Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis

Abstract 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 TG...

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Autores principales:	Meng-Zhi Wu, Yi-chuan Yuan, Bi-Yu Huang, Jin-Xi Chen, Bin-Kui Li, Jian-Hong Fang, Shi-Mei Zhuang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Medicine R Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/fbe62e45283a4e7e874c2f402866d1ea
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spelling	oai:doaj.org-article:fbe62e45283a4e7e874c2f402866d1ea2021-11-21T12:07:00ZIdentification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis10.1038/s41392-021-00781-32059-3635https://doaj.org/article/fbe62e45283a4e7e874c2f402866d1ea2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41392-021-00781-3https://doaj.org/toc/2059-3635Abstract 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-β stimulation, 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 lnc-UTGF. 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-β signaling and its deregulation promotes hepatoma metastasis. These findings may provide a new therapeutic target for HCC metastasis.Meng-Zhi WuYi-chuan YuanBi-Yu HuangJin-Xi ChenBin-Kui LiJian-Hong FangShi-Mei ZhuangNature Publishing GrouparticleMedicineRBiology (General)QH301-705.5ENSignal Transduction and Targeted Therapy, Vol 6, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Biology (General) QH301-705.5
spellingShingle	Medicine R Biology (General) QH301-705.5 Meng-Zhi Wu Yi-chuan Yuan Bi-Yu Huang Jin-Xi Chen Bin-Kui Li Jian-Hong Fang Shi-Mei Zhuang Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis
description	Abstract 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-β stimulation, 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 lnc-UTGF. 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-β signaling and its deregulation promotes hepatoma metastasis. These findings may provide a new therapeutic target for HCC metastasis.
format	article
author	Meng-Zhi Wu Yi-chuan Yuan Bi-Yu Huang Jin-Xi Chen Bin-Kui Li Jian-Hong Fang Shi-Mei Zhuang
author_facet	Meng-Zhi Wu Yi-chuan Yuan Bi-Yu Huang Jin-Xi Chen Bin-Kui Li Jian-Hong Fang Shi-Mei Zhuang
author_sort	Meng-Zhi Wu
title	Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis
title_short	Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis
title_full	Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis
title_fullStr	Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis
title_full_unstemmed	Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis
title_sort	identification of a tgf-β/smad/lnc-utgf positive feedback loop and its role in hepatoma metastasis
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/fbe62e45283a4e7e874c2f402866d1ea
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Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis

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