Aberrant activation of the TGF-β/SMAD signaling pathway is often observed in hepatocellular carcinoma(HCC).Whether lncRNA regulates the TGF-β/SMAD signaling remains largely unknown.Here,we identified an oncogenic ln...Aberrant activation of the TGF-β/SMAD signaling pathway is often observed in hepatocellular carcinoma(HCC).Whether lncRNA regulates the TGF-β/SMAD signaling remains largely unknown.Here,we identified an oncogenic lncRNA that was upregulated in HCC and was transcriptionally induced by TGF-β(named lnc-UTGF,lncRNA upregulated by TGF-β).Upon TGF-βstimulation,SMAD2/3 bound to the lnc-UTGF promoter and activated lnc-UTGF expression.In turn,the TGF-β/SMAD signaling was augmented by overexpressing lnc-UTGF,but was inhibited by silencing lnc-UTGF.Mechanism investigations revealed that lnc-UTGF interacted with the mRNAs of SMAD2 and SMAD4 via complementary base-pairing,resulting in enhanced stability of SMAD2/4 mRNAs.These data suggest a novel TGF-β/SMAD/lnc-UTGF positive feedback circuitry.Subsequent gain-and loss-of-function analyses disclosed that lnc-UTGF promoted the migration and invasion of hepatoma cells,and this effect of lnc-UTGF was attenuated by repressing SMAD2/4 expression or by mutating the SMAD2/4-binding sites in lnc-UTGF.Studies using mouse models further confirmed that in vivo metastasis of hepatoma xenografts was inhibited by silencing lnc-UTGF,but was enhanced by ectopic expression of lncUTGF.The lnc-UTGF level was positively correlated with the SMAD2/4 levels in xenografts.Consistently,we detected an association of lnc-UTGF upregulation with increase of SMAD2,SMAD4,and their metastasis effector SNAIL1 in human HCC.And high lnc-UTGF level was also significantly associated with enhanced metastasis potential,advanced TNM stages,and worse recurrence-free survival.Conclusion:there exists a lnc-UTGF-mediated positive feedback loop of the TGF-βsignaling and its deregulation promotes hepatoma metastasis.These findings may provide a new therapeutic target for HCC metastasis.展开更多
Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00781-3,published online 17 November 2021 In this article^(1) Jian-Hong Fang should have been denoted as a corresponding author...Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00781-3,published online 17 November 2021 In this article^(1) Jian-Hong Fang should have been denoted as a corresponding author along with Shi-Mei Zhuang,but was inadvertently removed during the production process.The original article has been corrected.展开更多
基金This work was supported by grants from the National Key R&D Program of China(2017YFA0504402)National Natural Science Foundation of China(91940305,31771554,81772608,32100573)+2 种基金Science and Information Technology Bureau of Guangzhou(201904020040)China Postdoctoral Science Foundation(2020M683034)Guangdong Basic and Applied Basic Research Foundation(2019A1515011586,2020A1515110124).
文摘Aberrant activation of the TGF-β/SMAD signaling pathway is often observed in hepatocellular carcinoma(HCC).Whether lncRNA regulates the TGF-β/SMAD signaling remains largely unknown.Here,we identified an oncogenic lncRNA that was upregulated in HCC and was transcriptionally induced by TGF-β(named lnc-UTGF,lncRNA upregulated by TGF-β).Upon TGF-βstimulation,SMAD2/3 bound to the lnc-UTGF promoter and activated lnc-UTGF expression.In turn,the TGF-β/SMAD signaling was augmented by overexpressing lnc-UTGF,but was inhibited by silencing lnc-UTGF.Mechanism investigations revealed that lnc-UTGF interacted with the mRNAs of SMAD2 and SMAD4 via complementary base-pairing,resulting in enhanced stability of SMAD2/4 mRNAs.These data suggest a novel TGF-β/SMAD/lnc-UTGF positive feedback circuitry.Subsequent gain-and loss-of-function analyses disclosed that lnc-UTGF promoted the migration and invasion of hepatoma cells,and this effect of lnc-UTGF was attenuated by repressing SMAD2/4 expression or by mutating the SMAD2/4-binding sites in lnc-UTGF.Studies using mouse models further confirmed that in vivo metastasis of hepatoma xenografts was inhibited by silencing lnc-UTGF,but was enhanced by ectopic expression of lncUTGF.The lnc-UTGF level was positively correlated with the SMAD2/4 levels in xenografts.Consistently,we detected an association of lnc-UTGF upregulation with increase of SMAD2,SMAD4,and their metastasis effector SNAIL1 in human HCC.And high lnc-UTGF level was also significantly associated with enhanced metastasis potential,advanced TNM stages,and worse recurrence-free survival.Conclusion:there exists a lnc-UTGF-mediated positive feedback loop of the TGF-βsignaling and its deregulation promotes hepatoma metastasis.These findings may provide a new therapeutic target for HCC metastasis.
文摘Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00781-3,published online 17 November 2021 In this article^(1) Jian-Hong Fang should have been denoted as a corresponding author along with Shi-Mei Zhuang,but was inadvertently removed during the production process.The original article has been corrected.
