방사선의학 웹진

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그림 1. miR-203을 transfection 시킨 U251 cell line에서 방사선조사시 surviving fraction 이 유의하게 감소하였다.

그림 2. Western blot 결과 homologous recombination 에 관여하는 ATM 과 RAD51 의 발현이 miR-203을 transfection 시킨 U251에서 감소하였다.

그림 3. miR-203 의 과발현은 U251 cell line에서 p-PI3K, p-AKT, p-JAK1, p-STAT3, p-SRC, PLD2 의 발현을 감소시켰다.

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그림 4. EMT 관련 단백질변화

miR-203 의 과발현으로 epithelial marker 는 증가하고 mesenchymal marker 는 감소하였다.

Abstract

PURPOSE:

We investigated whether miR-203 could modulate the radiation sensitivity of glioblastoma (GBM) cells and which target gene(s) could be involved.

METHODS AND MATERIALS:

Three human malignant glioma (MG) cell lines and normal human astrocytes were transfected with control microRNA, pre-miR-203, or antisense miR-203. Real-time PCR (RT-PCR), clonogenic assays, immunofluorescence, and invasion/migration assays were performed. To predict the target(s), bioinformatics analyses using microRNA target databases were performed.

RESULTS:

Overexpression of miR-203 increased the radiation sensitivity of all 3 human MG cell lines and prolonged radiation-induced γ-H2AX foci formation. Bioinformatics analyses suggested that miR-203 could be involved in post-transcriptional control of DNA repair, PI3K/AKT, SRC, and JAK/STAT3 and the vascular signaling pathway. Western blot analysis validated the fact that miR-203 downregulated ATM, RAD51, SRC, PLD2, PI3K-AKT, JAK-STAT3, VEGF, HIF-1α, and MMP2. Overexpression of miR-203 inhibited invasion and migration potentials, downregulated SLUG and Vimentin, and upregulated Claudin-1 and ZO1.

CONCLUSIONS:

These data demonstrate that miR-203 potentially controls DNA damage repair via the PI3K/AKT and JAK/STAT3 pathways and may collectively contribute to the modulation of radiation sensitivity in MG cells by inhibiting DNA damage repair, prosurvival signaling, and epithelium-mesenchyme transition. Taken together, these findings demonstrate that miR-203 could be a target for overcoming the radiation resistance of GBM.
 

Author information

Chang JH1, Hwang YH2, Lee DJ2, Kim DH2, Park JM2, Wu HG1, Kim IA3.

1Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.

2Medical Science Research Institute, Seoul National University Bundang Hospital, Kyeonggido, Republic of Korea.

3Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Kyeonggido, Republic of Korea; Cancer Research Institute, Seoul National University, Seoul, Republic of Korea. Electronic address: inah228@snu.ac.kr.