Radiation-inducible miR-770-5p sensitizes tumors to radiation through direct targeting of PDZ-binding kinase.
Radiotherapy represents the most effective non-surgical modality in cancer treatment. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression, and are involved in many biological processes and diseases. To identify miRNAs that influence the radiation response, we performed miRNA array analysis using MCF7 cells at 2, 8, and 24 h post irradiation. We demonstrated that miR-770-5p is a novel radiation-inducible miRNA. When miR-770-5p was overexpressed, relative cell number was reduced due to increased apoptosis in MCF7 and A549 cells. Transcriptomic and bioinformatic analyses revealed that PDZ-binding kinase (PBK) might be a possible target of miR-770-5p for regulation of radiosensitivity. PBK regulation mediated by direct targeting of miR-770-5p was demonstrated using luciferase reporter assays along with wild-type and mutant PBK-3'untranslated region constructs. Radiation sensitivity increased and decreased in miR-770-5p- and anti-miR-770-5p-transfected cells, respectively. Consistent with this result, transfection of short interfering RNA against PBK inhibited cell proliferation, while ectopic expression of PBK restored cell survival from miR-770-5p-induced cell death. In addition, miR-770-5p suppressed tumor growth, and miR-770-5p and PBK levels were inversely correlated in xenograft model mice. Altogether, these data demonstrated that miR-770-5p might be a useful therapeutic target miRNA that sensitizes tumors to radiation via negative regulation of PBK.
Department of Molecular Medicine, Inha University College of Medicine, Incheon, Korea.|Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, Korea.
Hyung Chul
HC
Lee
Division of Life Sciences, Korea University, Seoul, Korea.
Nam-Gu
NG
Her
Department of Molecular Medicine, Inha University College of Medicine, Incheon, Korea.|Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, Korea.
Donghee
D
Kang
Department of Molecular Medicine, Inha University College of Medicine, Incheon, Korea.|Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, Korea.
Seung Hee
SH
Jung
Department of Microbiology, Inha University College of Medicine, Incheon, Korea.
Jinwook
J
Shin
Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Minyoung
M
Lee
Division of Basic Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
In Hwa
IH
Bae
Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Korea.
Young-Nyun
YN
Kim
Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, Korea.|Department of Microbiology, Inha University College of Medicine, Incheon, Korea.
Heon Joo
HJ
Park
Division of Life Sciences, Korea University, Seoul, Korea.
Young-Gyu
YG
Ko
Department of Molecular Medicine, Inha University College of Medicine, Incheon, Korea.|Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, Korea.
Jae-Seon
0000-0001-6002-5267
JS
Lee
D020413:3' Untranslated Regions / Q000235:genetics; D000072283:A549 Cells; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
D020413:3' Untranslated Regions; C000609533:MIRN-770 microRNA, human; D035683:MicroRNAs; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase