MIR‐27a regulates the TGF‐β signaling pathway by targeting <i>SMAD2</i> and <i>SMAD4</i> in lung cancer

Chae, Dong Kyu; Ban, Eunmi; Yoo, Young Sook; Kim, Eunice Eun Kyeong; Baik, Ja Hyun; Song, Eun Joo

doi:10.1002/mc.22655

Cited by 59 publications

(51 citation statements)

References 22 publications

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“…Transforming growth factor beta (TGF-β) is a multifunctional cytokine that belongs to the transforming growth factor superfamily, which includes four different isoforms (TGF-β1, TGF-β2, TGF-β3, and TGF-β4) and many other signaling proteins produced by all white blood cell lineages [17]. The TGF-β signaling pathway is related to carcinogenesis and various biological processes, and the putative tumor suppressors Smad2 and Smad4 are critical in TGF-β signaling [18]. By inducing target genes, TGF-β signaling promotes fibroblast survival and proliferation, resulting in deposition and remodeling of ECM [19].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-27a Suppresses Detrusor Fibrosis in Streptozotocin-Induced Diabetic Rats by Targeting PRKAA2 Through the TGF-β1/Smad3 Signaling Pathway

Liu

Yuan

et al. 2018

Cell Physiol Biochem

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Background/Aims: We examined the effects of microRNA-27a (miR-27a) on detrusor fibrosis in streptozotocin (STZ)-induced diabetic rats. Methods: Eighty healthy Sprague-Dawley (SD) rats were randomly allocated into control, diabetic, miR-27a mimics, mimics control, miR-27a inhibitors, inhibitors control, siRNA-PRKAA2 (siPRKAA2) and inhibitors + siPRKAA2 groups (the latter 7 groups were established as STZ-induced diabetic rat models and treated in different manners). Detrusor cell apoptosis in bladder tissues was determined through terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining. Detrusor cells were assigned to the blank, miR-27a mimics, mimics control, miR-27a inhibitors, inhibitors control, siPRKAA2 and inhibitors + siPRKAA2 groups. Flow cytometry determined the cell cycle stage and apoptosis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting (WB) were used to assess the expression of miR-27a, PRKAA2, TGF-β1, Smad3, p-Smad3, fibronectin (FN), connective tissue growth (CTGF), and collagen-I (COL-I) in tissues and cells. Results: Compared with the control group, the diabetic, miR-27a mimics, and siPRKAA2 groups showed reduced weight and PRKAA2 expression, but elevated blood glucose, serum creatinine (sCr), blood urea nitrogen (BUN), cell apoptosis, and expression of TGF-β1, Smad3, FN, COL-I, CTGF, and p-Smad3. The opposite trend was observed in the miR-27a inhibitors group. PRKAA2 is a target gene of miR-27a. Compared to the blank group, the miR-27a mimics and siPRKAA2 groups indicated markedly increased TGF-β1, Smad3, FN, COL-I, CTGF and p-Smad3 expression; decreased PRKAA2 expression; and increased cell apoptosis. The miR-27a inhibitors group showed the opposite trend. Conclusion: These results indicate that miR-27a may contribute to detrusor fibrosis in STZ-induced diabetic rats by targeting PRKAA2 via the TGF-β1/Smad3 signaling pathway.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-27a Suppresses Detrusor Fibrosis in Streptozotocin-Induced Diabetic Rats by Targeting PRKAA2 Through the TGF-β1/Smad3 Signaling Pathway

Liu

Yuan

et al. 2018

Cell Physiol Biochem

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“…miR-23 targets TRIM63/MuRF1 and FBXO32/atrogin-1, PTEN, caspase-7, SMAD3, and RAS GTPase-activating protein SH3 domainbinding protein 2 (G3BP2), whereas miR-27 targets FoxO1, SMAD2, SMAD4, and myostatin. 18,20,[34][35][36] We found that miR-23a is lower in diabetic skeletal muscle, compared with controls. The decrease in miR-23a contributes to the welldocumented increase in expression of TRIM63/MuRF1 and FBXO32/atrogin-1 E3 ubiquitin ligases as well as dysfunctional insulin signalling (i.e., increased PTEN and decreased Akt phosphorylation).…”

Section: Discussionmentioning

confidence: 57%

“…In our study, delivery of the miR‐23a∼27a∼24‐2 precursor RNA by AAV produces both miR‐23a and miR‐27a, both of which target mRNAs that encode proteins which are relevant to the atrophy and fibrosis processes. miR‐23 targets TRIM63/MuRF1 and FBXO32/atrogin‐1, PTEN, caspase‐7, SMAD3, and RAS GTPase‐activating protein SH3 domain‐binding protein 2 (G3BP2), whereas miR‐27 targets FoxO1, SMAD2, SMAD4, and myostatin . We found that miR‐23a is lower in diabetic skeletal muscle, compared with controls.…”

Section: Discussionmentioning

confidence: 80%

miRNA‐23a/27a attenuates muscle atrophy and renal fibrosis through muscle‐kidney crosstalk

