Correction: MicroRNA-21 promotes TGF-?1-induced epithelial-mesenchymal transition in gastric cancer through up-regulating PTEN expression.
Ontology highlight
ABSTRACT:
SUBMITTER: Li C
PROVIDER: S-EPMC7456615 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
Correction: MicroRNA-21 promotes TGF-β1-induced epithelial-mesenchymal transition in gastric cancer through up-regulating PTEN expression.
Li Chang C Song Lei L Zhang Zhuo Z Bai Xiao-Xue XX Cui Ming-Fu MF Ma Lian-Jun LJ
Oncotarget 20200825 34
[This corrects the article DOI: 10.18632/oncotarget.11888.]. ...[more]
Similar Datasets
Project description:TGF-?1, upregulated in keloid tissue, promotes the proliferation, collagen formation and differentiation of dermal fibroblasts. miR-21 is one of microRNAs first found in human genome. The aim of our study is to explore the mechanisms of miR-21 in TGF-?1-induced scar fibroblasts proliferation and transdifferentiation. In the present study, first we found that TGF-?1 promoted scar fibroblasts proliferation and transdifferentiation via up-regulating miR-21 expression, which could be attenuated when miR-21 was inhibited. Overexpression of miR-21 had similar effect as TGF-?1 on proliferation and transdifferentiation. Additionally, TGF-?1 increased the expressions and activities of MMP2 and MMP9 in keloid fibroblasts, which was suppressed by miR-21 inhibition. Finally, the results demonstrated that PTEN/AKT signaling pathway played important role in TGF-?1-induced transdifferentiation. In conclusion, our study suggests that TGF-?1 promotes keloid fibroblasts proliferation and transdifferentiation via up-regulation of miR-21 and PTEN/AKT signalling pathway plays important role in this process, which provides a potential theoretical basis for clinical treatment of skin scars.
| S-EPMC4995376 | biostudies-literature
Project description:Multiple microRNAs (miRNAs) regulate epithelial-mesenchymal transition and endothelial-mesenchymal transition (EndMT). Here we report that microRNA-27b (miR-27b) positively regulates transforming growth factor-β (TGF-β)-induced EndMT of MS-1 mouse pancreatic microvascular endothelial cells. TGF-β induced miR-23b/24-1/27b expression, and inhibition of miR-27 suppressed TGF-β-mediated induction of mesenchymal genes. Genome-wide miRNA target analysis revealed that miR-27 targets Elk1, which acts as a competitive inhibitor of myocardin-related transcription factor-serum response factor signalling and as a myogenic repressor. miR-27b was also found to regulate several semaphorin receptors including Neuropilin 2, Plexin A2 and Plexin D1. These results suggest important roles of miR-27 in TGF-β-driven EndMT.
| S-EPMC5412016 | biostudies-literature
Project description:Pancreatic cancer patients are often resistant to chemotherapy treatment, which results in poor prognosis. The objective of this study was to delineate the mechanism by which miR-21 induces drug resistance to 5-fluorouracil (5-FU) in human pancreatic cancer cells (PATU8988 and PANC-1). We report that PATU8988 cells resistant to 5-FU express high levels of miR-21 in comparison to sensitive primary PATU8988 cells. Suppression of miR-21 expression in 5-Fu-resistant PATU8988 cells can alleviate its 5-FU resistance. Meanwhile, lentiviral vector-mediated overexpression of miR-21 not only conferred resistance to 5-FU but also promoted proliferation, migration, and invasion of PATU8988 and PANC-1 cells. The proresistance effects of miR-21 were attributed to the attenuated expression of tumor suppressor genes, including PTEN and PDCD4. Overexpression of PTEN and PDCD4 antagonized miR-21-induced resistance to 5-FU and migration activity. Our work demonstrates that miR-21 can confer drug resistance to 5-FU in pancreatic cancer cells by regulating the expression of tumor suppressor genes, as the target genes of miR-21, PTEN and PDCD4 can rescue 5-FU sensitivity and the phenotypic characteristics disrupted by miR-21.
| S-EPMC4831288 | biostudies-other
Project description:Radiation-induced pulmonary fibrosis (RIPF) results from thoracic radiotherapy and severely limits the use of radiotherapy. Recent studies suggest that epithelium-to-mesenchymal transition (EMT) contributes to pulmonary fibrosis. Although miRNA dysregulation participates in a variety of pathophysiologic processes, their roles in fibrotic lung diseases and EMT are unclear. In this study, we aimed to identify key miRNAs involved in this process using a mouse model of RIPF previously established by irradiation with a single dose (20 Gy) of 60Co γ-rays. At 2-weeks post-irradiation, a set of significantly upregulated miRNAs was identified in lung tissue by miRNA array analysis. This included miR-21, which has been reported to contribute to the pulmonary fibrotic response induced by stereotactic body radiotherapy. Here, we showed that miR-21 expression increased in parallel with EMT progression in the lungs of irradiated mice. Ectopic miR-21 expression promoted EMT progression in lung epithelial cells. Furthermore, downregulation of miR-21 expression by transfection of its inhibitor inhibited ionizing radiation (IR)-induced EMT. Knockdown of PTEN, which is the functional target of miR-21, reversed the attenuation of IR-induced EMT mediated by miR-21 downregulation. Radiation treatment decreased PTEN expression and increased Akt phosphorylation; these effects were abolished by the miR-21 inhibitor. MiR-21 overexpression in lung epithelial cell also downregulated PTEN expression and upregulated Akt phosphorylation. In conclusion, we have demonstrated that miR-21 functions as a key regulator of IR-induced EMT in lung epithelial cells via the PTEN/Akt pathway. Targeting miR-21 is implicated as a novel therapeutic strategy for the prevention of RIPF.
