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MiR?23a downregulation modulates the inflammatory response by targeting ATG12?mediated autophagy.

ABSTRACT: Autophagy, part of the innate immune defense mechanisms, is activated during the initial phase of septic insult. Previous studies indicated that micro (mi)RNAs are additionally involved in the host response to sepsis; however, the association between miRNAs and autophagy during this process is not fully understood. To study the role of miRNA (miR)?23a in autophagy initiated by sepsis, macrophages treated with lipopolysaccharides, in addition to blood samples from patients, were evaluated for miR?23a expression levels. Cell viability, inflammatory mediators and autophagic markers were investigated following overexpression or inhibition of miR?23a. The results suggested that miR?23a was suppressed subsequent to septic insult, promoting autophagy and suppressing a hyper inflammatory response, leading to enhanced cell viability. A luciferase assay and western blot analysis confirmed ubiquitin?like protein ATG12 to be the target of miR?23a. The present study revealed that the downregulation of miR?23a regulates an inflammatory response during septic insult via autophagy promotion.

SUBMITTER: Si X

PROVIDER: S-EPMC6072189 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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miR‑23a downregulation modulates the inflammatory response by targeting ATG12‑mediated autophagy.

Si Xiang X Cao Daiyin D Chen Juan J Nie Yao Y Jiang Zhiyi Z Chen Min-Ying MY Wu Jian-Feng JF Guan Xiang-Dong XD

Molecular medicine reports 20180529 2

Autophagy, part of the innate immune defense mechanisms, is activated during the initial phase of septic insult. Previous studies indicated that micro (mi)RNAs are additionally involved in the host response to sepsis; however, the association between miRNAs and autophagy during this process is not fully understood. To study the role of miRNA (miR)‑23a in autophagy initiated by sepsis, macrophages treated with lipopolysaccharides, in addition to blood samples from patients, were evaluated for miR ...[more]

PMID: 29845275

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Project description:BackgroundMetastasis is the main cause of tumor-associated death and mainly responsible for treatment failure of breast cancer. Autophagy accelerates tumor metastasis. In our work, we aimed to investigate the possibility of microRNAs (miRNAs) which participate in the regulation of autophagy to inhibit tumor metastasis.MethodsMiRNA array and comprehensive analysis were performed to identify miRNAs which participated in the regulation of autophagy to inhibit tumor metastasis. The expression levels of miR-3653 in breast cancer tissues and cells were detected by quantitative real-time polymerase chain reaction. In vivo and in vitro assays were conducted to determine the function of miR-3653. The target genes of miR-3653 were detected by a dual luciferase reporter activity assay and Western blot. The relationship between miR-3653 and epithelial-mesenchymal transition (EMT) was assessed by Western blot. Student's t -test was used to analyze the difference between any two groups, and the difference among multiple groups was analyzed with one-way analysis of variance and a Bonferroni post hoc test.ResultsmiR-3653 was downregulated in breast cancer cells with high metastatic ability, and high expression of miR-3653 blocked autophagic flux in breast cancer cells. Clinically, low expression of miR-3653 in breast cancer tissues (0.054 ± 0.013 vs . 0.131 ± 0.028, t = 2.475, P = 0.014) was positively correlated with lymph node metastasis (0.015 ± 0.004 vs . 0.078 ± 0.020, t = 2.319, P = 0.023) and poor prognosis ( P < 0.001). miR-3653 ameliorated the malignant phenotypes of breast cancer cells, including proliferation, migration (MDA-MB-231: 0.353 ± 0.013 vs . 1.000 ± 0.038, t = 16.290, P < 0.001; MDA-MB-468: 0.200 ± 0.014 vs . 1.000 ± 0.043, t = 17.530, P < 0.001), invasion (MDA-MB-231: 0.723 ± 0.056 vs . 1.000 ± 0.035, t = 4.223, P = 0.013; MDA-MB-468: 0.222 ± 0.016 vs . 1.000 ± 0.019, t = 31.050, P < 0.001), and colony formation (MDA-MB-231: 0.472 ± 0.022 vs . 1.000 ± 0.022, t = 16.620, P < 0.001; MDA-MB-468: 0.650 ± 0.040 vs . 1.000 ± 0.098, t = 3.297, P = 0.030). The autophagy-associated genes autophagy-related gene 12 ( ATG12 ) and activating molecule in beclin 1-regulated autophagy protein 1 ( AMBRA1 ) are target genes of miR-3653. Further studies showed that miR-3653 inhibited EMT by targeting ATG12 and AMBRA1 .ConclusionsOur findings suggested that miR-3653 inhibits the autophagy process by targeting ATG12 and AMBRA1 , thereby inhibiting EMT, and provided a new idea and target for the metastasis of breast cancer.

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MiR?23a downregulation modulates the inflammatory response by targeting ATG12?mediated autophagy.

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miR‑23a downregulation modulates the inflammatory response by targeting ATG12‑mediated autophagy.

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