circXRCC5 foster gastric cancer growth and metastasis by the HNRNPC/circXRCC5/miR-655-3p/RREB1/UBA2 positive feedback loop.

ABSTRACT

Gastric cancer (GC) is one of the most common malignancies, leading to millions of deaths each year. Here, we investigated the molecular mechanisms of GC, with a focus on circXRCC5/miR-655-3p/RREB1/UBA2 axis. circXRCC5 was identified in 62 paired cancer specimens and adjacent normal tissues by genome-wide bioinformatics analysis and verified by qRT-PCR and Sanger sequencing. Knockdown or exogenous expression of circXRCC5 was performed to validate the functional significance of circXRCC5 using both in vitro and in vivo assays, including CCK-8, colony formation, EdU incorporation, transwell system, as well as animal experiments. RNA immunoprecipitation, biotinylated RNA pull-down, ChIP, and dual-luciferase assays were employed to validate the regulatory network of circXRCC5/miR-655-3p/RREB1/UBA2. Frequently elevated circXRCC5 in GC tissues and cell lines was associated with poor prognosis of GC patients. Functionally, circXRCC5 overexpression facilitated GC cell proliferation, migration, and invasion, as well as promoted tumor growth and metastasis in vivo. Mechanistically, circXRCC5 served as a sponge of miR-655-3p to induce upregulation of RREB1. RREB1 was identified as a transcriptional activator of UBA2, thus contributing to GC tumorigenesis. Moreover, RNA binding protein (RBP) HNRNPC was proved to interact with circXRCC5 to promote circXRCC5 biogenesis. Collectively, circXRCC5 facilitates GC progression through the HNRNPC/circXRCC5/miR-655-3p/RREB1/UBA2 axis, which might bring novel therapeutic strategies for GC treatment.