DNAJA3/Tid1 Is Required for Mitochondrial DNA Maintenance and Regulates Migration and Invasion of Human Gastric Cancer Cells

SIMPLE SUMMARY: Mitochondrial stress responses play a key role in cancer progression. Tid1, a mitochondrial co-chaperone, has been investigated and may act as a tumor suppressor in several cancers. However, the role of Tid1 in gastric cancers has not been clearly identified. Herein, we uncovered the clinical effects of Tid1 expression in gastric cancer patients. Moreover, we dissected the possible regulatory mechanism of Tid1 for cancer progression in gastric cancer cells. Our results demonstrated that Tid1 might regulate cell migration and invasion of gastric cancers. Tid1 may also be a key player for mitochondrial DNA maintenance in gastric cancer cells. We also found that the Tid1-galectin-7-MMP-9 axis might be one of the malignant regulatory mechanisms for gastric cancer metastasis and provide a potential target for gastric cancer treatment. ABSTRACT: Background: Gastric cancer is a common health issue. Deregulated cellular energetics is regarded as a cancer hallmark and mitochondrial dysfunction might contribute to cancer progression. Tid1, a mitochondrial co-chaperone, may play a role as a tumor suppressor in various cancers, but the role of Tid1 in gastric cancers remains under investigated. Methods: The clinical TCGA online database and immunohistochemical staining for Tid1 expression in tumor samples of gastric cancer patients were analyzed. Tid1 knockdown by siRNA was applied to investigate the role of Tid1 in gastric cancer cells. Results: Low Tid1 protein-expressing gastric cancer patients had a poorer prognosis and higher lymph node invasion than high Tid1-expressing patients. Knockdown of Tid1 did not increase cell proliferation, colony/tumor sphere formation, or chemotherapy resistance in gastric cancer cells. However, Tid1 knockdown increased cell migration and invasion. Moreover, Tid1 knockdown reduced the mtDNA copy number of gastric cancer cells. In addition, the Tid1-galectin-7-MMP-9 axis might be associated with Tid1 knockdown–induced cell migration and invasion of gastric cancer cells. Conclusions: Tid1 is required for mtDNA maintenance and regulates migration and invasion of gastric cancer cells. Tid1 deletion may be a poor prognostic factor in gastric cancers and could be further investigated for development of gastric cancer treatments.