Dataset Information

MiR-199a-5p-HIF-1?-STAT3 Positive Feedback Loop Contributes to the Progression of Non-Small Cell Lung Cancer.

ABSTRACT: Background: Non-small cell lung cancer (NSCLC) is the most common malignancy worldwide. MiR-199a-5p has been reported to play important roles in multiple tumors, inclusive of NSCLC. However, little is definitively known pertaining to its explicit mechanism of action in NSCLC. Methods: The expressions of miR-199a-5p and hypoxia-inducible factor-1? (HIF-1?) mRNA were quantified employing qRT-PCR. H1299 and A549 cells were transiently transfected with miR-199a-5p mimics or inhibitors. Then, CCK-8 assays, flow cytometry analysis, and Transwell assay were performed for detecting cell proliferation, cell cycle, apoptosis, migration, and invasion of NSCLC cells, respectively. HIF-1?, signal transducer and activator of transcription 3 (STAT3), and p-STAT3 expressions were detected via Western blotting. Bioinformatic analysis and dual-luciferase assay were performed to investigate the interactions among miR-199a-5p, HIF-1?, and STAT3. Xenograft models were established with nude mice for further analyzing the bevacizumab resistance of NSCLC cells. Results: MiR-199a-5p expression was markedly attenuated in NSCLC tissues and cell lines. Overexpression of miR-199a-5p repressed the proliferation, migration, and invasion but induced the apoptosis of NSCLC cells. HIF-1? was identified as a direct target of miR-199a-5p. There was a positive feedback loop among miR-199a-5p, HIF-1?, and STAT3. Co-transfection of HIF-1? or STAT3 overexpression plasmids counteracted the effects of miR-199a-5p. In vivo experiments indicated that the feedback loop was in association with the bevacizumab resistance of NSCLC cells. Conclusion: MiR-199a-5p blocked the progression of NSCLC and sensitized NSCLC cells to bevacizumab by suppressing HIF-1? and STAT3, while the HIF-1?/STAT3 axis suppressed the expression of miR-199a-5p, which forms a positive feedback loop to promote the sustaining progression of NSCLC.

SUBMITTER: Yang X

PROVIDER: S-EPMC7929999 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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MiR-199a-5p-HIF-1α-STAT3 Positive Feedback Loop Contributes to the Progression of Non-Small Cell Lung Cancer.

Yang Xingping X Zheng Yuzhen Y Tan Jian J Tian Renjiang R Shen Piao P Cai Weijie W Liao Hongying H

Frontiers in cell and developmental biology 20210218

<b>Background:</b> Non-small cell lung cancer (NSCLC) is the most common malignancy worldwide. MiR-199a-5p has been reported to play important roles in multiple tumors, inclusive of NSCLC. However, little is definitively known pertaining to its explicit mechanism of action in NSCLC. <b>Methods:</b> The expressions of miR-199a-5p and hypoxia-inducible factor-1α (HIF-1α) mRNA were quantified employing qRT-PCR. H1299 and A549 cells were transiently transfected with miR-199a-5p mimics or inhibitors. ...[more]

PMID: 33681184

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Project description:BackgroundBoth E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa.MethodsThe expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real-time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo.ResultsHere we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation.ConclusionsThese findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance.

Dataset Information

MiR-199a-5p-HIF-1?-STAT3 Positive Feedback Loop Contributes to the Progression of Non-Small Cell Lung Cancer.

Publications

MiR-199a-5p-HIF-1α-STAT3 Positive Feedback Loop Contributes to the Progression of Non-Small Cell Lung Cancer.

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