Mitochondrial miRNA Determines Chemoresistance by Reprogramming Metabolism and Regulating Mitochondrial Transcription

被引：121

作者：

Fan, Song ^{[1
,2
,3
]}

Tian, Tian ^{[4
]}

Chen, Weixiong ^{[2
]}

Lv, Xiaobin ^{[5
,6
]}

Lei, Xinyuan ^{[2
]}

Zhang, Hanqing ^{[2
]}

Sun, Sheng ^{[7
]}

Cai, Lei ^{[3
]}

Pan, Guokai ^{[2
]}

He, Lile ^{[3
]}

Ou, Zhanpeng ^{[2
]}

Lin, Xinyu ^{[2
]}

Wang, Xinhui ^{[3
]}

Perez, Matthew Francis ^{[3
]}

Tu, Zhiming ^{[3
]}

Ferrone, Soldano ^{[3
]}

Tannous, Bakhos A. ^{[8
,9
]}

Li, Jinsong ^{[1
,2
]}

机构：

[1] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Oral & Maxillofacial Surg, Guangzhou, Guangdong, Peoples R China

[2] Sun Yat Sen Mem Hosp, Guangdong Prov Key Lab Malignant Tumor Epigenet &, Guangzhou 510120, Guangdong, Peoples R China

[3] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA

[4] Nanjing Med Univ, Dept Neurobiol, Key Lab Human Funct Genom Jiangsu, Nanjing, Jiangsu, Peoples R China

[5] Univ Kentucky, Coll Med, Markey Canc Ctr, Lexington, KY USA

[6] Nanchang Univ, Affiliated Hosp 3, Ctr Lab, Nanchang Key Lab Canc Pathogenesis & Translat Res, Nanchang, Jiangxi, Peoples R China

[7] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02115 USA

[8] Massachusetts Gen Hosp, Dept Neurol, Expt Therapeut & Mol Imaging Lab, Boston, MA 02114 USA

[9] Harvard Med Sch, Boston, MA 02115 USA

来源：

CANCER RESEARCH | 2019年 / 79卷 / 06期

基金：

中国国家自然科学基金;

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; HEAVY-STRAND PROMOTER; EXPRESSION; CISPLATIN; CHEMOTHERAPY; METASTASIS; MICRORNAS; CANCERS; CELLS;

D O I：

10.1158/0008-5472.CAN-18-2505

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

miRNAs that translocate from the nucleus to mitochondria are referred to as mitochondrial microRNAs (mitomiR). mitomiRs have been shown to modulate the translational activity of the mitochondrial genome, yet their role in mitochondrial DNA (mtDNA) transcription remains to be determined. Here we report that the mitomiR-2392 regulates chemoresistance in tongue squamous cell carcinoma (TSCC) cells by reprogramming metabolism via downregulation of oxidative phosphorylation and upregulation of glycolysis. These effects were mediated through partial inhibition of mtDNA transcription by mitomiR-2392 rather than through translational regulation. This repression required specific miRNA-mtDNA base pairing and Argonaute 2. mitomiR-2392 recognized target sequences in the H-strand and partially inhibited polycistronic mtDNA transcription in a cell-specific manner. A retrospective analysis of TSCC patient tumors revealed a significant association of miR-2392 and regulated mitochondrial gene expression with chemosensitivity and overall survival. The clinical relevance of targeted mitochondrial genes was consistently validated by The Cancer Genome Atlas RNA sequencing in multiple types of cancer. Our study revealed for the first time the role of mitomiR in mtDNA transcription and its contribution to the molecular basis of tumor cell metabolism and chemoresistance.

引用

页码：1069 / 1084

页数：16

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