Role of microRNA-27a in down-regulation of angiogenic factor AGGF1 under hypoxia associated with high-grade bladder urothelial carcinoma.
Hypoxia stimulates angiogenesis under a variety of pathological conditions, including malignant tumors by inducing expression of angiogenic factors such as VEGFA. Surprisingly, here we report significant association between down-regulation of a new angiogenic factor AGGF1 and high-grade urothelial carcinoma. The proportion of strong AGGF1 expression cases was significantly lower in the high-grade urothelial carcinoma group than that in the low-grade urothelial carcinoma group (P=1.40×10(-5)) or than that in the normal urothelium tissue group (P=2.11×10(-4)). We hypothesized that tumor hypoxia was responsible for differential expression of the AGGF1 protein in low- and high-grade urothelial carcinomas, and therefore investigated the molecular regulatory mechanism for AGGF1 expression under hypoxia. Under hypoxic conditions, AGGF1 protein levels declined without any change in mRNA levels and protein stability. Hypoxia-induced down-regulation of AGGF1 was mediated by miR-27a. Overexpression of miR-27a suppressed AGGF1 expression through translational inhibition, but not by RNA degradation. Moreover, the hypoxia-induced decrease of AGGF1 expression disappeared after miR-27a expression was inhibited. Furthermore, down-regulation of AGGF1 reduced hypoxia-induced apoptosis in cancer cells. Taken together, the results of this study indicate that (1) hypoxia down-regulates expression of the AGGF1 protein, but not AGGF1 mRNA, by inducing expression of miR-27a; (2) Down-regulation of AGGF1 had an apparent protective role for cancer cells under hypoxia; (3) Down-regulation of the AGGF1 protein confers a significant risk of high-grade human urothelial bladder carcinoma.
The Key Laboratory of Molecular Biophysics of the Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, PR China.
Yan
Y
Xu
Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
Ming
M
Zhou
The Key Laboratory of Molecular Biophysics of the Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, PR China.
Jingjing
J
Wang
The Key Laboratory of Molecular Biophysics of the Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, PR China.
Yuanyuan
Y
Zhao
The Key Laboratory of Molecular Biophysics of the Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, PR China.
Sisi
S
Li
The Key Laboratory of Molecular Biophysics of the Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, PR China.
Bisheng
B
Zhou
The Key Laboratory of Molecular Biophysics of the Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, PR China.
Zhenhong
Z
Su
The Key Laboratory of Molecular Biophysics of the Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, PR China.
Chengqi
C
Xu
Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
Yue
Y
Xia
Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
Huijun
H
Qian
The Key Laboratory of Molecular Biophysics of the Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, PR China.
Xin
X
Tu
Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.
Wei
W
Xiao
Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.
Xiaoping
X
Chen
Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Qiuyun
Q
Chen
The Key Laboratory of Molecular Biophysics of the Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, PR China; Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: qkwang@mail.hust.edu.cn.
Qing K
QK
Wang
D042501:Angiogenic Proteins / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D017931:DNA Primers; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001749:Urinary Bladder Neoplasms / Q000473:pathology*
C482200:AGGF1 protein, human; D042501:Angiogenic Proteins; D017931:DNA Primers; C531388:MIRN27 microRNA, human; D035683:MicroRNAs
AGGF1; Bladder urothelial carcinoma; Hypoxia; MiR-27a