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

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.

Circ_0006174 Accelerates Colorectal Cancer Progression Through Regulating miR-138-5p/MACC1 Axis

“…A number of studies have found that miR-138-5p exerted a tumor-suppression role in CRC. 25–27 Xu et al indicated that miR-138-5p inhibited cell migration and enhanced chemoresistance in CRC cells by NFIB-Snail1 axis. 26 In our research, miR-138-5p was downregulated in CRC tissues and cells and was negatively correlated with circ_0006174 expression.…”

Circular RNAs in Human Cancer

“…The number of microvessels were greatly increased in circERBIN overexpression tumors as analyzed by staining CD31, a sensitive vascular marker to evaluate tumor angiogenesis. They further confirmed that circERBIN promoted tumor angiogenesis by increasing a cap-independent protein translation of HIF-1α through miR-125a5p/miR-138-5p/4EBP-1 signaling ( 148 ).…”

Functional Role of circRNAs in the Regulation of Fetal Development, Muscle Development, and Lactation in Livestock

“…It has also been reported that circRNAs can be spliced with linear RNA, thereby smoothly "capturing" mRNA and then regulating the life process [42]; circRNAs can also interact with RNA polymerase II (Pol II), thereby promoting the transcription of parent genes [31]. Some circRNAs can regulate the normal physiological activities of biological individuals by participating in the synthesis of body proteins [43,44]. For example, circ-Amotl1 physically binds to both 3-phosphoinositidedependent protein kinase 1 (PDK1) and protein kinase B (AKT), facilitating the cardioprotective nuclear translocation of pAKT [45].…”

“…For example, circ-Amotl1 physically binds to both 3-phosphoinositidedependent protein kinase 1 (PDK1) and protein kinase B (AKT), facilitating the cardioprotective nuclear translocation of pAKT [45]. Very few circRNAs can be used as translation templates to promote translation [44]. Recently, some studies have shown that circRNAs can also be used as biomarker molecules [46,47] and are currently used as markers for the diagnosis of related diseases [45].…”