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Metformin-repressed miR-381-YAP-snail axis activity disrupts NSCLC growth and metastasis
1Clinical Medicine Laboratory, Binzhou Medical University Hospital, Binzhou, 256603, People's Republic of China.
Background:
Recent evidence indicates that metformin inhibits mammalian cancer growth and metastasis through the regulation of microRNAs. Metformin regulates miR-381 stability, which plays a vital role in tumor progression. Moreover, increased YAP expression and activity induce non-small cell lung cancer (NSCLC) tumor growth and metastasis. However, the molecular mechanism underpinning how metformin-induced upregulation of miR-381 directly targets YAP or its interactions with the epithelial-mesenchymal transition (EMT) marker protein Snail in NSCLC is still unknown.
Methods:
Levels of RNA and protein were analyzed using qPCR, western blotting and immunofluorescence staining. Cellular proliferation was detected using a CCK8 assay. Cell migration and invasion were analyzed using wound healing and transwell assays. Promoter activity and transcription were investigated using the luciferase reporter assay. Chromatin immunoprecipitation was used to detect the binding of YAP to the promoter of Snail. The interaction between miR-381 and the 3'UTR of YAP mRNA was analyzed using the MS2 expression system and co-immunoprecipitation with biotin.
Results:
We observed that miR-381 expression is negatively correlated with YAP expression and plays an opposite role to YAP in the regulation of cellular proliferation, invasion, migration, and EMT of NSCLC cells. The miR-381 function as a tumor suppressor was significantly downregulated in lung cancer tissue specimens and cell lines, which decreased the expression of its direct target YAP. In addition, metformin decreased cell growth, migration, invasion, and EMT via up-regulation of miR-381. Moreover, YAP, which functions as a co-transcription factor, enhanced NSCLC progression and metastasis by upregulation of Snail. Snail knockdown downregulated the mesenchymal marker vimentin and upregulated the epithelial marker E-cadherin in lung cancer cells. Furthermore, miR-381, YAP, and Snail constitute the miR-381-YAP-Snail signal axis, which is repressed by metformin, and enhances cancer cell invasiveness by directly regulating EMT.
Conclusions:
Metformin-induced repression of miR-381-YAP-Snail axis activity disrupts NSCLC growth and metastasis. Thus, we believe that the miR-381-YAP-Snail signal axis may be a suitable diagnostic marker and a potential therapeutic target for lung cancer.
Insights
Metformin inhibits non-small cell lung cancer (NSCLC) by regulating the miR-381-YAP-Snail axis. This pathway, involving microRNA-381, YAP, and Snail, is crucial for NSCLC growth and metastasis, offering a potential therapeutic target.
Area of Science:
- Molecular Oncology
- Cancer Biology
- Biochemistry
Background:
- Metformin demonstrates anti-cancer properties by regulating microRNAs, specifically miR-381, which impacts tumor progression.
- Elevated YAP expression drives non-small cell lung cancer (NSCLC) growth and metastasis.
- The precise mechanism of metformin's effect on miR-381 targeting of YAP and its interaction with epithelial-mesenchymal transition (EMT) markers in NSCLC remains unclear.
Purpose of the Study:
- To elucidate the molecular mechanism by which metformin-induced miR-381 targets YAP and interacts with Snail in NSCLC.
- To investigate the role of the miR-381-YAP-Snail axis in NSCLC progression and metastasis.
- To evaluate the therapeutic potential of targeting this axis in lung cancer.
Main Methods:
- Quantitative PCR, western blotting, and immunofluorescence staining were used to analyze RNA and protein levels.
- Cellular proliferation, migration, and invasion were assessed using CCK8, wound healing, and transwell assays.
- Luciferase reporter assays, chromatin immunoprecipitation, and co-immunoprecipitation were employed to study gene regulation and molecular interactions.
Main Results:
- miR-381 acts as a tumor suppressor in NSCLC, with its expression negatively correlated with YAP.
- Metformin suppresses NSCLC growth, migration, invasion, and EMT by upregulating miR-381.
- The miR-381-YAP-Snail axis, regulated by metformin, controls NSCLC invasiveness and metastasis by modulating EMT.
Conclusions:
- Metformin disrupts NSCLC growth and metastasis by repressing the miR-381-YAP-Snail signaling axis.
- The miR-381-YAP-Snail axis represents a promising diagnostic marker and therapeutic target for lung cancer.
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