Oncotarget

Research Papers:

miR-497-5p inhibits cell proliferation and invasion by targeting KCa3.1 in angiosarcoma

Yaobing Chen, Dong Kuang, Xia Zhao, Dong Chen, Xiaoyan Wang, Qin Yang, Jie Wan, Yuanli Zhu, Yu Wang, Shiying Zhang, Ying Wang, Qiang Tang, Mikio Masuzawa, Guoping Wang and Yaqi Duan _

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Oncotarget. 2016; 7:58148-58161. https://doi.org/10.18632/oncotarget.11252

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Abstract

Yaobing Chen1,*, Dong Kuang1,*, Xia Zhao1,2, Dong Chen1, Xiaoyan Wang1, Qin Yang1, Jie Wan1, Yuanli Zhu1, Yu Wang1, Shiying Zhang2, Ying Wang2, Qiang Tang3, Mikio Masuzawa4, Guoping Wang1,2, Yaqi Duan1,2

1Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

2Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

3Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

4Department of Regulation Biochemistry, Kitasato University School of Allied Health Sciences, Minamiku, Sagamihara Kanagawa, 252-0329, Japan

*These authors contributed equally to this work

Correspondence to:

Guoping Wang, email: [email protected]

Yaqi Duan, email: [email protected]

Keywords: sarcoma, cell cycle, potassium channel, hemangioma

Received: October 28, 2015     Accepted: July 26, 2016     Published: August 12, 2016

ABSTRACT

Angiosarcoma is a rare malignant mesenchymal tumor with poor prognosis. We aimed to identify malignancy-associated miRNAs and their target genes, and explore biological functions of miRNA and its target in angiosarcoma. By miRNA microarrays and reverse transcription polymerase chain reaction, we identified 1 up-regulated miRNA (miR-222-3p) and 3 down-regulated miRNAs (miR-497-5p, miR-378-3p and miR-483-5p) in human angiosarcomas compared with human capillary hemangiomas. The intermediate-conductance calcium activated potassium channel KCa3.1 was one of the putative target genes of miR-497-5p, and marked up-regulation of KCa3.1 was detected in angiosarcoma biopsy specimens by immunohistochemistry. The inverse correlation of miR-497-5p and KCa3.1 also was observed in the ISO-HAS angiosarcoma cell line at the mRNA and protein levels. The direct targeting of KCa3.1 by miR-497-5p was evidenced by reduced luciferase activity due to complementary binding of miR-497-5p to KCa3.1 mRNA 3’ untranslated region. For the functional role of miR-497-5p/KCa3.1 pair, we showed that application of TRAM-34, a specific KCa3.1 channel blocker, or transfection of ISO-HAS cells with KCa3.1 siRNA or miR-497-5p mimics inhibited cell proliferation, cell cycle progression, and invasion by down-regulating cell-cycle related proteins including cyclin D1, surviving and P53 and down-regulating matrix metallopeptidase 9. In an in vivo angiosarcoma xenograft model, TRAM-34 or miR-497-5p mimics both inhibited tumor growth. In conclusion, the tumor suppressor miR-497-5p down-regulates KCa3.1 expression and contributes to the inhibition of angiosarcoma malignancy development. The miR-497-5p or KCa3.1 might be potential new targets for angiosarcoma treatment.


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