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Published on: July 21, 2018
LIN28B confers radio-resistance through the posttranscriptional control of KRAS
Sun-Hye Jeong1, Hong-Gyun Wu, Woong-Yang Park
1Department of Biomedical Sciences, Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea.
Abstract:
To screen the differentially expressed microRNAs related to radio-resistance, we compared the microRNA profiles of lung cancer cells with different responses to ionizing radiation (IR). Of 328 microRNAs in microarray, 27 microRNAs were differentially expressed in NCI-H460 (H460) and NCI-H1299 (H1299) cells. Among them, let-7g was down-regulated in radio-resistant H1299 cells, and the level of let-7g was higher in radio-sensitive cells like Caski, H460, and ME180 in qRT-PCR analysis than in radio-resistant cells like A549, H1299, DLD1, and HeLa. Over-expression of let-7g in H1299 cells could suppress the translation of KRAS, and increase the sensitivity to IR. When we knockdown the expression of LIN28B, an upstream regulator of let-7g, the level of mature let-7g was increased in H1299 cells and the sensitivity to IR was also enhanced in LIN28B knockdown cells. From these data, we suggest that LIN28B plays an important role in radiation responses of lung cancer cells through inhibiting let-7g processing and increasing translation of KRAS.
Insights
This study identifies let-7g as a key microRNA in radio-resistance for lung cancer. LIN28B inhibits let-7g, increasing resistance to ionizing radiation (IR) by promoting KRAS translation.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Radio-resistance is a major challenge in lung cancer treatment.
- MicroRNAs (miRNAs) are increasingly recognized as regulators of cellular responses to radiation.
- Identifying specific miRNAs involved in radio-resistance can reveal novel therapeutic targets.
Purpose of the Study:
- To identify differentially expressed microRNAs associated with radio-resistance in lung cancer cells.
- To investigate the role of let-7g and its regulatory pathway in cellular response to ionizing radiation (IR).
Main Methods:
- Microarray analysis of miRNA profiles in lung cancer cell lines with varying IR responses.
- Quantitative real-time PCR (qRT-PCR) to validate miRNA expression levels.
- Functional studies involving miRNA over-expression, gene knockdown, and assessment of IR sensitivity.
Main Results:
- 27 microRNAs were differentially expressed between radio-resistant and sensitive lung cancer cells.
- let-7g was significantly down-regulated in radio-resistant cells and its over-expression increased IR sensitivity.
- Knockdown of LIN28B, an upstream regulator, increased mature let-7g levels and enhanced IR sensitivity.
Conclusions:
- LIN28B inhibits let-7g processing, contributing to radio-resistance in lung cancer cells.
- The LIN28B/let-7g/KRAS pathway is a critical determinant of cellular response to ionizing radiation.
- Targeting the LIN28B-let-7g axis may represent a novel strategy to overcome radio-resistance in lung cancer.
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