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 pattes 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 mlR-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.