State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China.
Center of Genetic & Prenatal Diagnosis, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
J Exp Clin Cancer Res. 2019 Mar 25;38(1):136. doi: 10.1186/s13046-019-1135-x.
Mitochondrial Ca 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.
The 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.
MCUR1 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 Ca signaling promoted the EMT of HCC cells by activating ROS/Nrf2/Notch1 pathway. Inhibition of ROS production, mitochondrial Ca uptake, Nrf2 expression or Notch1 activity significantly suppressed MCUR1-induced EMT of HCC cells. In addition, treatment with the mitochondrial Ca-buffering protein parvalbumin significantly inhibited ROS/Nrf2/Notch pathway and MCUR1-induced EMT and HCC metastasis.
Our study provides evidence supporting a metastasis-promoting role for MCUR1-dependent mitochondrial Ca uptake in HCC. Our findings suggest that MCUR1 may be a potential therapeutic target for HCC treatment.
线粒体钙在肿瘤发生中起着关键作用，包括细胞增殖和转移。已经表明，线粒体钙单向转运体调节蛋白 1（MCUR1）在 HCC 中经常上调，并促进癌细胞存活。然而，MCUR1 是否参与 HCC 的转移及其潜在机制尚不清楚。
首先通过免疫荧光染色和 Western blot 评估 MCUR1 表达对 HCC 细胞上皮-间充质转化（EMT）的影响。然后，通过体外侵袭和体内转移实验评估 MCUR1 在 HCC 转移中的功能。还通过研究 MCUR1 对 ROS/Nrf2/Notch1 通路的影响来探索潜在机制。
MCUR1 表达在有转移的 HCC 中明显更高，与肿瘤进展相关。MCUR1 通过促进 Snail 促进 HCC 细胞的体外侵袭和体内转移。在机制上，MCUR1 介导的线粒体钙信号通过激活 ROS/Nrf2/Notch1 通路促进 HCC 细胞的 EMT。抑制 ROS 产生、线粒体钙摄取、Nrf2 表达或 Notch1 活性可显著抑制 MCUR1 诱导的 HCC 细胞 EMT。此外，用线粒体钙缓冲蛋白 parvalbumin 处理可显著抑制 ROS/Nrf2/Notch 通路和 MCUR1 诱导的 EMT 和 HCC 转移。
我们的研究提供了证据，支持 MCUR1 依赖性线粒体钙摄取在 HCC 中促进转移的作用。我们的发现表明，MCUR1 可能是 HCC 治疗的潜在治疗靶点。
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