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环状TUBD1通过环状TUBD1/微小RNA-203a-3p/Smad3正反馈环调节辐射诱导的肝纤维化反应。

CircTUBD1 Regulates Radiation-induced Liver Fibrosis Response via a circTUBD1/micro-203a-3p/Smad3 Positive Feedback Loop.

作者信息

Niu Hao, Zhang Li, Wang Biao, Zhang Guang-Cong, Liu Juan, Wu Zhi-Feng, Du Shi-Suo, Zeng Zhao-Chong

机构信息

Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.

Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.

出版信息

J Clin Transl Hepatol. 2022 Aug 28;10(4):680-691. doi: 10.14218/JCTH.2021.00511. Epub 2022 Feb 28.

DOI:10.14218/JCTH.2021.00511
PMID:36062271
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9396324/
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.

摘要

背景与目的

放射性肝纤维化（RILF），即肝脏在放疗后受到的延迟性损伤，仍然是肝脏恶性肿瘤放疗面临的一项重大挑战。本研究调查了环状TUBD1在RILF发生发展中的潜在功能及机制。

方法

通过双荧光素酶报告基因检测、RNA下拉实验、RNA测序、染色质免疫沉淀（ChIP）实验以及一系列功能获得或缺失实验，发现在三维系统中，环状TUBD1通过环状TUBD1/微小RNA-203a-3p/Smad3正反馈环调控照射诱导的LX-2细胞活化及纤维化反应。

结果

敲低环状TUBD1不仅降低了作为LX-2细胞活化标志物的α-SMA的表达，还在三维培养系统和RILF模型中显著降低了肝纤维化分子I型胶原α1（COL1A1）、III型胶原α1（COL3A1）和结缔组织生长因子（CTGF）的水平。值得注意的是，敲低环状TUBD1减轻了小鼠模型中照射诱导的早期肝纤维化。

结论

本研究首次揭示了环状TUBD1通过环状TUBD1/微小RNA-203a-3p/Smad3反馈环在RILF中的机制和作用，为缓解RILF的进展提供了一种新的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/7c39e45c33df/JCTH-10-680-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/a7fbde30cb09/JCTH-10-680-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/50050e0f19e4/JCTH-10-680-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/a4b6207d9e5e/JCTH-10-680-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/a752acf2d1d0/JCTH-10-680-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/d884065c1346/JCTH-10-680-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/7c39e45c33df/JCTH-10-680-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/a7fbde30cb09/JCTH-10-680-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/50050e0f19e4/JCTH-10-680-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/a4b6207d9e5e/JCTH-10-680-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/a752acf2d1d0/JCTH-10-680-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/d884065c1346/JCTH-10-680-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c0e/9396324/7c39e45c33df/JCTH-10-680-g006.jpg

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