Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation.

Publisher: BioMed Central Country of Publication: England NLM ID: 101147698 Publication Model: Electronic Cited Medium: Internet ISSN: 1476-4598 (Electronic) Linking ISSN: 14764598 NLM ISO Abbreviation: Mol Cancer Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2002-

ELAV-Like Protein 1/*metabolism ; Exosomes/*genetics ; HSP90 Heat-Shock Proteins/*metabolism ; MicroRNAs/*genetics ; RNA, Circular/*genetics ; Stomach Neoplasms/*pathology ; Vascular Endothelial Growth Factor A/*metabolism; Adaptor Proteins, Signal Transducing/genetics ; Animals ; Apoptosis ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Case-Control Studies ; Cell Proliferation ; ELAV-Like Protein 1/genetics ; Female ; Gene Expression Regulation, Neoplastic ; HSP90 Heat-Shock Proteins/genetics ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Middle Aged ; Prognosis ; Proteolysis ; Stomach Neoplasms/genetics ; Stomach Neoplasms/metabolism ; Survival Rate ; Tumor Cells, Cultured ; Vascular Endothelial Growth Factor A/genetics ; Xenograft Model Antitumor Assays

Background: Circular RNAs (circRNAs) play important regulatory roles in the development of various cancers. However, biological functions and the underlying molecular mechanism of circRNAs in gastric cancer (GC) remain obscure.
Methods: Differentially expressed circRNAs were identified by RNA sequencing. The biological functions of circSHKBP1 in GC were investigated by a series of in vitro and in vivo experiments. The expression of circSHKBP1 was evaluated using quantitative real-time PCR and RNA in situ hybridization, and the molecular mechanism of circSHKBP1 was demonstrated by western blot, RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. Lastly, mouse xenograft and bioluminescence imaging were used to exam the clinical relevance of circSHKBP1 in vivo.
Results: Increased expression of circSHKBP1(hsa_circ_0000936) was revealed in GC tissues and serum and was related to advanced TNM stage and poor survival. The level of exosomal circSHKBP1 significantly decreased after gastrectomy. Overexpression of circSHKBP1 promoted GC cell proliferation, migration, invasion and angiogenesis in vitro and in vivo, while suppression of circSHKBP1 plays the opposite role. Exosomes with upregulated circSHKBP1 promoted cocultured cells growth. Mechanistically, circSHKBP1 sponged miR-582-3p to increase HUR expression, enhancing VEGF mRNA stability. Moreover, circSHKBP1 directly bound to HSP90 and obstructed the interaction of STUB1 with HSP90, inhibiting the ubiquitination of HSP90, resulting in accelerated GC development in vitro and in vivo.
Conclusion: Our findings demonstrate that exosomal circSHKBP1 regulates the miR-582-3p/HUR/VEGF pathway, suppresses HSP90 degradation, and promotes GC progression. circSHKBP1 is a promising circulating biomarker for GC diagnosis and prognosis and an exceptional candidate for further therapeutic exploration.

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Keywords: CircSHKBP1; Exosome; Gastric cancer; HSP90; HUR; MiR-582-3p; VEGF

0 (Adaptor Proteins, Signal Transducing)
0 (Biomarkers, Tumor)
0 (ELAV-Like Protein 1)
0 (ELAVL1 protein, human)
0 (HSP90 Heat-Shock Proteins)
0 (MIRN582 microRNA, human)
0 (MicroRNAs)
0 (RNA, Circular)
0 (VEGFA protein, human)
0 (Vascular Endothelial Growth Factor A)

Date Created: 20200701 Date Completed: 20210217 Latest Revision: 20210217

20231215

PMC7322843

10.1186/s12943-020-01208-3

32600329