ERO1α regulates colon cancer progression and 5-FU resistance through the miR-451a/ARF1 axis

Background: Colon Cancer (CC) is one of the three most common cancers worldwide. In the treatment of CC, 5-fluorouracil (5-FU) is one of the main components of chemotherapeutic combinations, but severe chemical resistance still occurs. In addition, endoplasmic reticulum (ER) oxidoreductase-1α (ERO1α) has been shown to be highly expressed in CC, but its specific molecular mechanisms remain unclear.

Methods: Via western blot, real-time quantitative polymerase chain reaction (RT‒qPCR), colony formation, Transwell, CCK-8, immunofluorescence, and immunohistochemistry experiments,we evaluated the expression of related genes and the progression of CC. RESULTS: In this study, we found that ERO1α was highly expressed in CC and that miR-451a expression was low. Knocking down ERO1α can restrain the proliferation and invasion of CC cells; facilitate the expression of the ER stress-related proteins inositol-requiring enzyme (IRE), phosphorylated IRE (Pho-IRE), glucose-regulated protein 78 (GRP78), and activating transcription factor 4 (ATF4) and the proapoptotic proteins Bcl-2-associated X protein (Bax) and cleaved-caspase-3 in CC cells; and alleviate the progression of CC. The addition of the miR-451a inhibitor weakened the effect of sh-ERO1α. In terms of mechanism, we predicted that miR-451a targets ADP-ribosylation factor 1 (ARF1) through the StarBase website and confirmed the interaction between the two through a dual-luciferase gene reporter assay. Next, we verified that knocking down ERO1α promoted miR-451a and inhibited ARF1 expression, thus promoting ER stress and ultimately inhibiting the progression of CC. In addition, knocking down ERO1α promoted ER stress and weakened CC cell resistance to 5-FU. CONCLUSION: Our studies revealed that ERO1α could mediate ER stress to regulate the progression of CC and 5-FU resistance through the miR-451a/ARF1 axis, which may provide new treatment directions and molecular targets for CC.

5-FU; ARF1; Colorectal cancer; ERO1α; MiR-451a.