Circular RNA circVAPA promotes chemotherapy drug resistance in gastric cancer progression by regulating miR-125b-5p/STAT3 axis

Abstract

BACKGROUND Gastric cancer (GC) is a prevalent malignancy, leading to a high incidence of cancer-associated death. Cisplatin (DDP)-based chemotherapy is the principal therapy for clinical GC treatment, but DDP resistance is a severe clinical challenge and the mechanism remains poorly understood. Circular RNAs (circRNAs) have been identified to play crucial roles in modulating the chemoresistance of gastric cancer cells. AIM To explore the effect of circVAPA on chemotherapy resistance during GC progression. METHODS The effect of circVAPA on GC progression and chemotherapy resistance was analyzed by MTT assay, colony formation assay, Transwell assay, wound healing assay, and flow cytometry analysis in GC cells and DDP resistant GC cell lines, and tumorigenicity analysis in nude mice in vivo . The mechanism was investigated by luciferase reporter assay, quantitative real-time PCR, and Western blot analysis. RESULTS CircVAPA expression was up-regulated in clinical GC tissues compared with normal samples. CircVAPA depletion inhibited proliferation, migration, and invasion and increased apoptosis of GC cells. The expression of circVAPA, STAT3, and STAT3 downstream genes was elevated in DDP resistant SGC7901/DDP cell lines. CircVAPA knockdown attenuated the DDP resistance of GC cells. Mechanically, circVAPA was able to sponge miR-125b-5p, and miR-125b-5p could target STAT3 in the GC cells. MiR-125b-5p inhibitor reversed circVAPA depletion-enhanced inhibitory effect of DDP on GC cells, and STAT3 knockdown blocked circVAPA overexpression-induced proliferation of DDP-treated SGC7901/DDP cells. The depletion of STAT3 and miR-125b-5p inhibitor reversed circVAPA depletion-induced GC cell apoptosis. Functionally, circVAPA contributed to the tumor growth of SGC7901/DDP cells in vivo . CONCLUSION CircVAPA promotes chemotherapy resistance and malignant progression in GC by miR-125b-5p/STAT3 signaling. Our findings present novel insights into the mechanism by which circVAPA regulates chemotherapy resistance of GC cells. CircVAPA and miR-125b-5p may be considered as the potential targets for GC therapy.

Propofol induces ferroptosis and inhibits malignant phenotypes of gastric cancer cells by regulating miR-125b-5p/STAT3 axis

“…Previous studies have revealed that miRNAs participate in the development of gastric cancer[ 16 , 17 ]. Meanwhile, a recent study has shown that miR-125b-5p is a tumor suppressor and involved in the modulation of gastric cancer[ 18 ]. In addition, signal transducer and activator of transcription (STAT)3 has been identified as an oncogene in gastric cancer[ 19 - 21 ].…”

Construction of miRNA‐mRNA‐TF Regulatory Network for Diagnosis of Gastric Cancer

“…Different from miR-199a-3p and miR-199a-5p, the role of miR-125b-5p in the pathogenesis of GC is not fully understood, but the identification results at the cell level and tissue level indicate that miR-125b-5p is significantly upregulated during the development of GC [ 39 ]. In addition, in a study on drug resistance, it was found that STAT3 may be a potential target of miR-125b-5p, and the signaling cascades involved in the regulation of chemotherapy drug resistance in GC [ 40 ].…”

The Emerging Roles of Circular RNAs in the Chemoresistance of Gastrointestinal Cancer

“…CircVAPA was expressed at high levels in GC tissues, and its downregulation enhanced the susceptibility of chemoresistant GC cells to DDP (Deng et al, 2021). CircVAPA upregulated STAT3 by interacting with miR-125b-5p.…”

“…Thus, further functional and mechanistic studies are required to define the function of circ_0000338-miR-217/miR-485-3p feedback loops in CRC chemoresistance. Similarly, circ_0071589 expression was significantly elevated in DDP-resistant CRC tissues compared with sensitive tissues (Zhang W. et al, 2021). Circ_0071589 increased the expression of the oncogene kruppel-like factor 12 (KLF12) by interacting with miR-526b-3p.…”