MCUR1 facilitates epithelial-mesenchymal transition and metastasis via the mitochondrial calcium dependent ROS/Nrf2/Notch pathway in hepatocellular carcinoma
MCUR1 facilitates epithelial-mesenchymal transition and metastasis via the mitochondrial calcium dependent ROS/Nrf2/Notch pathway in hepatocellular carcinoma
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MCUR1通过线粒体钙依赖性ROS/Nrf2/Notch通路促进肝细胞癌上皮-间质转化和转移
DOI：
10.1186/s13046-019-1135-x
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发表时间：
2019-03-25
影响因子：
11.3
通讯作者：
Xing, Jinliang
中科院分区：
文献类型：
--
作者：
Jin, Mingpeng;Wang, Jiaojiao;Xing, Jinliang
研究背景线粒体Ca ~（2+）在肿瘤的发生、增殖和转移过程中起重要作用。线粒体钙单向转运体调节因子1（MCUR 1）已被证明在HCC中频繁上调并促进癌细胞存活。然而，是否MCUR 1参与肝癌的转移及其潜在的mechanisms仍然unknows.MethodsThe影响MCUR 1的表达对上皮间质转化（EMT）在肝癌细胞中的免疫荧光染色和Western blot进行了首次评估。然后，通过体外侵袭和体内转移实验来评估MCUR 1在HCC转移中的功能。结果MCUR 1在肝癌组织中的表达与肿瘤进展密切相关，且与肿瘤转移相关。MCUR 1通过Snail促进EMT，从而促进肝癌细胞的体外侵袭和体内转移。MCUR 1介导的线粒体Ca 2+信号通过激活ROS/Nrf 2/Notch 1通路促进肝癌细胞EMT的发生。抑制ROS产生、线粒体Ca 2+摄取、Nrf 2表达或Notch 1活性可显著抑制MCUR 1诱导的HCC细胞EMT。此外，治疗与线粒体Ca 2+缓冲蛋白parvalbumin显着抑制ROS/Nrf 2/Notch途径和MCUR 1诱导的EMT和HCC metastasis.ConclusionsOur的研究提供了证据支持转移促进作用的MCUR 1依赖的线粒体Ca 2+摄取在HCC中。我们的研究结果表明，MCUR 1可能是一个潜在的治疗肝癌的治疗靶点。
BackgroundMitochondrial Ca2+plays a critical role in tumorigenesis, including cell proliferation and metastasis. Mitochondrial calcium uniporter regulator 1 (MCUR1) has been shown to be frequently upregulated in HCC and promote cancer cell survival. However, whether MCUR1 is involved in the metastasis of HCC and its underlying mechanisms remain unknown.MethodsThe effect of MCUR1 expression on epithelial-mesenchymal transition (EMT) in HCC cells was first evaluated by immunofluorescent staining and Western blot. Then, in vitro invasion and in vivo metastasis assays were used to evaluate the function of MCUR1 in HCC metastasis. The underlying mechanism has also been explored by investigating the effect of MCUR1 on ROS/Nrf2/Notch1 pathway.ResultsMCUR1 expression was significantly higher in HCC with metastasis and associated with tumor progression. MCUR1 promoted in vitro invasion and in vivo metastasis of HCC cells by promoting EMT via Snail. Mechanistically, MCUR1-mediated mitochondrial Ca2+signaling promoted the EMT of HCC cells by activating ROS/Nrf2/Notch1 pathway. Inhibition of ROS production, mitochondrial Ca2+uptake, Nrf2 expression or Notch1 activity significantly suppressed MCUR1-induced EMT of HCC cells. In addition, treatment with the mitochondrial Ca2+-buffering protein parvalbumin significantly inhibited ROS/Nrf2/Notch pathway and MCUR1-induced EMT and HCC metastasis.ConclusionsOur study provides evidence supporting a metastasis-promoting role for MCUR1-dependent mitochondrial Ca2+uptake in HCC. Our findings suggest that MCUR1 may be a potential therapeutic target for HCC treatment.