Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1–miR-593-5p–MFF axis
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Song Fan1,2,*, Bodu Liu1,3,*, Lijuan Sun1,3,*, Xiao-bin Lv1,4,*, Zhaoyu Lin1,2,*, Weixiong Chen2, Weiliang Chen2, Qionglan Tang5, Youyuan Wang2, Yuxiong Su6, Shaowen Jin7, Daming Zhang2, Jianglong Zhong2, Yilin Li8, Bin Wen9, Zhang Zhang10, Pu Yang11, Bin Zhou2, Qixiang Liang2, Xing Yu2, Yinghua Zhu4, Pengnan Hu3, Junjun Chu3, Wei Huang3, Yuhuan Feng2, Hongzhuang Peng12, Qihong Huang12, Erwei Song1,3, Jinsong Li1,2
1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
2 Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
3 Department of Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
4 Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
5 Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
6 Division of Oral and Maxillofacial Surgery, Faculty of Dentistry, the University of Hong Kong, Hong Kong
7 Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
8 Xaverian Brothers High School, Westwood, MA, USA
9 Department of Pathology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China
10 Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
11 State Key Laboratory of Oral Diseases, West China Hospital, Stomatology of Sichuan University, Chengdu, China
12 The Wistar Institute, Philadelphia, PA, USA
* These authors have contributed equally to this work
Jinsong Li, email:
Erwei Song, email:
Keywords: mitochondrial fission, cisplatin sensitivity, BRCA1, miR-593-5p, MFF
Received: January 12, 2015 Accepted: February 28, 2015 Published: March 26, 2015
Cisplatin has been widely employed as a cornerstone chemotherapy treatment for a wide spectrum of solid neoplasms; increasing tumor responsiveness to cisplatin has been a topic of interest for the past 30 years. Strong evidence has indicated that mitochondrial fission participates in the regulation of apoptosis in many diseases; however, whether mitochondrial fission regulates cisplatin sensitivity remains poorly understood. Here, we show that MFF mediated mitochondrial fission and apoptosis in tongue squamous cell carcinoma (TSCC) cells after cisplatin treatment and that miR-593-5p was downregulated in this process. miR-593-5p attenuated mitochondrial fission and cisplatin sensitivity by targeting the 3’ untranslated region sequence of MFF and inhibiting its translation. In exploring the underlying mechanism of miR-593-5p downregulation, we observed that BRCA1 transactivated miR-593-5p expression and attenuated cisplatin sensitivity in vitro. The BRCA1-miR-593-5p-MFF axis also affected cisplatin sensitivity in vivo. Importantly, in a retrospective analysis of multiple centers, we further found that the BRCA1-miR-593-5p-MFF axis was significantly associated with cisplatin sensitivity and the survival of patients with TSCC. Together, our data reveal a model for mitochondrial fission regulation at the transcriptional and post-transcriptional levels; we also reveal a new pathway for BRCA1 in determining cisplatin sensitivity through the mitochondrial fission program.
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