Abstract
BackgroundCircular 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.MethodsqRT-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.ResultsCirc-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).ConclusionsOur 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.
Highlights
CircRNAs are a class of abundant and ubiquitous noncoding RNA molecules that been found recently in eukaryotic cells [1, 2]
Several studies including ours have demonstrated that Erbin is involved in colorectal cancer (CRC) [20], hepatocellular carcinoma (HCC) [22], breast cancer [23]
QRT-PCR experiments showed that only has_circ_0001492, termed as circ-ERBIN, which is formed by circularization of 2–4 exons of the ERBIN gene, was highly expressed in different CRC cells, and significantly increased in more aggressive CRC cells (Fig. 1b)
Summary
CircRNAs are a class of abundant and ubiquitous noncoding RNA molecules that been found recently in eukaryotic cells [1, 2]. Hypoxia is one of basic characteristics of the microenvironment in the majority of solid tumors and plays a vital role in cancer cell proliferation, angiogenesis, therapy resistance and development of aggressive tumor phenotype [11,12,13,14]. There are few studies on the role of specific circRNAs in regulating hypoxia-induced CRC metastasis, and the circRNAs that are relevant to regulate HIF-1α levels in CRC cells remain largely unknown. Circular RNA (circRNAs) and hypoxia have been found to play the key roles in the pathogenesis and progression of cancer including colorectal cancer (CRC). 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
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