| S-EPMC6505383 | biostudies-literature
Project description:MicroRNA (miR)-21 is known to act as an oncogene in cervical cancer by promoting cell proliferation and migration; however, the underlying molecular mechanisms have remained to be fully elucidated. The present study revealed that the gene expression levels of miR-21 and epithelial-mesenchymal transition (EMT)-associated transcription factor Zinc finger E-box-binding homeobox 1 (ZEB1), in cervical cancer and lymphatic metastatic carcinoma tissues were significantly higher than those in normal tissues (P<0.05). Furthermore, the gene expression levels of miR-21 and ZEB1 were positively associated with muscular infiltration depth, parametrical invasion and lymph node metastasis in patients with cervical cancer. Immunohistochemistry assays indicated that the expression levels of ZEB1 and the mesenchymal cell marker Vimentin in cervical cancer tissues were significantly higher than those in normal cervical tissues (P<0.05). Overexpression of miR-21 in HeLa and SiHa cells caused the upregulation of the mesenchymal cell markers Vimentin and N-cadherin, and downregulation of the epithelial cell marker E-cadherin at the proteins level. In addition, overexpression of miR-21 enhanced the invasiveness of HeLa and SiHa cells. These results demonstrated that miR-21 was upregulated in cervical cancer tissues and promoted cell metastasis through modulating EMT. A better understanding of the role of miR-21 and EMT may lead to the development of more effective therapies for patients with cervical cancer.
| S-EPMC7074379 | biostudies-literature
Project description:Transforming growth factor-? (TGF?) promotes glomerular hypertrophy and matrix expansion, leading to glomerulosclerosis. MicroRNAs are well suited to promote fibrosis because they can repress gene expression, which negatively regulate the fibrotic process. Recent cellular and animal studies have revealed enhanced expression of microRNA, miR-21, in renal cells in response to TGF?. Specific miR-21 targets downstream of TGF? receptor activation that control cell hypertrophy and matrix protein expression have not been studied. Using 3'UTR-driven luciferase reporter, we identified the tumor suppressor protein PTEN as a target of TGF?-stimulated miR-21 in glomerular mesangial cells. Expression of miR-21 Sponge, which quenches endogenous miR-21 levels, reversed TGF?-induced suppression of PTEN. Additionally, miR-21 Sponge inhibited TGF?-stimulated phosphorylation of Akt kinase, resulting in attenuation of phosphorylation of its substrate GSK3?. Tuberin and PRAS40, two other Akt substrates, and endogenous inhibitors of mTORC1, regulate mesangial cell hypertrophy. Neutralization of endogenous miR-21 abrogated TGF?-stimulated phosphorylation of tuberin and PRAS40, leading to inhibition of phosphorylation of S6 kinase, mTOR and 4EBP-1. Moreover, downregulation of miR-21 significantly suppressed TGF?-induced protein synthesis and hypertrophy, which were reversed by siRNA-targeted inhibition of PTEN expression. Similarly, expression of constitutively active Akt kinase reversed the miR-21 Sponge-mediated inhibition of TGF?-induced protein synthesis and hypertrophy. Furthermore, expression of constitutively active mTORC1 prevented the miR-21 Sponge-induced suppression of mesangial cell protein synthesis and hypertrophy by TGF?. Finally, we show that miR-21 Sponge inhibited TGF?-stimulated fibronectin and collagen expression. Suppression of PTEN expression and expression of both constitutively active Akt kinase and mTORC1 independently reversed this miR-21-mediated inhibition of TGF?-induced fibronectin and collagen expression. Our results uncover an essential role of TGF?-induced expression of miR-21, which targets PTEN to initiate a non-canonical signaling circuit involving Akt/mTORC1 axis for mesangial cell hypertrophy and matrix protein synthesis.
