TDP-43 regulates cancer-associated microRNAs.

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.

• Authors: Xiaowei Chen, Zhen Fan, Warren McGee, Mengmeng Chen, Ruirui Kong, Pushuai Wen, Tengfei Xiao, Xiaomin Chen, Jianghong Liu, Li Zhu, Runsheng Chen, Jane Y Wu
• Journal: Protein & cell (Protein Cell) Vol. 9 Issue 10 Pg. 848-866 (10 2018) ISSN: 1674-8018 [Electronic] Germany
• PMID: 28952053 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• MicroRNAs
• TARDBP protein, human

Topics

• Animals
• Cells, Cultured
• DNA-Binding Proteins (metabolism)
• Electrophoretic Mobility Shift Assay
• Humans
• Immunoprecipitation
• Mice
• MicroRNAs (genetics, metabolism)
• Neoplasms (genetics, metabolism)