Mitochondrial dysfunction promotes cell migration via reactive oxygen species-enhanced 尾5-integrin expression in human gastric cancer SC-M1 cells

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• 作者：Wen-Yi Hung^a ; Kuo-Hung Huang^b ; ^c ; Chew-Wun Wu^b ; ^c ; Chin-Wen Chi^a ; ^d ; Hwa-Li Kao^d ; Anna Fen-Yau Li^e ; Pen-Hui Yin^d ; Hsin-Chen Lee^a ; ^{hclee2@ym.edu.tw}
• 关键词：Mitochondrial dysfunction ; Reactive oxygen species ; 尾5-Integrin ; Migration ; Gastric cancer
• 刊名：Biochimica et Biophysica Acta (BBA)/General Subjects
• 出版年：2012
• 期刊代码：16_03044165
• 类别：bio
• 出版时间：July, 2012
• 卷：1820
• 期：7
• 页码：1102-1110
• 文件大小：1154 K

摘要

Background

Mitochondrial dysfunction has been shown to promote cancer cell migration. However, molecular mechanism by which mitochondrial dysfunction enhances gastric cancer (GC) cell migration remains unclear.

Methods

Mitochondria specific inhibitors, oligomycin and antimycin A, were used to induce mitochondrial dysfunction and to enhance cell migration of human gastric cancer SC-M1 cells. Antioxidant N-acetylcysteine (NAC) was used for evaluating the effect of reactive oxygen species (ROS). Protein expressions of epithelial-to-mesenchymal transition (EMT) markers and the cell-extracellular matrix (ECM) adhesion molecules, the integrin family, were analyzed. A migratory subpopulation of SC-M1 cells (SC-M1-3rd) was selected using a transwell assay for examining the association of mitochondrial bioenergetic function, intracellular ROS content and 尾5-integrin expression. Clinicopathologic characteristics of 尾5-integrin expression were analyzed in GC specimens by immunohistochemical staining.

Results

Treatments with mitochondrial inhibitors elevated mitochondria-generated ROS and cell migration of SC-M1 cells. The protein expression of 尾5-integrin and cell surface expression of 伪v尾5-integrin were upregulated, and which were suppressed by NAC. Pretreatments with NAC and anti-伪v尾5-integrin neutralizing antibody respectively prevented the mitochondrial dysfunction-induced cell migration. The selected migratory SC-M1-3rd cells showed impaired mitochondrial function, higher mitochondria-generated ROS, and increased 尾5-integrin expression. The migration ability was also repressed by anti-伪v尾5-integrin neutralizing antibody. In clinical specimens, GCs with higher 尾5-integrin protein expression had more aggressive behavior. In conclusion, mitochondrial dysfunction may lead to GC progression by enhancing migration through mitochondria-generated ROS mediated 尾5-integrin expression.

General significance

These results support the role of mitochondrial dysfunction in GC progression.