Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis;identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for ...Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis;identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for cancer diagnosis and therapeutics.Highly conserved RNA-binding protein Pumilio-1(PUM1)regulates mouse growth and cell proliferation,propelling us to examine its role in cancer.We found human PUM1 is highly expressed in a diverse group of cancer,including prostate cancer;enhanced PUM1 expression is also correlated with reduced survival among prostate cancer patients.Detailed expression analysis in twenty prostate cancer tissues showed enhanced expression of PUM1 at mRNA and protein levels.Knockdown of PUM1 reduced prostate cancer cell proliferation and colony formation,and subcutaneous injection of PUM1 knockdown cells led to reduced tumor size.Downregulation of PUM1 in prostate cancer cells consistently elevated cyclin-dependent kinase inhibitor 1B(CDKN1B)protein expression through increased translation but did not impact its mRNA level,while overexpression of PUM1 reduced CDKN1B protein level.Our finding established a critical role of PUM1 mediated translational control,particularly the PUM1-CDKN1B axis,in prostate cancer cell growth and tumorigenesis.We proposed that PUM1-CDKN1B regulatory axis may represent a novel mechanism for the loss of CDKN1B protein expression in diverse cancers and potential targets for therapeutics development.展开更多
The functional properties of endogenous Schwann cells(SCs)during nerve repair are dynamic.Optimizing the functional properties of SCs at different stages of nerve repair may have therapeutic benefit in improving the r...The functional properties of endogenous Schwann cells(SCs)during nerve repair are dynamic.Optimizing the functional properties of SCs at different stages of nerve repair may have therapeutic benefit in improving the repair of damaged nerves.Previous studies showed that miR-221-3p promotes the proliferation and migration of SCs,and miR-338-3p promotes the myelination of SCs.In this study,we established rat models of sciatic nerve injury by bridging the transected sciatic nerve with a silicone tube.We injected a miR-221 lentiviral vector system together with a doxycycline-inducible Tet-On miR-338 lentiviral vector system into the cavity of nerve conduits of nerve stumps to sequentially regulate the biological function of endogenous SCs at different stages of nerve regeneration.We found that the biological function of SCs was sequentially regulated,the diameter and density of myelinated axons were increased,the expression levels of NF200 and myelin basic protein were increased,and the function of injured peripheral nerve was improved using this system.miRNA Target Prediction Database prediction,Nanopore whole transcriptome sequencing,quantitative PCR,and dual luciferase reporter gene assay results predicted and verified Cdkn1b and Nrp1 as target genes of miR-221-3p and miR-338-3p,respectively,and their regulatory effects on SCs were confirmed in vitro.In conclusion,here we established a new method to enhance nerve regeneration through sequential regulation of biological functions of endogenous SCs,which establishes a new concept and model for the treatment of peripheral nerve injury.The findings from this study will provide direct guiding significance for clinical treatment of sciatic nerve injury.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.31771652 and No.81270737).
文摘Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis;identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for cancer diagnosis and therapeutics.Highly conserved RNA-binding protein Pumilio-1(PUM1)regulates mouse growth and cell proliferation,propelling us to examine its role in cancer.We found human PUM1 is highly expressed in a diverse group of cancer,including prostate cancer;enhanced PUM1 expression is also correlated with reduced survival among prostate cancer patients.Detailed expression analysis in twenty prostate cancer tissues showed enhanced expression of PUM1 at mRNA and protein levels.Knockdown of PUM1 reduced prostate cancer cell proliferation and colony formation,and subcutaneous injection of PUM1 knockdown cells led to reduced tumor size.Downregulation of PUM1 in prostate cancer cells consistently elevated cyclin-dependent kinase inhibitor 1B(CDKN1B)protein expression through increased translation but did not impact its mRNA level,while overexpression of PUM1 reduced CDKN1B protein level.Our finding established a critical role of PUM1 mediated translational control,particularly the PUM1-CDKN1B axis,in prostate cancer cell growth and tumorigenesis.We proposed that PUM1-CDKN1B regulatory axis may represent a novel mechanism for the loss of CDKN1B protein expression in diverse cancers and potential targets for therapeutics development.
基金supported by the National Natural Science Foundation of China,No.81771351the National Key R&D Program of China,No.2017YFA0105802+1 种基金the Joint Research Fund Liaoning-Shenyang National Laboratory for Materials Science,No.2019JH3/30100022the National Science Foundation for Post-doctoral Scientists of China,No.2018M641732(all to QA and LLW)。
文摘The functional properties of endogenous Schwann cells(SCs)during nerve repair are dynamic.Optimizing the functional properties of SCs at different stages of nerve repair may have therapeutic benefit in improving the repair of damaged nerves.Previous studies showed that miR-221-3p promotes the proliferation and migration of SCs,and miR-338-3p promotes the myelination of SCs.In this study,we established rat models of sciatic nerve injury by bridging the transected sciatic nerve with a silicone tube.We injected a miR-221 lentiviral vector system together with a doxycycline-inducible Tet-On miR-338 lentiviral vector system into the cavity of nerve conduits of nerve stumps to sequentially regulate the biological function of endogenous SCs at different stages of nerve regeneration.We found that the biological function of SCs was sequentially regulated,the diameter and density of myelinated axons were increased,the expression levels of NF200 and myelin basic protein were increased,and the function of injured peripheral nerve was improved using this system.miRNA Target Prediction Database prediction,Nanopore whole transcriptome sequencing,quantitative PCR,and dual luciferase reporter gene assay results predicted and verified Cdkn1b and Nrp1 as target genes of miR-221-3p and miR-338-3p,respectively,and their regulatory effects on SCs were confirmed in vitro.In conclusion,here we established a new method to enhance nerve regeneration through sequential regulation of biological functions of endogenous SCs,which establishes a new concept and model for the treatment of peripheral nerve injury.The findings from this study will provide direct guiding significance for clinical treatment of sciatic nerve injury.
