The circular RNA circ-ERBIN promotes growth and metastasis of colorectal cancer by miR-125a-5p and miR-138-5p/4EBP-1 mediated cap-independent HIF-1α translation

• Published in: Molecular cancer Vol. 19; no. 1; pp. 1 - 164
• Main Authors: Chen, Liang-Yan, Wang, Lian, Ren, Yue-Xiang, Pang, Zheng, Liu, Yao, Sun, Xiao-Dong, Tu, Jian, Zhi, Zheng, Qin, Yan, Sun, Li-Na, Li, Jian-Ming
• Format: Journal Article
• Language: English
• Published: London BioMed Central 23-11-2020
• Subjects: Angiogenesis; Cancer; Cell growth; Cell proliferation; Circular RNA; Colorectal cancer; Colorectal carcinoma; Experiments; Fluorescence in situ hybridization; Gene expression; Hypoxia; Hypoxia-inducible factor 1a; Metastases; Metastasis; mRNA; Plasmids; Protein expression; Proteins; Translation; Tumors; Western blotting; China
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-020-01272-9

Abstract
Background
Circular RNA (circRNAs) and hypoxia have been found to play the key roles in the pathogenesis and progression of cancer including colorectal cancer (CRC). However, the expressions and functions of the specific circRNAs in regulating hypoxia-involved CRC metastasis, and the circRNAs that are relevant to regulate HIF-1α levels in CRC remain elusive.
Methods
qRT-PCR was used to detect the expression of circRNAs and mRNA in CRC cells and tissues. Fluorescence in situ hybridization (FISH) was used to analyze the location of circ-ERBIN. Function-based experiments were performed using circ-ERBIN overexpression and knockdown cell lines in vitro and in vivo, including CCK8, colony formation, EdU assay, transwell, tumor growth and metastasis models. Mechanistically, luciferase reporter assay, western blots and immunohistochemical stainings were performed.
Results
Circ-Erbin was highly expressed in the CRC cells and Circ-Erbin overexpression facilitated the proliferation, migration and metastasis of CRC in vitro and in vivo. Notably, circ-Erbin overexpression significantly promoted angiogenesis by increasing the expression of hypoxia induced factor (HIF-1α) in CRC. Mechanistically, circ-Erbin accelerated a cap-independent protein translation of HIF-1α in CRC cells as the sponges of miR-125a-5p and miR-138-5p, which synergistically targeted eukaryotic translation initiation factor 4E binding protein 1(4EBP-1).
Conclusions
Our findings uncover a key mechanism for circ-Erbin mediated HIF-1α activation by miR-125a-5p-5p/miR-138-5p/4EBP-1 axis and circ-ERBIN is a potential target for CRC treatment.