Loss of miR-26b-5p promotes gastric cancer progression via miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop

• Published in: Journal of translational medicine Vol. 21; no. 1; pp. 77 - 17
• Main Authors: Xu, Tingting, Xie, Mengyan, Jing, Xinming, Jiang, Huning, Wu, Xi, Wang, Xinzhu, Shu, Yongqian
• Format: Journal Article
• Language: English
• Published: London BioMed Central 03.02.2023; BioMed Central Ltd; BMC
• Subjects: Animals; Antibodies; Bacteria; Biomedical and Life Sciences; Biomedicine; Cell cycle; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Cyclic Nucleotide Phosphodiesterases, Type 4 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Cyclin-Dependent Kinase 8 - genetics; Cyclin-Dependent Kinase 8 - metabolism; Development and progression; Epithelium; Feedback; Flow cytometry; Gastric cancer; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; Health aspects; Humans; Immunofluorescence; Immunohistochemistry; Infections; Inflammation; Kinases; Liver cancer; Medical prognosis; Medicine/Public Health; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miR-26b-5p; Molecular modelling; Nuclear transport; Phosphorylation; Proteins; Risk factors; Signal transduction; STAT3; Stat3 protein; STAT3 Transcription Factor - metabolism; Stomach cancer; Stomach Neoplasms - pathology; Therapeutic targets; Translational Signaling and System Biology; Xenografts; China; Inflammation; Gastric cancer; miR-26b-5p; STAT3
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-023-03933-x

Background Chronic inflammation is a well-known risk factor for the development of gastric cancer (GC). Nevertheless, the molecular mechanisms underlying inflammation-related GC progression are incompletely defined. Methods Bioinformatic analysis was performed based on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and the expression of miR-26b-5p in GC cells and tissues was validated by quantitative real-time PCR (qRT-PCR). Cell proliferation was examined through Cell Counting Kit-8 (CCK8), 5-Ethynyl-2’-deoxyuridine (EdU), colony formation, flow cytometry, and tumor xenografts. Correlation between miR-26b-5p and Cyclin dependent kinase 8 (CDK8) or Phosphodiesterase 4B (PDE4B) was analyzed by dual-luciferase reporter assays, qRT-PCR, and Western blot. The effect of miR-26b-5p on the Signal transducer and activator of transcription 3 (STAT3) pathway was investigated using Western blot, immunofluorescence (IF), and immunohistochemistry (IHC). The impact of STAT3 on miR-26b-5p was determined by dual-luciferase reporter assays and qRT-PCR. Results The expression of miR-26b-5p was significantly downregulated in Helicobacter Pylori (H. pylori )-infected GC cells. The decreased expression of miR-26b-5p was also detected in GC cells and tissues compared to normal gastric epithelium cells (GES1) and normal adjacent gastric tissues. The low expression of miR-26b-5p promoted GC proliferation in vitro and in vivo and was related to the poor outcome of GC patients. In terms of mechanism, miR-26b-5p directly targeted PDE4B and CDK8, resulting in decreased phosphorylation and nuclear translocation of STAT3, which was associated with the regulation of GC proliferation by miR-26b-5p. Notably, miR-26b-5p was transcriptionally suppressed by STAT3, thus forming the miR-26b-5p-PDE4B/CDK8-STAT3 positive feedback loop. Conclusion The newly identified miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop plays an important role in inflammation-related GC progression and may serve as a promising therapeutic target for GC.