Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells

Ji Young Kim, Kyu Min Kim, Ji Hye Yang, Sam Seok Cho, Seung Jung Kim, Su Jung Park, Sang Gun Ahn, Gum Hwa Lee, Jin Won Yang, Sung Chul Lim, Keon Wook Kang, Sung Hwan Ki

Research output: Contribution to journalArticle

Abstract

Hepatic stellate cells (HSCs) are essential for liver fibrosis. E6 associated protein (E6AP) is one of the E3-ubiquitin-protein ligase and has been studied in proliferation and cellular stress. Currently, no information is available on the role of E6AP on transforming growth factor-β (TGF-β) signaling and hepatic fibrogenesis. This study examined whether E6AP is overexpressed in activated HSCs, and if so, its effect on hepatic fibrogenesis and the molecular mechanism. E6AP was expressed higher in HSCs than hepatocytes, and was up-regulated in activated HSCs, HSCs from the livers of carbon tetrachloride-injected mice, or TGF-β-treated LX-2 cells. The TGF-β-mediated E6AP up-regulation was not due to altered mRNA level nor protein stability. Thus, we performed microRNA (miRNA, miR) analysis and found that miR-302c was dysregulated in TGF-β-treated LX-2 cells or activated primary HSCs. We revealed that miR-302c was a modulator of E6AP. E6AP overexpression inhibited TGF-β-induced expression of plasminogen activator inhibitor-1 in LX-2 cells, albeit it was independent of Smad pathway. Additionally, E6AP inhibited TGF-β-mediated phosphorylation of mitogen-activated protein kinases. To conclude, E6AP overexpression due to decreased miR-302c in HSCs attenuated hepatic fibrogenesis through inhibition of the TGF-β-induced mitogen-activated protein kinase signaling pathway, implying that E6AP and other molecules may contribute to protection against liver fibrosis.

Original languageEnglish
Article number444
JournalScientific Reports
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2020

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Hepatic Stellate Cells
Transforming Growth Factors
MicroRNAs
Proteins
Liver
Mitogen-Activated Protein Kinases
Liver Cirrhosis
Ubiquitin-Protein Ligases
Carbon Tetrachloride
Protein Stability
Plasminogen Activator Inhibitor 1
Hepatocytes
Up-Regulation
Phosphorylation
Cell Proliferation
Messenger RNA

Cite this

Kim, Ji Young ; Kim, Kyu Min ; Yang, Ji Hye ; Cho, Sam Seok ; Kim, Seung Jung ; Park, Su Jung ; Ahn, Sang Gun ; Lee, Gum Hwa ; Yang, Jin Won ; Lim, Sung Chul ; Kang, Keon Wook ; Ki, Sung Hwan. / Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells. In: Scientific Reports. 2020 ; Vol. 10, No. 1.
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title = "Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells",
abstract = "Hepatic stellate cells (HSCs) are essential for liver fibrosis. E6 associated protein (E6AP) is one of the E3-ubiquitin-protein ligase and has been studied in proliferation and cellular stress. Currently, no information is available on the role of E6AP on transforming growth factor-β (TGF-β) signaling and hepatic fibrogenesis. This study examined whether E6AP is overexpressed in activated HSCs, and if so, its effect on hepatic fibrogenesis and the molecular mechanism. E6AP was expressed higher in HSCs than hepatocytes, and was up-regulated in activated HSCs, HSCs from the livers of carbon tetrachloride-injected mice, or TGF-β-treated LX-2 cells. The TGF-β-mediated E6AP up-regulation was not due to altered mRNA level nor protein stability. Thus, we performed microRNA (miRNA, miR) analysis and found that miR-302c was dysregulated in TGF-β-treated LX-2 cells or activated primary HSCs. We revealed that miR-302c was a modulator of E6AP. E6AP overexpression inhibited TGF-β-induced expression of plasminogen activator inhibitor-1 in LX-2 cells, albeit it was independent of Smad pathway. Additionally, E6AP inhibited TGF-β-mediated phosphorylation of mitogen-activated protein kinases. To conclude, E6AP overexpression due to decreased miR-302c in HSCs attenuated hepatic fibrogenesis through inhibition of the TGF-β-induced mitogen-activated protein kinase signaling pathway, implying that E6AP and other molecules may contribute to protection against liver fibrosis.",
author = "Kim, {Ji Young} and Kim, {Kyu Min} and Yang, {Ji Hye} and Cho, {Sam Seok} and Kim, {Seung Jung} and Park, {Su Jung} and Ahn, {Sang Gun} and Lee, {Gum Hwa} and Yang, {Jin Won} and Lim, {Sung Chul} and Kang, {Keon Wook} and Ki, {Sung Hwan}",
year = "2020",
month = "12",
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doi = "10.1038/s41598-019-57322-w",
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Kim, JY, Kim, KM, Yang, JH, Cho, SS, Kim, SJ, Park, SJ, Ahn, SG, Lee, GH, Yang, JW, Lim, SC, Kang, KW & Ki, SH 2020, 'Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells', Scientific Reports, vol. 10, no. 1, 444. https://doi.org/10.1038/s41598-019-57322-w

Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells. / Kim, Ji Young; Kim, Kyu Min; Yang, Ji Hye; Cho, Sam Seok; Kim, Seung Jung; Park, Su Jung; Ahn, Sang Gun; Lee, Gum Hwa; Yang, Jin Won; Lim, Sung Chul; Kang, Keon Wook; Ki, Sung Hwan.

In: Scientific Reports, Vol. 10, No. 1, 444, 01.12.2020.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells

AU - Kim, Ji Young

AU - Kim, Kyu Min

AU - Yang, Ji Hye

AU - Cho, Sam Seok

AU - Kim, Seung Jung

AU - Park, Su Jung

AU - Ahn, Sang Gun

AU - Lee, Gum Hwa

AU - Yang, Jin Won

AU - Lim, Sung Chul

AU - Kang, Keon Wook

AU - Ki, Sung Hwan

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Hepatic stellate cells (HSCs) are essential for liver fibrosis. E6 associated protein (E6AP) is one of the E3-ubiquitin-protein ligase and has been studied in proliferation and cellular stress. Currently, no information is available on the role of E6AP on transforming growth factor-β (TGF-β) signaling and hepatic fibrogenesis. This study examined whether E6AP is overexpressed in activated HSCs, and if so, its effect on hepatic fibrogenesis and the molecular mechanism. E6AP was expressed higher in HSCs than hepatocytes, and was up-regulated in activated HSCs, HSCs from the livers of carbon tetrachloride-injected mice, or TGF-β-treated LX-2 cells. The TGF-β-mediated E6AP up-regulation was not due to altered mRNA level nor protein stability. Thus, we performed microRNA (miRNA, miR) analysis and found that miR-302c was dysregulated in TGF-β-treated LX-2 cells or activated primary HSCs. We revealed that miR-302c was a modulator of E6AP. E6AP overexpression inhibited TGF-β-induced expression of plasminogen activator inhibitor-1 in LX-2 cells, albeit it was independent of Smad pathway. Additionally, E6AP inhibited TGF-β-mediated phosphorylation of mitogen-activated protein kinases. To conclude, E6AP overexpression due to decreased miR-302c in HSCs attenuated hepatic fibrogenesis through inhibition of the TGF-β-induced mitogen-activated protein kinase signaling pathway, implying that E6AP and other molecules may contribute to protection against liver fibrosis.

AB - Hepatic stellate cells (HSCs) are essential for liver fibrosis. E6 associated protein (E6AP) is one of the E3-ubiquitin-protein ligase and has been studied in proliferation and cellular stress. Currently, no information is available on the role of E6AP on transforming growth factor-β (TGF-β) signaling and hepatic fibrogenesis. This study examined whether E6AP is overexpressed in activated HSCs, and if so, its effect on hepatic fibrogenesis and the molecular mechanism. E6AP was expressed higher in HSCs than hepatocytes, and was up-regulated in activated HSCs, HSCs from the livers of carbon tetrachloride-injected mice, or TGF-β-treated LX-2 cells. The TGF-β-mediated E6AP up-regulation was not due to altered mRNA level nor protein stability. Thus, we performed microRNA (miRNA, miR) analysis and found that miR-302c was dysregulated in TGF-β-treated LX-2 cells or activated primary HSCs. We revealed that miR-302c was a modulator of E6AP. E6AP overexpression inhibited TGF-β-induced expression of plasminogen activator inhibitor-1 in LX-2 cells, albeit it was independent of Smad pathway. Additionally, E6AP inhibited TGF-β-mediated phosphorylation of mitogen-activated protein kinases. To conclude, E6AP overexpression due to decreased miR-302c in HSCs attenuated hepatic fibrogenesis through inhibition of the TGF-β-induced mitogen-activated protein kinase signaling pathway, implying that E6AP and other molecules may contribute to protection against liver fibrosis.

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