Abstract
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.
Highlights
Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide despite recent advances in surgery, radiotherapy, and chemotherapy.[1]
Our findings demonstrate that increased mitochondrial DNA (mtDNA) plays a critical Clone-formation assay role in regulating MSS CRC cell survival and metastasis by Log-phase SW480 cells or Caco-2 cells were plated in 6-well plates promoting mitochondrial oxidative phosphorylation (OXPHOS), which provides novel evi- at a density of 103 cells/well or 0.6 × 103 cells/well, respectively
Most free energy is produced by mitochondrial OXPHOS, during which electrons derived from NADH and FADH2 are transported to the electron transport chain (ETC) to generate ATP
Summary
Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide despite recent advances in surgery, radiotherapy, and chemotherapy.[1]. We still do not know precisely how mitochondria are involved in CRC progression Mitochondria contain their own genome, which encodes 13 polypeptides involved in the electron transport chain (ETC) and ATP synthase.[7,8] Cumulative evidence has indicated that variation of mitochondrial DNA (mtDNA) copy number is closely associated with types of cancers. The cells were trypsinized and counted at 0, 1, 2, 3, and copy number on the tumor progression of MSS CRC, the majority 4 days. Our findings demonstrate that increased mtDNA plays a critical Clone-formation assay role in regulating MSS CRC cell survival and metastasis by Log-phase SW480 cells or Caco-2 cells were plated in 6-well plates promoting mitochondrial OXPHOS, which provides novel evi- at a density of 103 cells/well or 0.6 × 103 cells/well, respectively.
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