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
Ubiquitin specific protease 33 （USP33） is a multifunctional protein regulating diverse cellular processes. The expression and role of USP33 in lung cancer remain unexplored. In this study, we show that USP33 is down...Ubiquitin specific protease 33 （USP33） is a multifunctional protein regulating diverse cellular processes. The expression and role of USP33 in lung cancer remain unexplored. In this study, we show that USP33 is down-regulated in multi- ple cohorts of lung cancer patients and that low expression of USP33 is associated with poor prognosis. USP33 medi- ates Slit-Robo signaling in lung cancer cell migration. Downregulation of USP33 reduces the protein stability of Robol in lung cancer cells, providing a previously unknown mechanism for USP33 function in mediating Slit activity in lung cancer ceils. Taken together, USP33 is a new player in lung cancer that regulates Slit-Robo signaling. Our data suggest that USP33 may be a candidate tumor suppressor for lung cancer with potential as a prognostic marker.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.
基金ACKNOWLEDGEMENTS We gratefully thank Dr. Zhipei Zhang for the assistance in lung cancers sample collection. We thank Mang Zheng for technical assistance. We thank other members of Wu lab for stimulating dis- cussion and helpful suggestions. This work was supported by the National Basic Research Program （973 Program） （2010CB529603 and 2013CB917803） and the National Natural Science Foundation of China （Grant No. 91132710）. RK was supported by China Post- doctoral Science Foundation （20110490615）. JYW is supported by NIH （Nos. RO1AG033004 and RO1CA175360）. JYW designed the study PW, XC and RK performed the experiments and analyzed the data+2 种基金 XL, YN and KW provided tissue samples and important suggestions LZ, JL and JYW supervised the experiments and analyzed the data PW and JYW wrote the paper.
文摘Ubiquitin specific protease 33 （USP33） is a multifunctional protein regulating diverse cellular processes. The expression and role of USP33 in lung cancer remain unexplored. In this study, we show that USP33 is down-regulated in multi- ple cohorts of lung cancer patients and that low expression of USP33 is associated with poor prognosis. USP33 medi- ates Slit-Robo signaling in lung cancer cell migration. Downregulation of USP33 reduces the protein stability of Robol in lung cancer cells, providing a previously unknown mechanism for USP33 function in mediating Slit activity in lung cancer ceils. Taken together, USP33 is a new player in lung cancer that regulates Slit-Robo signaling. Our data suggest that USP33 may be a candidate tumor suppressor for lung cancer with potential as a prognostic marker.
