CircTUBD1 Regulates Radiation-induced Liver Fibrosis Response Via a CircTUBD1/micro-203a-3p/Smad3 Positive Feedback Loop

Overview

Journal J Clin Transl Hepatol

Specialty Gastroenterology

Date 2022 Sep 5

PMID 36062271

Authors

Hao Niu

Li Zhang

Biao Wang

Guang-Cong Zhang

Juan Liu

Zhi-Feng Wu

Shi-Suo Du

Zhao-Chong Zeng

Affiliations

Soon will be listed here.

Abstract

Background And Aims: Radiation-induced liver fibrosis (RILF), delayed damage to the liver (post-irradiation) remains a major challenge for the radiotherapy of liver malignancies. This study investigated the potential function and mechanism of circTUBD1 in the development of RILF.

Methods: By using a dual luciferase assay, RNA pull-down assays, RNA sequencing, chromatin immunoprecipitation (known as ChIP) assays, and a series of gain- or loss-of-function experiments, it was found that circTUBD1 regulated the activation and fibrosis response of LX-2 cells induced by irradiation via a circTUBD1/micro-203a-3p/Smad3 positive feedback loop in a 3D system.

Results: Knockdown of circTUBD1 not only reduced the expression of α-SMA, as a marker of LX-2 cell activation, but also significantly decreased the levels of hepatic fibrosis molecules, collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1), and connective tissue growth factor (CTGF) in a three-dimensional (3D) culture system and RILF model . Notably, knockdown of circTUBD1 alleviated early liver fibrosis induced by irradiation in mice models.

Conclusions: This study is the first to reveal the mechanism and role of circTUBD1 in RILF via a circTUBD1/micro-203a-3p/Smad3 feedback loop, which provides a novel therapeutic strategy for relieving the progression of RILF.

Citing Articles

Noncoding RNA-Mediated Epigenetic Regulation in Hepatic Stellate Cells of Liver Fibrosis.

Gao R, Mao J Noncoding RNA. 2024; 10(4).

PMID: 39195573 PMC: 11357158. DOI: 10.3390/ncrna10040044.

Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances.

Yu Z, Xu C, Song B, Zhang S, Chen C, Li C J Transl Med. 2023; 21(1):708.

PMID: 37814303 PMC: 10563272. DOI: 10.1186/s12967-023-04554-0.

ZEB1-mediated biogenesis of circNIPBL sustains the metastasis of bladder cancer via Wnt/β-catenin pathway.

Li Y, Kong Y, An M, Luo Y, Zheng H, Lin Y J Exp Clin Cancer Res. 2023; 42(1):191.

PMID: 37528489 PMC: 10394821. DOI: 10.1186/s13046-023-02757-3.

Overview of CircRNAs Roles and Mechanisms in Liver Fibrosis.

Wang G, Tong J, Li Y, Qiu X, Chen A, Chang C Biomolecules. 2023; 13(6).

PMID: 37371520 PMC: 10296239. DOI: 10.3390/biom13060940.

Circular RNA Tmcc1 improves astrocytic glutamate metabolism and spatial memory via NF-κB and CREB signaling in a bile duct ligation mouse model: transcriptional and cellular analyses.

Jo D, Lim Y, Jung Y, Kim Y, Song J J Neuroinflammation. 2023; 20(1):121.

PMID: 37217942 PMC: 10204305. DOI: 10.1186/s12974-023-02806-w.

References

Lang C, Dai Y, Wu Z, Yang Q, He S, Zhang X . SMAD3/SP1 complex-mediated constitutive active loop between lncRNA PCAT7 and TGF-β signaling promotes prostate cancer bone metastasis. Mol Oncol. 2020; 14(4):808-828. PMC: 7138406. DOI: 10.1002/1878-0261.12634. View

Meng J, Chen S, Han J, Qian B, Wang X, Zhong W . Twist1 Regulates Vimentin through Cul2 Circular RNA to Promote EMT in Hepatocellular Carcinoma. Cancer Res. 2018; 78(15):4150-4162. DOI: 10.1158/0008-5472.CAN-17-3009. View

Koay E, Owen D, Das P . Radiation-Induced Liver Disease and Modern Radiotherapy. Semin Radiat Oncol. 2018; 28(4):321-331. PMC: 6402843. DOI: 10.1016/j.semradonc.2018.06.007. View

Zhang F, Zhang R, Zhang X, Wu Y, Li X, Zhang S . Comprehensive analysis of circRNA expression pattern and circRNA-miRNA-mRNA network in the pathogenesis of atherosclerosis in rabbits. Aging (Albany NY). 2018; 10(9):2266-2283. PMC: 6188486. DOI: 10.18632/aging.101541. View

