Abstract
Metastasis remains the major cause of death from colon cancer. We intend to identify differentially expressed genes that are associated with the metastatic process and prognosis in colon cancer. ATP synthase epsilon subunit (ATP5E) gene was found to encode the mitochondrial F0F1 ATP synthase subunit epsilon that was overexpressed in tumor cells compared to their normal counterparts, while other genes encoding the ATP synthase subunit were repressed in public microarray datasets. CRC cells in which ATP5E was silenced showed markedly reduced invasive and migratory abilities. ATP5E inhibition significantly reduced the incidence of distant metastasis in a mouse xenograft model. Mechanistically, increased ATP5E expression resulted in a prominent reduction in E-cadherin and an increase in Snail expression. Our data also showed that an elevated ATP5E level in metastatic colon cancer samples was significantly associated with the AMPK-AKT-hypoxia-inducible factor-1α (HIF1α) signaling axis; silencing ATP5E led to the degradation of HIF1α under hypoxia through AMPK-AKT signaling. Our findings suggest that elevated ATP5E expression could serve as a marker of distant metastasis and a poor prognosis in colon cancer, and ATP5E functions via modulating AMPK-AKT-HIF1α signaling.
Highlights
Colorectal cancer (CRC) is one of the leading causes of morbidity and mortality worldwide, with about 1.4 million new cases reported in 2012 [1]
A hierarchical clustering analysis showed that expression profiles of genes coding adenosine triphosphate (ATP) synthase subunits were suppressed in tumor tissues compared to normal tissues (Figure 1a)
We found that ATP5E, which encodes the ATP synthase epsilon subunit, was uniquely overexpressed in tumor tissues compared to normal tissues (Figure 1b)
Summary
Colorectal cancer (CRC) is one of the leading causes of morbidity and mortality worldwide, with about 1.4 million new cases reported in 2012 [1]. Significant increases in ATP synthase α- and δ-subunits expressions were observed in primary tumors compared to the normal mucosa, while downregulation of the α- and δ-subunits led to decreased invasion in vitro in liver metastasis of primary CRC [17,18]. Based on these premises, we hypothesized that metastasis is an energy-demanding process that prompts cancer cells to acquire extra energy by upregulating energy-producing machinery. We investigated functional consequences of ATP5E alterations in CRC tumor cells, and the signaling axis that causes the EMT
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