Hsa_circ_0079480 enhances cell proliferation, migration, and invasion in colorectal cancer through miR-498/ATP5E axis.

Circular RNAs play critical roles in tumorigenesis. hsa_circ_0079480 was reported to be upregulated in colorectal cancer (CRC). However, its specific molecule in CRC is poorly understood. Hsa_circ_0079480, miR-498, and ATP5E expressions in CRC tissues and CRC cells were determined using quantitative real-time polymerase chain reaction assay. ATP5E protein level was assessed using Western blot. Cell proliferation, migration, and invasion were examined by 3-(4, 5-Dimethylthiazolyl2)-2, 5-diphenyltetrazolium bromide assay and Transwell assays, respectively. Dual-luciferase reporter gene assay was performed to analyze the interactions between hsa_circ_0079480, miR-498, and ATP5E. This study results showed that hsa_circ_0079480 and ATP5E expressions were significantly increased in CRC tissues and CRC cells, while miR-498 was downregulated. Hsa_circ_0079480 knockdown dramatically suppressed CRC cell proliferation, migration, and invasion. Meanwhile, it turned out that hsa_circ_0079480 knockdown inhibited CRC tumor growth in vivo. Hsa_circ_0079480 could negatively regulate miR-498 expression by directly targeting miR-498. MiR-498 overexpression dramatically inhibited CRC cell malignant behaviors. miR-498 negatively regulated ATP5E expression by directly binding to ATP5E. ATP5E knockdown suppressed CRC cell malignant behaviors. ATP5E overexpression mitigated the inhibitory effect of hsa_circ_0079480 on CRC cell malignant behaviors. Since hsa_circ_0079480 knockdown inhibited CRC cells malignant behaviors through regulation of the miR-498/ATP5E axis, it can be concluded that hsa_circ_0079480 might have great potential as therapeutic target for CRC.

ATP Synthase Subunit Epsilon Overexpression Promotes Metastasis by Modulating AMPK Signaling to Induce Epithelial-to-Mesenchymal Transition and Is a Poor Prognostic Marker in Colorectal Cancer Patients.

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.