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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.

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Fig. 1: Identification and characterization of circXRCC5 in GC cells.
Fig. 2: circXRCC5 was elevated in GC cells and tissues.
Fig. 3: circXRCC5 promoted GC cell proliferation in vitro and GC tumor growth in vivo.
Fig. 4: circXRCC5 facilitated GC cell migration and invasion in vitro and tumor metastasis in vivo.
Fig. 5: circXRCC5 directly bound with miR-655-3p.
Fig. 6: miR-655-3p was involved in the regulation of GC cell proliferation and migration by circXRCC5.
Fig. 7: miR-655-3p directly targeted RREB1.
Fig. 8: RREB1 promoted GC progression and activated UBA2 transcription.
Fig. 9: Knockdown of UBA2 suppressed GC cell proliferation, migration, and invasion.
Fig. 10: circXRCC5/miR-655-3p regulated GC tumor growth in vivo.
Fig. 11: HNRNPC promoted biogenesis of circXRCC5.

Data availability

All data generated or analysed during this study are included in this published article

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Funding

This work was supported by Natural Science Foundation of Jilin Province (20200201458JC).

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Contributions

ZLL: Conceptualization, writing- original draft preparation, investigation, validation, visualization, methodology; SW: Data curation, Software; LP: Conceptualization, writing- original draft preparation, supervision, writing- reviewing and editing; XWM: Conceptualization, writing- original draft preparation, supervision, writing- reviewing and editing.

Corresponding authors

Correspondence to Li Pang or Xiang-Wei Meng.

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The authors declare no competing interests.

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The protocol has been approved by the First Hospital of Jilin University. All patients have been informed of the study and consented with a written form. All animal experiments have been reviewed and received approval by the Animal Care and Use Committee of the First Hospital of Jilin University.

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Liu, ZL., Wang, SK., Pang, L. et al. circXRCC5 foster gastric cancer growth and metastasis by the HNRNPC/circXRCC5/miR-655-3p/RREB1/UBA2 positive feedback loop. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00482-1

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