Niu H, Zhang L, Chen Y, Yuan B, Wu Z, Cheng J . Circular RNA TUBD1 Acts as the miR-146a-5p Sponge to Affect the Viability and Pro-Inflammatory Cytokine Production of LX-2 Cells through the TLR4 Pathway. Radiat Res. 2020; 193(4):383-393. DOI: 10.1667/RR15550.1. View

van Grunsven L . 3D in vitro models of liver fibrosis. Adv Drug Deliv Rev. 2017; 121:133-146. DOI: 10.1016/j.addr.2017.07.004. View

Xu F, Liu C, Zhou D, Zhang L . TGF-β/SMAD Pathway and Its Regulation in Hepatic Fibrosis. J Histochem Cytochem. 2016; 64(3):157-67. PMC: 4810800. DOI: 10.1369/0022155415627681. View

Coll M, Perea L, Boon R, Leite S, Vallverdu J, Mannaerts I . Generation of Hepatic Stellate Cells from Human Pluripotent Stem Cells Enables In Vitro Modeling of Liver Fibrosis. Cell Stem Cell. 2018; 23(1):101-113.e7. DOI: 10.1016/j.stem.2018.05.027. View

Hu H, Chen D, Wang Y, Feng Y, Cao G, Vaziri N . New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact. 2018; 292:76-83. DOI: 10.1016/j.cbi.2018.07.008. View

10.

Chou C, Chen P, Lee P, Cheng A, Hsu H, Cheng J . Radiation-induced hepatitis B virus reactivation in liver mediated by the bystander effect from irradiated endothelial cells. Clin Cancer Res. 2007; 13(3):851-7. DOI: 10.1158/1078-0432.CCR-06-2459. View

11.

Hu Z, Qin F, Gao S, Zhen Y, Huang D, Dong L . Paeoniflorin exerts protective effect on radiation-induced hepatic fibrosis in rats via TGF-β1/Smads signaling pathway. Am J Transl Res. 2018; 10(3):1012-1021. PMC: 5883141. View

12.

Ji D, Chen G, Wang J, Ji S, Wu X, Lu X . Hsa_circ_0070963 inhibits liver fibrosis via regulation of miR-223-3p and LEMD3. Aging (Albany NY). 2020; 12(2):1643-1655. PMC: 7053641. DOI: 10.18632/aging.102705. View

13.

Chen Y, Yuan B, Wu Z, Dong Y, Zhang L, Zeng Z . Microarray profiling of circular RNAs and the potential regulatory role of hsa_circ_0071410 in the activated human hepatic stellate cell induced by irradiation. Gene. 2017; 629:35-42. DOI: 10.1016/j.gene.2017.07.078. View

14.

Kristensen L, Andersen M, Stagsted L, Ebbesen K, Hansen T, Kjems J . The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019; 20(11):675-691. DOI: 10.1038/s41576-019-0158-7. View

15.

Puche J, Saiman Y, Friedman S . Hepatic stellate cells and liver fibrosis. Compr Physiol. 2013; 3(4):1473-92. DOI: 10.1002/cphy.c120035. View

16.

Ravi M, Paramesh V, Kaviya S, Anuradha E, Paul Solomon F . 3D cell culture systems: advantages and applications. J Cell Physiol. 2014; 230(1):16-26. DOI: 10.1002/jcp.24683. View

17.

Tang C, Zhang M, Huang L, Hu Z, Zhu J, Xiao Z . CircRNA_000203 enhances the expression of fibrosis-associated genes by derepressing targets of miR-26b-5p, Col1a2 and CTGF, in cardiac fibroblasts. Sci Rep. 2017; 7:40342. PMC: 5228128. DOI: 10.1038/srep40342. View

18.

Straub J, New J, Hamilton C, Lominska C, Shnayder Y, Thomas S . Radiation-induced fibrosis: mechanisms and implications for therapy. J Cancer Res Clin Oncol. 2015; 141(11):1985-94. PMC: 4573901. DOI: 10.1007/s00432-015-1974-6. View

19.

Kumar D, Yalamanchali S, New J, Parsel S, New N, Holcomb A . Development and Characterization of an In Vitro Model for Radiation-Induced Fibrosis. Radiat Res. 2018; 189(3):326-336. PMC: 5837959. DOI: 10.1667/RR14926.1. View

20.

Dawson L, Normolle D, Balter J, McGinn C, Lawrence T, Ten Haken R . Analysis of radiation-induced liver disease using the Lyman NTCP model. Int J Radiat Oncol Biol Phys. 2002; 53(4):810-21. DOI: 10.1016/s0360-3016(02)02846-8. View