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  • br Discussion br Despite the rapid advancement

    2019-10-21


    4. Discussion
    Despite the rapid advancement of early diagnosis and therapy in GC, most GC patients inevitably progress to an advanced stage, which is characterized by metastatic and chemo-resistant disease [5,19]. During the last few years, scientists have realized that screening effective new biomarkers and exploring the signaling pathways associated with GC initiation and progression are extremely important for improving the prognosis of GC patients. In this study, we focused on circFAT1(e2), which was identified by circRNAs microarray, and validated the downregulation of circFAT1(e2) in GC human tissue specimens and cell lines. Patients with high circFAT1(e2) expression showed a better prognosis. Mechanistic analysis demonstrated that overexpression of circFAT1(e2) inhibited the capacity of proliferation, invasion, and mi-gration of GC Angeli’s Salt by specifically binding miR-548g and releasing RUNX1. In addition, circFAT1(e2) could suppress GC growth by tar-geting YBX1.
    The term “circRNA” was first proposed by Sanger in 1976 and then achieved more and more attention all over the world [20,21]. CircRNAs exist as an enigmatic type of ncRNAs with unclear functions in mammal 
    cells, and frequently exhibit tissue or developmental-stage specific ex-pression [22,23]. Due to their excellent conservatism and stability properties, circRNAs were considered to be a promising biomarker of tumors in precision medicine [24]. Although the exact functions of the majority of circRNAs remain undetermined, emerging evidence has revealed that circRNAs are involved in the development of multiple diseases, such as neurodegenerative disorders, metabolic disorders, and different types of cancer [25–27]. For example, Xijing He et al. have identified that circRNA-0008717 may serve as an oncogene by targeting miR-203 in osteosarcoma [28]. Wang J and Li H reported that knock-down of circ_0067934 significantly inhibited proliferation, invasion, and migration of human nonsmall cell lung cancer (NSCLC) cells [29]. Zhang and coworkers indicated that circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression [30]. However, the exact role of cir-cRNAs in GC remains largely unclear. In this study, a circRNA micro-array analysis was carried out to examine the circRNA expression profiles of GC tissues and related normal tissues to investigate the correlation between circRNAs and GC. We found that circFAT1(e2) was significantly downregulated in GC tissues and cell lines, and Kaplan-Meier analysis indicated that circFAT1(e2) may be a promising prog-nostic biomarker for GC patients. CircFAT1(e2) originates from exon 2 of the FAT1 gene and is distributed in both the cytoplasm and nucleus of GC cells. Moreover, we demonstrated that overexpression of cir-cFAT1(e2) suppressed cell proliferation, migration, and invasion, im-plying that circFAT1(e2) may play as a tumor suppressor in GC.
    MiRNAs, characterized by short sequence (∼22 nt), are an abun-dant type of ncRNAs without protein encoding ability [31]. Previously, studies have revealed that miRNAs may bind to the 3′-untranslated
    Fig. 7. circFAT1(e2) inhibited GC cell tumorigenesis through YBX1. (A and B) Relative mRNA expression of three targeted genes of YBX1 (EGFP, c-Met, and CDC25A) were measured by RT-PCR in MGC-803 and MKN-28 cells treated with circFAT1(e2) or YBX1. (C and D) Cell number of MGC-803 and MKN-28 cells treated with circFAT1(e2) or YBX1 were evaluated by MTT assay at 1, 2, 3, 4, and 5 days after transfection. Angeli’s Salt (E and F) Colony formation assay was carried out to examine cell proliferation in MGC-803 and MKN-28 cells treated with circFAT1(e2) or YBX1.