Zhang

Wang

et al. 2018

J cachexia sarcopenia muscle

126

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BackgroundThe treatment of muscle wasting is accompanied by benefits in other organs, possibly resulting from muscle–organ crosstalk. However, how the muscle communicates with these organs is less understood. Two microRNAs (miRs), miR‐23a and miR‐27a, are located together in a gene cluster and regulate proteins that are involved in the atrophy process. MiR‐23a/27a has been shown to reduce muscle wasting and act as an anti‐fibrotic agent. We hypothesized that intramuscular injection of miR‐23a/27a would counteract both muscle wasting and renal fibrosis lesions in a streptozotocin‐induced diabetic model.MethodsWe generated an adeno‐associated virus (AAV) that overexpresses the miR‐23a∼27a∼24‐2 precursor RNA and injected it into the tibialis anterior muscle of streptozotocin‐induced diabetic mice. Muscle cross‐section area (immunohistology plus software measurement) and muscle function (grip strength) were used to evaluate muscle atrophy. Fibrosis‐related proteins were measured by western blot to monitor renal damage. In some cases, AAV‐GFP was used to mimic the miR movement in vivo, allowing us to track organ redistribution by using the Xtreme Imaging System.ResultsThe injection of AAV‐miR‐23a/27a increased the levels of miR‐23a and miR‐27a as well as increased phosphorylated Akt, attenuated the levels of FoxO1 and PTEN proteins, and reduced the abundance of TRIM63/MuRF1 and FBXO32/atrogin‐1 in skeletal muscles. It also decreased myostatin mRNA and protein levels as well as the levels of phosphorylated pSMAD2/3. Provision of miR‐23a/27a attenuates the diabetes‐induced reduction of muscle cross‐sectional area and muscle function. Curiously, the serum BUN of diabetic animals was reduced in mice undergoing the miR‐23a/27a intervention. Renal fibrosis, evaluated by Masson trichromatic staining, was also decreased as were kidney levels of phosphorylated SMAD2/3, alpha smooth muscle actin, fibronectin, and collagen. In diabetic mice injected intramuscularly with AAV‐GFP, GFP fluorescence levels in the kidneys showed linear correlation with the levels in injected muscle when examined by linear regression. Following intramuscular injection of AAV‐miR‐23a∼27a∼24‐2, the levels of miR‐23a and miR‐27a in serum exosomes and kidney were significantly increased compared with samples from control virus‐injected mice; however, no viral DNA was detected in the kidney.ConclusionsWe conclude that overexpression of miR‐23a/27a in muscle prevents diabetes‐induced muscle cachexia and attenuates renal fibrosis lesions via muscle–kidney crosstalk. Further, this crosstalk involves movement of miR potentially through muscle originated exosomes and serum distribution without movement of AAV. These results could provide new approaches for developing therapeutic strategies for diabetic nephropathy with muscle wasting.

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“…suggested that miR‐27a was highly induced in cancer stem cells, which promoted invasion, migration and cell proliferation. In lung cancer, Chae et al . demonstrated that miR‐27a modulated the TGF‐β pathway via targeting SMAD4 and SMAD2.…”

Section: Discussionmentioning

confidence: 99%

Low abundance of TFPI‐2 by both promoter methylation and miR‐27a‐3p regulation is linked with poor clinical outcome in gastric cancer

Geng

Liu

et al. 2020

The Journal of Gene Medicine

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Background:The tumor suppressor role of tissue factor pathway inhibitor 2 (TFPI-2) has been reported in various tumors. The present study aimed to improve the understanding of the oncogenic properties of TFPI-2 in gastric cancer. Methods:Relative expression of TFPI-2 was determined by a real-time polymerase chain reaction (PCR) and western blotting, respectively. Cell viability was measured via a cell counting kit-8 assay and proliferation was evaluated by a colony formation assay. Cell apoptosis was assessed with a caspase-3 activity kit and invasion was evaluated by a transwell chamber assay. The methylation level of TFPI-2 promoter was assayed by methylation-specific PCR. The regulatory effect of miR-27a-3p on TFPI-2 was analyzed with a luciferase reporter assay. The direct association between miR-27a-3p and TFPI-2 was shown by biotin-labelling pulldown.Results: TFPI-2 was down-regulated in gastric cancer, which associated with an unfavorable prognosis clinically. Ectopic introduction of TFPI-2 greatly compromised cell viability, colony formation and invasive capacity, and also induced cell apoptosis simultaneously. The promoter region of TFPI-2 was extensively methylated in gastric cancer tissues compared to normal tissues, suggesting the epigenetic inhibition of TFPI-2 expression. We further identified that TFPI-2 functioned as sponge RNA against miR-27a-3p. Most importantly, miR-27a-3p-specific inhibitor significantly exerted a tumor suppressor function akin to TFPI-2 itself, and the anti-tumoral activities were completely abolished by TFPI-2 knockdown. Conclusions:We found that the epigenetically suppressed TFPI-2 compromised sponging effects with respect to miR-27a-3p in gastric cancer, which consequently and mechanistically contributed to the tumor biology of gastric cancer. K E Y W O R D Sgastric cancer, methylation, miR-27a-3p, TFPI-2 Geng and Liu contributed equally to this work.

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MIR‐27a regulates the TGF‐β signaling pathway by targeting SMAD2 and SMAD4 in lung cancer

Cited by 59 publications

References 22 publications

MicroRNA-27a Suppresses Detrusor Fibrosis in Streptozotocin-Induced Diabetic Rats by Targeting PRKAA2 Through the TGF-β1/Smad3 Signaling Pathway

MicroRNA-27a Suppresses Detrusor Fibrosis in Streptozotocin-Induced Diabetic Rats by Targeting PRKAA2 Through the TGF-β1/Smad3 Signaling Pathway

miRNA‐23a/27a attenuates muscle atrophy and renal fibrosis through muscle‐kidney crosstalk

Low abundance of TFPI‐2 by both promoter methylation and miR‐27a‐3p regulation is linked with poor clinical outcome in gastric cancer

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