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MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia.

ABSTRACT: Despite their potential to regulate approximately one-third of the whole genome, relatively few microRNA (miRNA) targets have been experimentally validated, particularly in stratified squamous epithelia. Here we demonstrate not only that the lipid phosphatase SHIP2 is a target of miRNA-205 (miR-205) in epithelial cells, but, more importantly, that the corneal epithelial-specific miR-184 can interfere with the ability of miR-205 to suppress SHIP2 levels. This is the first example of a miRNA negatively regulating another to maintain levels of a target protein. Interfering with miR-205 function by using a synthetic antagomir, or by the ectopic expression of miR-184, leads to a coordinated damping of the Akt signaling pathway via SHIP2 induction. This was associated with a marked increase in keratinocyte apoptosis and cell death. Aggressive squamous cell carcinoma (SCC) cells exhibited elevated levels of miR-205. This was associated with a concomitant reduction in SHIP2 levels. Partial knockdown of endogenous miR-205 in SCCs markedly decreased phosphorylated Akt and phosphorylated BAD levels and increased apoptosis. We were able to increase SHIP2 levels in SCC cells after inhibition of miR-205. Therefore, miR-205 might have diagnostic value in determining the aggressivity of SCCs. Blockage of miR-205 activity with an antagomir or via ectopic expression of miR-184 could be novel therapeutic approaches for treating aggressive SCCs.

SUBMITTER: Yu J

PROVIDER: S-EPMC2587229 | biostudies-literature |

REPOSITORIES: biostudies-literature

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MicroRNA-205 promotes keratinocyte migration via the lipid phosphatase SHIP2.

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microRNA-184 Induces a Commitment Switch to Epidermal Differentiation.

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BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells.

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Oncosuppressive role of MicroRNA-205-3p in gastric cancer through inhibition of proliferation and induction of senescence: Oncosuppressive role of MicroRNA-205 in gastric cancer.

Project description:BackgroundOur previous study showed that CXCL11 could play an immunomodulatory role. In this study, we investigated the regulator (miR-205-3p) of CXCL11 and the mechanism of miR-205-3p as a tumor suppressor gene in gastric cancer (GC).Materials and methodsA target relationship between miR-205-3p and CXCL11 was revealed by using the bioinformatics method. This study detected the expressions of miR-205-3p and CXCL11 through qRT-PCR and Western blotting. Moreover, the expressions of Akt, PD-L1, p16, p21, and senescence-associated secretory phenotype (SASP) factor were determined. The effects of miR-205 on proliferation, invasion, and senescence of GC cells were assessed by using methods, such as transfection, Transwell assay, tablet cloning, flow cytometry, and senescence-associated beta-galactosidase (SA-β-gal) staining. Furthermore, the effects were verified using methods, like immunohistochemistry, flow cytometry and SA-β-gal in animal experiments.ResultsBased on the study, it is found that the expression of miR-205-3p is down-regulated, while that of CXCL11 is up-regulated in GC cell lines. By regulating CXCL11, miR-205-3p inhibits Akt activation, reduces the proliferation and invasion of GC cells, promotes cell apoptosis, induces senescence of GC cells, and secretes immunostimulatory SASP factor. The animal experiments confirm that miR-205-3p promotes cell senescence, down-regulates the immunosuppressive signal induced by PD-L1, and promotes secretion of immunostimulatory SASP factor, so that more T cells are recruited in blood and tumors.ConclusionsThis study revealed the molecular mechanism of miR-205-3p in inhibiting proliferation and invasion and inducing senescence of GC cells by regulating CXCL11 and Akt pathways in animal and cell experiments.

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| S-EPMC4593481 | biostudies-literature

Melanosomes in pigmented epithelia maintain eye lens transparency during zebrafish embryonic development.

Project description:Altered levels of trace elements are associated with increased oxidative stress that is eventually responsible for pathologic conditions. Oxidative stress has been proposed to be involved in eye diseases, including cataract formation. We visualized the distribution of metals and other trace elements in the eye of zebrafish embryos by micro X-ray fluorescence (μ-XRF) imaging. Many elements showed highest accumulation in the retinal pigment epithelium (RPE) of the zebrafish embryo. Knockdown of the zebrafish brown locus homologues tyrp1a/b eliminated accumulation of these elements in the RPE, indicating that they are bound by mature melanosomes. Furthermore, albino (slc45a2) mutants, which completely lack melanosomes, developed abnormal lens reflections similar to the congenital cataract caused by mutation of the myosin chaperon Unc45b, and an in situ spin trapping assay revealed increased oxidative stress in the lens of albino mutants. Finally transplanting a wildtype lens into an albino mutant background resulted in cataract formation. These data suggest that melanosomes in pigment epithelial cells protect the lens from oxidative stress during embryonic development, likely by buffering trace elements.

| S-EPMC4855227 | biostudies-literature

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