| S-EPMC3411779 | biostudies-literature
Project description:BackgroundAccumulating evidence indicates that N-cadherin is a cell adhesion molecule that has critical roles in tumour progression. However, the role of N-cadherin in hepatocellular carcinoma (HCC) remains controversial.MethodsThis study aims to investigate the expression status of N-cadherin and its molecular mechanisms in HCC.ResultsThe expression of N-cadherin was markedly overexpressed in HCC tissues and cell lines. We identified that miR-199b-5p binds to the 3'-UTR of N-cadherin mRNA, thus decreasing N-cadherin expression in HCC cells. We also found the downregulation of miR-199b-5p in HCC specimens, which was inversely correlated with N-cadherin upregulation, predicted poor clinical outcomes in HCC patients. Next, we determined that miR-199b-5p overexpression promoted cell aggregation, suppressed cell migration and invasion in HCC cells, and inhibited xenografts tumour metastasis in nude mice. Moreover, we demonstrated that miR-199b-5p attenuated TGF-?1 induced epithelial-mesenchymal transition (EMT) -associated traits, while its effects could be partially reversed by N-cadherin restoration. Finally, we examined that N-cadherin downregulation or miR-199b-5p overexpression suppressed TGF-?1-induced Akt phosphorylation, and inhibition of PI3K/Akt pathway blocked TGF-?1-induced N-cadherin overexpression in HCC cells.ConclusionsOur data demonstrate that N-Cadherin was markedly overexpressed and miR-199b-5p was significantly downregulated in HCC. MiR-199b-5p exerts inhibitory effects on EMT, and directly targets N-cadherin in HCC, supporting the potential utility of miR-199b-5p as a promising strategy to treat HCC. Also, a positive regulatory loop exists between N-cadherin and Akt signalling represents a novel mechanism of TGF-?1-mediated EMT in HCC cells.
| S-EPMC5520514 | biostudies-literature
Project description:BACKGROUND:Epithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study. METHODS:Type 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-α (p53 inhibitor) or 10-[4'-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months. RESULTS:DN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-β)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-α inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2). CONCLUSION:FGF21 prevents renal fibrosis via negative regulation of the TGF-β/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.
| S-EPMC7043973 | biostudies-literature
Project description:Gypenoside XVII (GP‑17), one of the dominant active components of Gynostemma pentaphyllum, has been studied extensively and found to have a variety of pharmacological effects, including neuroprotective properties. However, the neuroprotective effects of GP‑17 against spinal cord injury (SCI), as well as its underlying mechanisms of action remain unknown. The present study aimed to investigate the effects of GP‑17 on motor recovery and histopathological changes following SCI and to elucidate the mechanisms underlying its neuroprotective effects in a mouse model of SCI. Motor recovery was evaluated using the Basso, Beattie and Bresnahan (BBB) locomotor rating scale. Spinal cord edema was detected by the wet/dry weight method. H&E staining was performed to examine the effect of GP‑17 on spinal cord damage. Inflammatory response production was assessed by ELISA. Candidate miRNAs were identified following the integrated analysis of the Gene Expression Omnibus (GEO) dataset GSE67515. Western blot analysis was also performed to detect the expression levels of associated proteins. The results revealed that GP‑17 treatment improved functional recovery, and suppressed neuronal apoptosis and the inflammatory response in the mouse model of SCI. Moreover, it was observed that miR‑21 expression was downregulated following SCI, whereas it was upregulated following the administration of GP‑17. The inhibition of miR‑21 eliminated the protective effects of GP‑17 on SCI‑induced neuronal apoptosis and the inflammatory response. In addition, phosphatase and tensin homologue (PTEN), a key molecule in the activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, was identified as a target of miR‑21, and PTEN expression was downregulated by GP‑17 through miR‑21. Furthermore, the PTEN/AKT/mTOR pathway was inactivated by SCI, whereas it was re‑activated by GP‑17 through the regulation of miR‑21 in mice with SCI. On the whole, the findings of the present study suggest that GP‑17 plays a protective role in SCI via regulating the miR‑21/PTEN/AKT/mTOR pathway.
| S-EPMC8208621 | biostudies-literature
Project description:Canine Visceral leishmaniasis (CanL) poses a severe public health threat in several countries. Disease progression depends on the degree of immune response suppression. MicroRNAs (miRs) modulate mRNA translation into proteins and regulate various cellular functions and pathways associated with immune responses. MiR-21 and miR-148a can alter the parasite load and M1 macrophages are the principal cells in dogs' leishmanicidal activity. A previous study found increased miR-21 and miR-148a in splenic leukocytes (SL) of dogs with CanL using microarray analysis and in silico analysis identified PTEN pathway targets. PTEN is involved in the immune regulation of macrophages. We measured PTEN and the production of reactive oxygen species (ROS) and nitric oxide (NO) before and after transfection SLs of dogs with CanL with mimic and inhibition of miR-21 and miR-148a. PTEN levels increased, NO and ROS decreased in SLs from dogs with CanL. Inhibition of miRNA-21 resulted in PTEN increase; in contrast, PTEN decreased after miR-148a inhibition. Nitrite (NO2) levels increased after transfection with miR-21 inhibitor but were decreased with miR-148a inhibitor. The increase in miR-21 promoted a reduction in ROS and NO levels, but miR-148a inhibition increased NO and reduced ROS. These findings suggest that miR-21 and miR-148a can participate in immune response in CanL, affecting PTEN, NO, and ROS levels.
| S-EPMC10137164 | biostudies-literature