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 RNAJDNA binding protein associated with neu- rodegeneration, is ...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 RNAJDNA binding protein associated with neu- rodegeneration, 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 dif- ferent isoforms of miRNAs （isomiRs） and miRNA arm selection, suggesting a previously unknown role of TDP- 43 in miRNA processing. A number of TDP-43 associ- ated 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 regulat- ing 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.展开更多
基金We thank Geir SkogerbФ for careful reading of the manuscript and valuable suggestions. 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 issupported by National Natural Science Foundation of China （Grant No. 31501133）. WM is supported by NIH （F30 NS090893）. JYW is supported by NIH （R01CA175360）.
文摘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 RNAJDNA binding protein associated with neu- rodegeneration, 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 dif- ferent isoforms of miRNAs （isomiRs） and miRNA arm selection, suggesting a previously unknown role of TDP- 43 in miRNA processing. A number of TDP-43 associ- ated 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 regulat- ing 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.
