Colorectal cancer is one of the leading causes of
cancer death worldwide. According to global genomic status,
colorectal cancer can be classified into two main types: microsatellite-stable and microsatellite-instable
tumors. Moreover, the two subtypes also exhibit different responses to chemotherapeutic agents through distinctive molecular mechanisms. Recently,
mitochondrial DNA depletion has been shown to induce apoptotic resistance in microsatellite-instable
colorectal cancer. However, the effects of altered
mitochondrial DNA copy number on the progression of microsatellite-stable
colorectal cancer, which accounts for the majority of
colorectal cancer, remain unclear. In this study, we systematically investigated the functional role of altered
mitochondrial DNA copy number in the survival and
metastasis of microsatellite-stable
colorectal cancer cells. Moreover, the underlying molecular mechanisms were also explored. Our results demonstrated that increased
mitochondrial DNA copy number by forced
mitochondrial transcription factor A expression significantly facilitated cell proliferation and inhibited apoptosis of microsatellite-stable
colorectal cancer cells both in vitro and in vivo. Moreover, we demonstrated that increased
mitochondrial DNA copy number enhanced the
metastasis of microsatellite-stable
colorectal cancer cells. Mechanistically, the survival advantage conferred by increased
mitochondrial DNA copy number was caused in large part by elevated mitochondrial oxidative phosphorylation. Furthermore, treatment with
oligomycin significantly suppressed the survival and
metastasis of microsatellite-stable
colorectal cancer cells with increased
mitochondrial DNA copy number. Our study provides evidence supporting a possible
tumor-promoting role for
mitochondrial DNA and uncovers the underlying mechanism, which suggests a potential novel therapeutic target for microsatellite-stable
colorectal cancer.