CCBE1 promotes mitochondrial fusion by inhibiting the TGFβ-DRP1 axis to prevent the progression of hepatocellular carcinoma

生物 癌症研究 磷酸化 线粒体 细胞生物学 线粒体融合 癌变 线粒体DNA 癌症 生物化学 基因 遗传学
作者
Guang-Ang Tian,Wenting Xu,Xueli Zhang,Yaoqi Zhou,Yue Sun,Li-Peng Hu,Shu‐Heng Jiang,Hui Nie,Zhigang Zhang,Lei Zhu,Jun Li,Xiaomei Yang,Linli Yao
出处
期刊:Matrix Biology [Elsevier]
卷期号:117: 31-45 被引量:9
标识
DOI:10.1016/j.matbio.2023.02.007
摘要

The extracellular matrix (ECM), as an important component of the tumor microenvironment, exerts various roles in tumor formation. Mitochondrial dynamic disorder is closely implicated in tumorigenesis, including hyperfission in HCC. We aimed to determine the influence of the ECM-related protein CCBE1 on mitochondrial dynamics in HCC. Here, we found that CCBE1 was capable of promoting mitochondrial fusion in HCC. Initially, CCBE1 expression was found to be significantly downregulated in tumors compared with nontumor tissues, which resulted from hypermethylation of the CCBE1 promoter in HCC. Furthermore, CCBE1 overexpression or treatment with recombinant CCBE1 protein dramatically inhibited HCC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, CCBE1 functioned as an inhibitor of mitochondrial fission by preventing the location of DRP1 on mitochondria through inhibiting its phosphorylation at Ser616 by directly binding with TGFβR2 to inhibit TGFβ signaling activity. In addition, a higher percentage of specimens with higher DRP1 phosphorylation was present in patients with lower CCBE1 expression than in patients with higher CCBE1 expression, which further confirmed the inhibitory effect of CCBE1 on DRP1 phosphorylation at Ser616. Collectively, our study highlights the crucial roles of CCBE1 in mitochondrial homeostasis, suggesting strong evidence for this process as a potential therapeutic strategy for HCC.
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