Long non-coding RNA PVT1 activates hepatic stellate cells through competitively binding microRNA-152.

Jianjian Zheng,Limei Wu,Lei Zheng,Yuan Zhang,Peihong Dong,Yanwei Hu,Fujun Yu

doi:10.18632/oncotarget.11709

Abstract

Epithelial-mesenchymal transition (EMT) process is considered as a key event in the activation of hepatic stellate cells (HSCs). Hedgehog (Hh) pathway is known to be required for EMT process. Long non-coding RNAs (lncRNAs) have been reported to be involved in a wide range of biological processes. Plasmacytoma variant translocation 1 (PVT1), a novel lncRNA, is often up-regulated in various human cancers. However, the role of PVT1 in liver fibrosis remains undefined. In this study, PVT1 was increased in fibrotic liver tissues and activated HSCs. Depletion of PVT1 attenuated collagen deposits in vivo. In vitro, PVT1 down-regulation inhibited HSC activation including the reduction of HSC proliferation, α-SMA and type I collagen. Further studies showed that PVT1 knockdown suppressed HSC activation was through inhibiting EMT process and Hh pathway. Patched1 (PTCH1), a negative regulator factor of Hh pathway, was enhanced by PVT1 knockdown. PTCH1 demethylation caused by miR-152 was responsible for the effects of PVT1 knockdown on PTCH1 expression. Notably, miR-152 inhibitor reversed the effects of PVT1 knockdown on HSC activation. Luciferase reporter assays and pull-down assays showed a direct interaction between miR-152 and PVT1. Collectively, we demonstrate that PVT1 epigenetically down-regulates PTCH1 expression via competitively binding miR-152, contributing to EMT process in liver fibrosis.

Highlights

Liver fibrosis occurs in almost all patients with chronic liver diseases (CLDs) and represents the final common pathway of virtually all types of CLDs [1]
To explore the biological role of Plasmacytoma variant translocation 1 (PVT1) in liver fibrosis, we firstly detected the expression of PVT1 in primary 2-dayold hepatic stellate cells (HSCs) and primary 10-day-old HSCs
As shown by quantitative real-time PCR analysis, the expressions of all PVT1 variants were up-regulated at day 10 compared with those at day 2 (Figure 1B)

Summary

Introduction

Liver fibrosis occurs in almost all patients with chronic liver diseases (CLDs) and represents the final common pathway of virtually all types of CLDs [1]. Liver fibrosis is considered as a reversible wound-healing process and featured with the excess deposition of extracellular matrix (ECM) proteins [2]. The activation and transdifferentiation of hepatic stellate cells (HSCs) are pivotal events in liver fibrosis [1, 4]. To explore the effective treatments on the suppression of activated HSCs is a potential targeted therapy for liver fibrosis. EMT process is involved in the activation of HSCs [5]. Activated EMT process contributes to HSC trans-differentiation and liver fibrosis via activating Hedgehog (Hh) signaling pathway [6]. Hh pathway inactivation contributes to the suppression of EMT process in HSCs [7]. Our previous study showed that microRNA-152 (miR-152) inhibits liver fibrosis by attenuating DNA methyltransferase 1(DNMT1)-mediated PTCH1 methylation [8]

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