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MicroRNA-31-5p Exacerbates Lipopolysaccharide-Induced Acute Lung Injury via Inactivating Cab39/AMPK? Pathway.

ABSTRACT: Acute lung injury (ALI) and the subsequent acute respiratory distress syndrome remain devastating diseases with high mortality rates and poor prognoses among patients in intensive care units. The present study is aimed at investigating the role and underlying mechanisms of microRNA-31-5p (miR-31-5p) on lipopolysaccharide- (LPS-) induced ALI. Mice were pretreated with miR-31-5p agomir, antagomir, and their negative controls at indicated doses for 3 consecutive days, and then they received a single intratracheal injection of LPS (5?mg/kg) for 12?h to induce ALI. MH-S murine alveolar macrophage cell lines were cultured to further verify the role of miR-31-5p in vitro. For AMP-activated protein kinase ? (AMPK?) and calcium-binding protein 39 (Cab39) inhibition, compound C or lentiviral vectors were used in vivo and in vitro. We observed an upregulation of miR-31-5p in lung tissue upon LPS injection. miR-31-5p antagomir alleviated, while miR-31-5p agomir exacerbated LPS-induced inflammation, oxidative damage, and pulmonary dysfunction in vivo and in vitro. Mechanistically, miR-31-5p antagomir activated AMPK? to exert the protective effects that were abrogated by AMPK? inhibition. Further studies revealed that Cab39 was required for AMPK? activation and pulmonary protection by miR-31-5p antagomir. We provide the evidence that endogenous miR-31-5p is a key pathogenic factor for inflammation and oxidative damage during LPS-induced ALI, which is related to Cab39-dependent inhibition of AMPK?.

SUBMITTER: Jiang WL

PROVIDER: S-EPMC7568166 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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MicroRNA-31-5p Exacerbates Lipopolysaccharide-Induced Acute Lung Injury via Inactivating Cab39/AMPKα Pathway.

Jiang Wan-Li WL Zhao Kao-Chang KC Yuan Wen W Zhou Fang F Song Heng-Ya HY Liu Gao-Li GL Huang Jie J Zou Jin-Jing JJ Zhao Bo B Xie Song-Ping SP

Oxidative medicine and cellular longevity 20201008

Acute lung injury (ALI) and the subsequent acute respiratory distress syndrome remain devastating diseases with high mortality rates and poor prognoses among patients in intensive care units. The present study is aimed at investigating the role and underlying mechanisms of microRNA-31-5p (miR-31-5p) on lipopolysaccharide- (LPS-) induced ALI. Mice were pretreated with miR-31-5p agomir, antagomir, and their negative controls at indicated doses for 3 consecutive days, and then they re ...[more]

PMID: 33101593

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Project description:BackgroundMicroRNAs (miRNAs) posttranscriptionally regulate gene expression and thereby contribute to the modulation of numerous complex and disease-relevant cellular processes, including cell proliferation, cell motility, apoptosis and stress response. miRNA-31-5p is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many hepatocellular carcinoma (HCC) tumors. Based on previous findings, we hypothesized that miR-31-5p alters chemosensitivity and that miR-31-5p mimics may influence sensitivity to chemotherapeutics in HCC as well as in a variety of other cancers.MethodsMiR-31-5p and PARP1 in HCC tissues were tested by RT-PCR and histological analysis, respectively. Next, clonogenic assay and western blot were used to detect miR-31-5p and PARP1 to modulate sensitivity to OXA-based chemotherapy. The distribution of OXA in the nuclear and intracellular was detected by ICP-MS. Coimmunoprecipitation was used to characterize the protein-protein interaction between PARP1 and ABCB9. A xenograft nude mouse model was used to examine the in vivo effects of miR-31-5p.ResultsReintroduction of miR-31-5p into miR-31-5p-null Hep3B cells significantly enhanced clonogenic resistance to oxaliplatin. Although miR-31-5p re-expression increased chemoresistance, it paradoxically increased the relative intracellular accumulation of oxaliplatin. This effect was coupled with a significantly decreased intranuclear concentration of oxaliplatin by ICP-MS. miR-31-5p prevents the nuclear location of PARP1 detected by immunofluorescence, histological analysis and Western blotting analysis. We subsequently identified an indirect miR-31-5p-mediated upregulation of ABCB9, which is a transporter associated with drug accumulation in lysosomes, along with an increased uptake of oxaliplatin to lysosomes; these phenomena were associated with a downregulation of PARP1, a bipotential transcriptional regulator with multiple miR-31-5p binding sites. However, the indirect overexpression of ABCB9 promoted cellular chemosensitivity, suggesting that miR-31-5p promotes chemoresistance largely via an ABCB9-independent mechanism.ConclusionsOverall, our data suggest that the loss of miR-31-5p from HCC tumors promotes chemosensitivity, and this knowledge may be prognostically beneficial in the context of therapeutic sensitivity.

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Dataset Information

MicroRNA-31-5p Exacerbates Lipopolysaccharide-Induced Acute Lung Injury via Inactivating Cab39/AMPK? Pathway.

Publications

MicroRNA-31-5p Exacerbates Lipopolysaccharide-Induced Acute Lung Injury via Inactivating Cab39/AMPK<i>α</i> Pathway.

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