MicroRNA-143 Targets ATG2B to Inhibit Autophagy and Increase Inflammatory Responses in Crohn’s Disease

Lin, Xutao; Zheng, Xiaobin; Fan, Dejun; Yao, Qiuqiong; Hu, Jiancong; Lian, Lei; Wu, Xiaojian; Lan, Ping; He, Xiaosheng

doi:10.1093/ibd/izx075

Cited by 45 publications

(36 citation statements)

References 47 publications

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“…Our findings suggest that autophagy was facilitated in the hearts of L9 mice. This result is unexpected, because previous studies demonstrated that miR-143 suppressed autophagy through downregulation of ATG2B [61,62]. Since those investigators used human cancer cell lines for the miR-143-transfection assays, the discrepancy may be due to differences in cellular context or animal species.…”

Section: Discussionmentioning

confidence: 94%

Forced expression of miR-143 and -145 in cardiomyocytes induces cardiomyopathy with a reductive redox shift

et al. 2020

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Background Animal model studies show that reductive stress is involved in cardiomyopathy and myopathy, but the exact physiological relevance remains unknown. In addition, the microRNAs miR-143 and miR-145 have been shown to be upregulated in cardiac diseases, but the underlying mechanisms associated with these regulators have yet to be explored. Methods We developed transgenic mouse lines expressing exogenous miR-143 and miR-145 under the control of the alpha-myosin heavy chain (αMHC) promoter/enhancer. Results The two transgenic lines showed dilated cardiomyopathy-like characteristics and early lethality with markedly increased expression of miR-143. The expression of hexokinase 2 (HK2), a cardioprotective gene that is a target of miR-143, was strongly suppressed in the transgenic hearts, but the in vitro HK activity and adenosine triphosphate (ATP) content were comparable to those observed in wild-type mice. In addition, transgenic complementation of HK2 expression did not reduce mortality rates. Although HK2 is crucial for the pentose phosphate pathway (PPP) and glycolysis, the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) was unexpectedly higher in the hearts of transgenic mice. The expression of gamma-glutamylcysteine synthetase heavy subunit (γ-GCSc) and the in vitro activity of glutathione reductase (GR) were also higher, suggesting that the recycling of GSH and its de novo biosynthesis were augmented in transgenic hearts. Furthermore, the expression levels of glucose-6-phosphate dehydrogenase (G6PD, a rate-limiting enzyme for the PPP) and p62/SQSTM1 (a potent inducer of glycolysis and glutathione production) were elevated, while p62/SQSTM1 was upregulated at the mRNA level rather than as a result of autophagy inhibition. Consistent with this observation, nuclear factor erythroid-2 related factor 2 (Nrf2), Jun N-terminal kinase (JNK) and inositol-requiring enzyme 1 alpha (IRE1α) were activated, all of which are known to induce p62/SQSTM1 expression. Conclusions Overexpression of miR-143 and miR-145 leads to a unique dilated cardiomyopathy phenotype with a reductive redox shift despite marked downregulation of HK2 expression. Reductive stress may be involved in a wider range of cardiomyopathies than previously thought.

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Section: Discussionmentioning

confidence: 94%

Forced expression of miR-143 and -145 in cardiomyocytes induces cardiomyopathy with a reductive redox shift

et al. 2020

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“…Of note, this is what distinguishes this result from those of previous reports. MIR143 has been reported to inhibit autophagy [46,47] and the induction of autophagy by CM-MIR143#12 may be one of the processes leading to apoptosis; this is an issue that needs to be clarified in future studies.…”

Section: Discussionmentioning

confidence: 99%

Synthetic MIR143-3p Suppresses Cell Growth in Rhabdomyosarcoma Cells by Interrupting RAS Pathways Including PAX3–FOXO1

