The Regulatory Mechanism and Biological Significance of Mitochondrial Calcium Uniporter in the Migration, Invasion, Angiogenesis and Growth of Gastric Cancer

Xiaofei Wang,1,* Xudong Song,1,* Guang Cheng,2,* Jingwen Zhang,3 Liru Dong,1 Jie Bai,1 Dan Luo,1 Yanjie Xiong,1 Shuang Li,1 Fang Liu,1 Yuanyuan Sun,1 Xin Wang,1 Yuyang Li,1 Yunning Huang4 1Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei, People’s Republic of China; 2Central Laboratory of Clinical Medical College, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei, People’s Republic of China; 3School of Basic Medical Science, NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, NingXia Medical University, Yinchuan 750004, NingXia, People’s Republic of China; 4Department of Gastrointestinal Surgery, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750001, Ningxia, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunning HuangDepartment of Gastrointestinal Surgery, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750001, Ningxia, People’s Republic of ChinaEmail nxhyncc@126.comObjective: Increasing evidences suggest that mitochondrial calcium uniporter (MCU), a selective channel responsible for mitochondrial Ca2+ uptake, is involved in the progression of several cancers. In this study, we aimed to observe the clinical implications and biological functions of MCU in gastric cancer.Methods: The expression of MCU in 90 pairs of gastric cancer tissues and adjacent normal tissues was examined using immunohistochemistry and correlation between MCU expression and clinical features was analyzed. After construction of stable MCU knockdown or overexpression gastric cancer cells, mitochondrial membrane potential (MMP), wound healing and transwell assays were performed to examine MMP levels, migration and invasion. Subcutaneous xenograft tumors induced by gastric cancer cells transfected with MCU siRNAs or controls were constructed. Immunofluorescence was used to detect CD34 expression. Western blot was used to detect the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), epithelial-mesenchymal transition (EMT)-related proteins.Results: MCU had a higher expression in gastric cancer tissues than normal tissues. Compared to gastric cancer tissues, its expression was significantly higher after omental metastasis. MCU expression was significantly correlated with depth of invasion (p=0.048), lymph metastasis (p=0.027), TNM stage (p=0.036) and distant metastasis (p=0.029). Patients with high MCU expression indicated a worse prognosis than those with its low expression (p=0.0098). MCU significantly increased the MMP levels of gastric cancer cells. Wound healing and transwell assay results showed that MCU promoted migration and invasion of gastric cancer cells. In vivo, MCU knockdown significantly inhibited tumor growth and angiogenesis. Both in vitro and in vivo, silencing MCU suppressed the expression of HIF-1α and VEGF as well as activity of EMT processes.Conclusion: Our findings suggested that highly expressed MCU could promote migration, invasion, angiogenesis and growth of gastric cancer, which could become a potential therapeutic marker for gastric cancer.Keywords: gastric cancer, mitochondrial calcium uniporter, invasion, angiogenesis, epithelial–mesenchymal transition