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

Abstract

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.

Establishment of a 5-gene risk model related to regulatory T cells for predicting gastric cancer prognosis

“…Prognostic biomarkers refer to biomarkers related to prognosis of cancer patients, and they can be gene expression (mRNA), protein content or small molecular metabolites [ 28 ]. As prognostic markers can be independent to determine the prognosis of patients and assist the diagnosis and treatment of cancer in clinical practice, searching for prognostic markers related to cancer prognosis has become a hot research topic [ 29 – 31 ]. Many experiments have been conducted to screen and explore prognostic markers of GC, among which the most famous one is PD-L1 gene.…”

Identification of Candidate Circular RNAs Underlying Intramuscular Fat Content in the Donkey

“…Previous studies have demonstrated that circRNAs are a large class of widespread and diverse endogenous RNAs in animals that play critical roles in many physiological and pathological processes, including fat (Jiang et al, 2020), muscle (Zhang P. et al, 2019), and cancer (Xie et al, 2020) development. For example, Jiang et al (2020) characterized the expression profile of circRNA in fat tissue during developmental stages of the calf and adult cow and demonstrated that the circFUT10 regulates adipocyte cell proliferation and differentiation by sponging the miRNA let-7c (Jiang et al, 2020).…”

Circular RNAs: Emerging Role in Cancer Diagnostics and Therapeutics

“…It promotes GC tumorigenesis by regulating the miR-140-3p/YY1 signaling axis (Zhang L. et al, 2020). CircSHKBP1 was overexpressed in tumors and serum exosomes of GC patients, and it correlated with advanced pathological staging and poor OS (Xie M. et al, 2020). CircSHKBP1 promotes GC progression by sponging miR-582-3p to increase HuR levels and promoting VEGF stability, and also by binding HSP90 to prevent its interaction with STUB1 (Xie M. et al, 2020).…”