Sugito

Heishima

Ito

et al. 2020

Cancers

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Rhabdomyosarcoma (RMS) is a soft tissue sarcoma most frequently found in children. In RMS, there are two major subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). ARMS has the worse prognosis of the two owing to the formation of the chimeric PAX3–FOXO1 gene. A novel therapeutic method is required for treating ARMS. In our previous study, we found that the ectopic expression of chemically modified MIR143-3p#12 (CM-MIR143#12), which is RNase-resistant and shows the highest anti-proliferation activity among the synthesized MIR143 derivatives that were tested, induces significant cell growth suppression by targeting KRAS, AKT, and ERK in colorectal cancer cells. The expression of MIR143-3p in RMS was dramatically downregulated compared with that of normal tissue. Ectopic expression of CM-MIR143#12 in RMS cells resulted in a significant growth inhibitory effect through the induction of apoptosis and autophagy. Interestingly, we found that CM-MIR143#12 also silenced the expression of chimeric PAX3–FOXO1 directly and, using siR-KRAS or siR-AKT, that KRAS networks regulated the expression of PAX3–FOXO1 in ARMS cells. In ERMS harboring NRAS mutation, CM-MIR143#12 silenced mutated NRAS. These findings indicate that CM-MIR143#12 efficiently perturbed the RAS signaling pathway, including the ARMS-specific KRAS/PAX3–FOXO1 networks.

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“…When Lin et al . [ 20 ] studied the expression level of miR-143 at inflamed and non inflamed colon tissues of patients with Crohn’s disease, there was a significantly increased expression in inflamed tissue compared to normal tissue. They showed that the expression of ATG2B , which is the target of miR-143 playing a role in autophagy, was decreased in inflamed tissues.…”

Section: Discussionmentioning

confidence: 99%

The expression levels of microRNAs associated with T and B cell differentiation/stimulation in ankylosing spondylitis

Turkyilmaz

Ata

Akbaş

et al. 2020

Balkan Journal of Medical Genetics

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Spondyloarthropathies (SpAs), are a group of chronic inflammatory diseases with a number of genetic, physiopathological, clinical and radiological features. Ankylosing spondylitis (AS) is the most common type of spondylo-arthropathies, and >90.0% of patients with ankylosing spondylitis are human leukocyte antigen-B27 (HLA-B2 7)-positive. In recent years, non-HLA genetic factors have been reported to have an effect on ankylosing spondylitis. MicroRNAs (miRNAs), are endogenous non coding RNA molecules containing 18-23 nucleotides that play a role in the post-transcriptional regulation of gene expression. In this study, we aimed to determine the expression levels of miRNAs associated with T- and B-cell differentiation/stimulation in peripheral blood mononuclear cells and their relationship with the etiology of the AS in patients and healthy controls. In a molecular study, peripheral blood mononuclear cell isolation, and total RNA isolation were performed first. In the second step, cDNA synthesis and quantitative real-time PCR (qPCR) expression analysis were completed. Ultimately, in the patient and control group, the expression levels of miR-142-5p and miR-143 were found to be significantly different (p <0.05). According to current knowledge, miR-142-5p andmiR-143 expressions were found to be important for those diseases that share similar etiology with AS. We suggest that miR-142-5p and miR-143 may play a role in the pathogenesis, especially miR- 142-5p may be a potential biomarker and a target molecule for the treatment.

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MicroRNA-143 Targets ATG2B to Inhibit Autophagy and Increase Inflammatory Responses in Crohn’s Disease

Abstract: miR-143 may induce bowel inflammation by regulating ATG2B and autophagy, suggesting that miR-143 might play a critical role in the development of CD. Therefore, miR-143 could be a promising novel target for gene therapy in CD patients.

Cited by 45 publications

References 47 publications

Forced expression of miR-143 and -145 in cardiomyocytes induces cardiomyopathy with a reductive redox shift

Forced expression of miR-143 and -145 in cardiomyocytes induces cardiomyopathy with a reductive redox shift

Synthetic MIR143-3p Suppresses Cell Growth in Rhabdomyosarcoma Cells by Interrupting RAS Pathways Including PAX3–FOXO1

The expression levels of microRNAs associated with T and B cell differentiation/stimulation in ankylosing spondylitis

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