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Published on: March 30, 2019
Radio-sensitizing effects of microRNA-27a elevation in lung cancer cells by inhibiting ZEB1 expression and activating
1Department of Radiotherapy, Dongyang People's Hospital of Zhejiang Province, Jinhua, Zhejiang, P.R. China.
Abstract:
MicroRNAs (miRNAs or miRs) exert either as tumor-inhibiting or oncogenic roles in tumorigenesis of lung cancer. In the present study, we identified a novel microRNA (miR)-27a as being involved in the radiosensitivity of lung cancer cells. Therefore, we sought to characterize its potential underlying mechanism in lung cancer cell sensitivity to radiotherapy. To this end, A549 and H460 cells irradiated with 8 Gy irradiation (IR) were used as a cell model. RT-qPCR exhibited that the expression of miR-27a increased, whereas ZEB1 was poorly expressed in A549 and H460 cells exposed to IR. As reflected by dual-luciferase reporter gene assay, miR-27a could target and inversely modulate ZEB1 expression. Gain- and loss-of-function experiments exhibited that miR-27 inhibition promoted proliferation of IR-treated A549 and H460 cells and reduced the sensitivity of A549 and H460 cells to radiotherapy, which was rescued by silencing of ZEB1. Further, miR-27a inhibition disrupted the homologous recombination (HR)-mediated DNA repair, evidenced by reduced ATM, pCHK2 and Rad51 levels. Collectively, miR-27a activates HR-mediated DNA repair by inhibiting ZEB1 expression to enhance the radiosensitivity of lung cancer cells, highlighting a therapeutic target for lung cancer radiosensitivity.
Insights
MicroRNA-27a enhances lung cancer cell radiosensitivity by activating DNA repair pathways through ZEB1 inhibition. This finding highlights miR-27a as a potential therapeutic target for improving radiotherapy outcomes in lung cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- MicroRNAs (miRNAs) play dual roles in lung cancer tumorigenesis.
- Understanding miRNA roles in radiosensitivity is crucial for effective lung cancer treatment.
Purpose of the Study:
- To identify novel microRNAs involved in lung cancer radiosensitivity.
- To elucidate the underlying molecular mechanism of miR-27a in modulating lung cancer cell response to radiotherapy.
Main Methods:
- Utilized A549 and H460 lung cancer cell lines exposed to 8 Gy irradiation.
- Employed RT-qPCR to assess miR-27a and ZEB1 expression.
- Performed dual-luciferase reporter gene assays to confirm miR-27a targeting of ZEB1.
- Conducted gain- and loss-of-function experiments for miR-27a and ZEB1.
- Assessed homologous recombination DNA repair by measuring ATM, pCHK2, and Rad51 levels.
Main Results:
- miR-27a expression increased, while ZEB1 expression decreased in irradiated lung cancer cells.
- miR-27a directly targets and inversely modulates ZEB1 expression.
- Inhibition of miR-27a reduced radiosensitivity and promoted proliferation, effects rescued by ZEB1 silencing.
- miR-27a inhibition impaired homologous recombination DNA repair, indicated by reduced ATM, pCHK2, and Rad51.
Conclusions:
- miR-27a enhances lung cancer cell radiosensitivity by inhibiting ZEB1.
- This mechanism involves the activation of homologous recombination-mediated DNA repair.
- miR-27a represents a potential therapeutic target for improving lung cancer radiotherapy.
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