Background and Aims: Radiation-induced liver fibrosis (RILF), delayed damage to the liver (post-irradiation) re-mains a major challenge for the radiotherapy of liver ma-lignancies. This study investigated the potentia...Background and Aims: Radiation-induced liver fibrosis (RILF), delayed damage to the liver (post-irradiation) re-mains a major challenge for the radiotherapy of liver ma-lignancies. 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 immunoprecipi-tation (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 mol-ecules, 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 in vivo. Notably, knockdown of circTUBD1 al-leviated 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.展开更多
基金This work was supported by National Natural Science Foundation of China(Grant Nos.81773220 and 82003225)Shanghai Sailing Program(Grant No.20YF1405500)the Youth Programme of Zhongshan Hospital,Fudan University(Grant No.2020ZSQN24).
文摘Background and Aims: Radiation-induced liver fibrosis (RILF), delayed damage to the liver (post-irradiation) re-mains a major challenge for the radiotherapy of liver ma-lignancies. 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 immunoprecipi-tation (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 mol-ecules, 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 in vivo. Notably, knockdown of circTUBD1 al-leviated 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.
