MCUR1 facilitates epithelial-mesenchymal transition and metastasis via the mitochondrial calcium dependent ROS/Nrf2/Notch pathway in hepatocellular carcinoma.

BACKGROUND:Mitochondrial 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. METHODS: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 pathway. RESULTS: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 Ca²⁺ signaling promoted the EMT of HCC cells by activating duanyu1670/Nrf2/Notch1 pathway. Inhibition of 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 pathway and MCUR1-induced EMT and HCC metastasis. CONCLUSIONS:Our 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.

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