miR‐449c‐5p availability is antagonized by circ‐NOTCH1 for MYC‐induced NOTCH1 upregulation as well as tumor metastasis and stemness in gastric cancer

Abstract

Gastric cancer (GC), identified as the most common gastrointestinal malignancy, is one of the primary causes of cancer‐related mortality in the world. Although surgery and chemotherapy for GC treatment have been improved, the 5‐year overall survival rate is still unsatisfactory. Circ‐NOTCH1 is a novel circular RNA derived from its host gene NOTCH1, and has not been studied in any cancers. Here we explored the potential role and mediatory mechanism of circ‐NOTCH1 in GC. In this study, circ‐NOTCH1 exhibited increased expression in GC tissues and cells. Suppression of circ‐NOTCH1 inhibited cell migration, invasion, tumor spheroids number, and side population ratio. Circ‐NOTCH1 also promoted GC growth and metastasis in vivo. Additionally, it was found that circ‐NOTCH1 could bind to miR‐449c‐5p. Circ‐NOTCH1 promoted metastasis and stemness in GC through sponging miR‐449c‐5p. Subsequently, MYC was identified as a downstream gene of miR‐449c‐5p. MYC could bind to the promoter of NOTCH1 to regulate GC progression. Furthermore, rescue assays demonstrated that NOTCH1 knockdown reversed the effects of overexpression of MYC in metastasis and stemness in AGS cells/sh‐circNOTCH1. Above findings explained that circ‐NOTCH1 promoted metastasis and stemness in GC by targeting miR‐449c‐5p/MYC/NOTCH1 axis, suggesting the possibility of circ‐NOTCH1 as a therapeutic marker for GC.

Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance

“…Circ_001680 and circ-NOTCH1 are increased in colorectal cancer (CRC) and gastric cancer (GC), respectively. Both promote the cancer stem cell (CSC) population in cancer [46,47]. Failing to eradicate cancer cells that acquire stemness via activation of EMT or senescence is another reason for compromised therapy outcomes in cancer [48][49][50][51].…”

Circular RNAs in Embryogenesis and Cell Differentiation With a Focus on Cancer Development

“…Increasing evidence obtained analyzing circRNA/miRNA network by bioinformatics approaches has established that specific circRNAs are implicated in stemness via serving as miRNA sponges in different cancers, such as breast cancer (Yan et al, 2017), laryngeal cancer , gastric cancer (Zhao X. et al, 2020), and hepatocellular carcinoma (Zhu et al, 2019). As for glioma, since circPTN was shown to sponge miR-145-5p, which is a negative regulator of stemness (Zhao X. et al, 2020) and self-renewal (Rani et al, 2013) and since circPTN expression was more than 10-fold higher in glioma cells compared with normal glial cells, hypothesized that circPTN may be a positive regulator of stemness. As expected, tumor sphere formation assays determined that circPTN promoted increased levels of stemness markers, such as Nestin, CD133, SOX2, and SOX9, and tumor growth in vitro and in vivo, primarily via sponging miR-145-5p/miR-330-5p .…”

Circular RNAs in Gastric Cancer: Potential Biomarkers and Therapeutic Targets

“…Similarly, Cheng et al also found that upregulation of circHIPK3 promotes cell proliferation by sponging miR-124/miR-29b to regulate the human collagen genes (COL1A1, COL4A1) and CDK6 [ 41 ]. Furthermore, it has been shown that circNOTCH1 can function as a promoting factor for the migration, invasion, and stemness of tumors by binding to miR-449c-5p to influence Myc expression, further modulating the transcription of NOTCH1 [ 42 ]. In addition, circPVT1 possesses two binding sites for miR-125b and, by sponging to miR-125b, can promote expression of the E2F2 gene and facilitate GC cell proliferation [ 43 ].…”