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Alcohol induces TGF?1 via downregulation of miR-1946a in murine lung fibroblast.

ABSTRACT: Exaggerated transforming growth factor-beta 1 (TGF?1) expression worsens fibroproliferation following bleomycin-induced lung injury in alcohol-fed mice. MicroRNA (miR)-1946a is predicted to bind to the TGF?1 3' untranslated region (UTR), thereby inhibiting its transcription. We hypothesize that alcohol suppresses miR-1946a and induces TGF?1. Primary murine lung fibroblasts (PLFs) were cultured?±?alcohol, miR-1946a mimic or inhibitor, and TGF?1 signaling inhibitors. miR-1946a was analyzed after alcohol treatment in vitro and in vivo. TGF?1 expression and TGF?1 3'UTR-luciferase activity was quantified. We showed that alcohol suppressed miR-1946a in the alcohol-fed mouse lungs and PLFs. MiR-1946a inhibitor increased TGF?1 expression in the fibroblast. MiR-1946a mimic treatment suppressed TGF?1 gene expression and TGF?1 3'UTR activity. Overexpression of miR1946a inhibited alcohol-induced TGF?1 gene and protein expression as well as alcohol-induced TGF?1 and ?-smooth muscle actin (SMA) protein expression in PLFs. In conclusion, miR-1946a modulates TGF?1 expression through direct interaction with TGF?1 3'UTR. These findings identify a novel mechanism by which alcohol induces TGF?1 in the lung.

SUBMITTER: Fan X

PROVIDER: S-EPMC7644620 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Alcohol induces TGFβ1 via downregulation of miR-1946a in murine lung fibroblast.

Fan Xian X Mills Stephen T ST Kaalla Mevelyn J MJ Sueblinvong Viranuj V

Scientific reports 20201105 1

Exaggerated transforming growth factor-beta 1 (TGFβ1) expression worsens fibroproliferation following bleomycin-induced lung injury in alcohol-fed mice. MicroRNA (miR)-1946a is predicted to bind to the TGFβ1 3' untranslated region (UTR), thereby inhibiting its transcription. We hypothesize that alcohol suppresses miR-1946a and induces TGFβ1. Primary murine lung fibroblasts (PLFs) were cultured ± alcohol, miR-1946a mimic or inhibitor, and TGFβ1 signaling inhibitors. miR-1946a was analyzed after a ...[more]

PMID: 33154445

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Project description:BackgroundLINC00173 had been reported as a cisplatin (cis-diamminedichloroplatinum, DDP) chemotherapy-resistant inducer in small-cell lung cancer (SCLC) and lung squamous cell carcinoma (LUSC). This study aimed to display reverse data for LINC00173 as a DDP chemosensitivity-inducing factor in lung adenocarcinoma (LUAD).MethodsLINC00173 was screened from the Gene Expression Omnibus database (GSE43493). The expression level of LINC00173 in LUAD tissues and cell lines was detected using in situ hybridization and quantitative reverse transcription-polymerase chain reaction. Colony formation, cell viability, half-maximal inhibitory concentration, flow cytometry, and xenograft mouse model were used to evaluate the role of LINC00173 in the chemosensitivity of LUAD to DDP. The mechanism of LINC00173 in DDP resistance by mediating miR-1275/PROCA1/ZFP36L2 axis to impair BCL2 mRNA stability was applied, and co-immunoprecipitation, chromatin immunoprecipitation, RNA antisense purification, RNA immunoprecipitation, and luciferase reporter assays were performed.ResultsLINC00173 downregulation in patients with DDP-resistant LUAD was correlated with poor prognosis. Further, LINC00173 expression was significantly reduced in DDP-resistant LUAD cells and DDP-treated human LUAD tissues. Suppressed LINC00173 expression in LUAD cells enhanced DDP chemoresistance in vivo and in vitro, while restored LINC00173 expression in DDP-resistant LUAD cells markedly regained chemosensitivity to DDP. Mechanistically, DDP-resistant LUAD cells activated PI3K/AKT signal and further elevated the c-Myc expression. The c-Myc, as an oncogenic transcriptional factor, bound to the promoter of LINC00173 and suppressed its expression. The reduced LINC00173 expression attenuated the adsorption of oncogenic miR-1275, downregulating the expression of miR-1275 target gene PROCA1. PROCA1 played a potential tumor-suppressive role inducing cell apoptosis and DDP chemosensitivity via recruiting ZFP36L2 to bind to the 3' untranslated region of BCL2, reducing the stability of BCL2 mRNA and thus activating the apoptotic signal.ConclusionsThis study demonstrated a novel and critical role of LINC00173. It was transcriptionally repressed by DDP-activated PI3K/AKT/c-Myc signal in LUAD, promoting DDP-acquired chemotherapeutic resistance by regulating miR-1275 to suppress PROCA1/ZFP36L2-induced BCL2 degradation, which led to apoptotic signal reduction. These data were not consistent with the previously described role of LINC00173 in SCLC or LUSC, which suggested that LINC00173 could play fine-tuned DDP resistance roles in different pathological subtypes of lung cancer. This study demonstrated that the diminished expression of LINC00173 might serve as an indicator of DDP-acquired resistance in LUAD.

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Alcohol induces TGF?1 via downregulation of miR-1946a in murine lung fibroblast.

Publications

Alcohol induces TGFβ1 via downregulation of miR-1946a in murine lung fibroblast.

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