Zhen Fan
Warren McGee
Mengmeng Chen
Ruirui Kong
Pushuai Wen
Tengfei Xiao
Xiaomin Chen
Jianghong Liu
Li Zhu
Runsheng Chen
Jane Y. Wu
1 CAS Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
2 Research Network of Computational Biology, RNCB, Beijing 100101, China;
3 Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
4 State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
5 Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA;
6 Guangdong Geneway Decoding Bio-Tech Co. Ltd, Foshan 528316, China
Funds: This work was supported by National Natural Science Foundation of China (Grant Nos. 31520103905 and 31701122) and National High Technology Research and Development Program ("863" Program) of China (2014AA021502). MC, LZ, JL are supported by grants from the the National Basic Research Program (973 Program) (No. 2013CB917803) and the National Natural Science Foundation of China (Grant No. 91132710). RK is supported by National Natural Science Foundation of China (Grant No. 31501133). WM is supported by NIH (F30 NS090893). JYW is supported by NIH (R01CA175360).
Received Date: 2017-08-15
Rev Recd Date:2017-08-31
Abstract
Abstract
Aberrant regulation of miRNA genes contributes to pathogenesis of a wide range of human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a RNA/DNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs regulated by TDP-43 using RNA-Seq coupled with an siRNA-mediated knockdown approach. TDP-43 knockdown affected the expression of a number of miRNAs. In addition, TDP-43 down-regulation led to alterations in the patterns of different isoforms of miRNAs (isomiRs) and miRNA arm selection, suggesting a previously unknown role of TDP-43 in miRNA processing. A number of TDP-43 associated miRNAs, and their candidate target genes, are associated with human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p. In contrast, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Reduced expression of miR-500a-3p is associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Cancer-associated genes LIF and PAPPA are possible targets of miR-500a-3p. Our work suggests that TDP-43-regulated miRNAs may play multifaceted roles in the pathogenesis of cancer.Keywords: TDP-43,
miRNA,
cancer,
migration,
prognosis
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