Abstract
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.
Highlights
Mitochondrial Ca2+ plays a critical role in tumorigenesis, including cell proliferation and metastasis
We have demonstrated that Mitochondrial calcium uniporter regulator 1 (MCUR1)-mediated mitochondrial calcium signaling triggers reactive oxygen species (ROS) generation and subsequent Notch signaling pathway, which contributes to the epithelial-mesenchymal transition (EMT) of Hepatocellular carcinoma (HCC) cells and poor prognosis of patients
As shown in Additional file 2: Figure S1a, our results showed that HCC cells with MCUR1 knockdown exhibited the morphological change from mesenchymal to epithelial and had a significantly decreased basal mitochondrial Ca2+ ([Mitochondrial Ca2+ (Ca2+]m)) when compared with the control cells
Summary
Mitochondrial Ca2+ plays a critical role in tumorigenesis, including cell proliferation and metastasis. Whether MCUR1 is involved in the metastasis of HCC and its underlying mechanisms remain unknown. 90% of cancer death are caused by metastasis, a complicated process involving tumor cell motility, intravasation, circulation, extravasation and growth in new tissues and organs [3]. The increased motility and invasive properties of metastatic tumor cells are reminiscent of events that occur during epithelial-mesenchymal transition (EMT). EMT is a process in which epithelial cells lose their cell polarity and cell-cell adhesion, and gain a mesenchymal phenotype with migratory and invasive properties. EMT has been proposed as a vital mechanism for epithelial cancer cells to acquire a malignant phenotype, especially invasion and metastasis [4]. The mechanism by which tumors induce EMT to facilitate invasion and metastasis remains largely unknown
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