molecular level, p62 in cytoplasm positively regulated the expression of EPLIN via enhancing its protein stability. Data from the TCGA and GEO database displayed a significant up-regulation of EPLIN mRNA expression in ESCC tissues compared with corresponding paired esophageal epithelial samples. Our findings present evidence that the nuclear-cytoplasmic translocation of p62 protein contributes to an aggressive malignancy phenotype, providing candidate molecular biomarkers and potential molecular targets for the diagnosis and treatment of ESCC. [ABSTRACT FROM AUTHOR]

Abstract: We studied the role of hypoxia-inducible factor-1α (HIF-1α) in human lung adenocarcinoma cell invasion using a metastatic cell model composed of low invasive CL1 and highly invasive CL1-5 cells. We showed that HIF-1α was expressed in CL1-5 but not in CL1 cells under normoxic condition, and that inhibition of HIF-1α expression by a small interfering RNA decreased invasiveness of CL1-5 cells. Complementary, overexpression of HIF-1α increased the invasiveness of CL1 and gastric cancer SC-M1 cells. Subsequently, we showed that urokinase-type plasminogen activator receptor (uPAR), and matrix metalloproteinases (MMPs) 1 and 2 were critical in HIF-1α-induced invasion. Mechanistic studies revealed that HIF-1α overexpression could increase the expression of uPAR and MMP1, but not MMP2. However, ELISA assays on the conditioned media generated from control CL1 and CL1 cells overexpressing HIF-1α showed that overexpression of HIF-1α increased the levels of endogenous free active MMP2 and total free MMP2, and the former was blocked by inhibition of MMP1 expression. We conclude that (i) HIF-1α overexpression enhances lung cancer cell invasion at least through up-regulating the expression and activities of uPAR, MMP1, and MMP2; and (ii) induction of MMP1 participates in cell invasion and also plays an important role in HIF-1α-induced activation of MMP2. [Copyright &y& Elsevier]

The retinal pigment epithelium cells (RPE) are sensitive to oxidative stimuli due to long-term exposure to various environmental stimuli. Thus, the oxidative injury of RPE cells caused by the imbalance of redox homeostasis is one of the main pathogenic factors of age-related macular degeneration (AMD). But the sophisticated mechanisms linking AMD to oxidative stress are not fully elucidated. Activation of Nrf2 signal pathway can protect RPE cells from oxidative damage. The present study investigated the regulating mechanism of miR-125b in Nrf2 cascade and evaluated its antioxidant capacity. The in vitro studies indicated that overexpression of miR-125b substantially inhibited Keap1 expression, enhanced Nrf2 expression and induced Nrf2 nuclear translocation. Importantly, functional studies demonstrated that forced expression of miR-125b could significantly elevate cell proliferation and superoxide dismutase (SOD) levels while reduce reactive oxygen species (ROS) overproduction and malondialdehyde (MDA) formation. Further studies showed that miR-125b had no effect when Nrf2 was silenced in ARPE-19 cells. Additionally, the results identified that Nrf2 silence induced ROS accumulation enhances HIF-1α protein expression, while miR-125b could offset this effect via promoting HIF-1α protein degradation. Subsequent in vivo studies demonstrated that sodium iodate induced outer retina thinner was reversed with exogenous supplementation of miR-125b, which was cancelled in Nrf2 knockout mice. In conclusion, this study illustrated that miR-125b can protect RPE from oxidative damage via targeting Nrf2/HIF-1α signal pathway and potentially may serve as a therapeutic agent of AMD. [ABSTRACT FROM AUTHOR]