A miR-567-PIK3AP1-PI3K/AKT-c-Myc feedback loop regulates tumour growth and chemoresistance in gastric cancer

• Published in: EBioMedicine 2019-06, Vol.44, p.311-321
• Main Authors: Zhang, Feifei, Li, Kaitao, Yao, Xueqing, Wang, Hui, Li, Weidong, Wu, Juan, Li, Mingyi, Zhou, Rui, Xu, Lijun, Zhao, Liang
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Animals; Carcinogenesis - genetics; Carcinogenesis - metabolism; Cell Line, Tumor; Cell Proliferation; Chemoresistance; Drug Resistance, Neoplasm - genetics; Fluorouracil - pharmacology; Gastric cancer; Gene Expression Regulation, Neoplastic; Humans; microRNA-567; MicroRNAs - genetics; Models, Biological; Oxaliplatin - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Prognostic biomarker; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-myc - metabolism; Research paper; RNA Interference; Signal Transduction; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Tumour growth
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2019.05.003

Gastric cancer (GC) ranks the fifth most common cancer, and chemotherapy is one of the most common treatments for GC. However, chemoresistance limits the effectiveness of chemotherapy and leads to treatment failure. This study aims to investigate the biological effect of miR-567 on gastric tumourigenesis and chemoresistance and reveal the possible mechanism. We measured the expression of miR-567 in 37 paired normal and stomach tumour specimens, as well as GC cell lines by Real-time PCR. The functional effects of miR-567 were validated using in vitro and in vivo assays. Dual-luciferase report assays and Chromatin immunoprecipitation (ChIP) assay were conducted for target evaluation, western blot assay was used to confirm the relationships. Our data showed that miR-567 was downregulated in gastric tissues and gastric cancer cells compared with normal tissues and gastric epithelial cells. In vitro, Gain- and lose-of-function assays showed miR-567 not only weakened cells proliferative ability, but also sensitized GC cells to 5-FU and oxaliplatin. In vivo, miR-567 overexpression significantly repressed the tumourigenesis of GC cells compared with the vector control. Mechanistic analysis showed that PIK3AP1 activated AKT phosphorylation in GC. Meanwhile, miR-567 directly targeted PIK3AP1 to inactivate PI3K/AKT/c-Myc pathway and c-Myc inversely regulated miR-567 expression, thus forming a miR-567-PIK3AP1- PI3K/AKT-c-Myc feedback loop explaining the function of miR-567. Our studies revealed that miR-567 acts as a tumour suppressor gene and suppresses GC tumorigenesis and chemoresistance via a miR-567-PIK3AP1- PI3K/AKT-c-Myc feedback loop. These results suggest that miR-567 may serve as a target for chemoresistance and a potential prognostic biomarker for GC. •miR-567 sensitized GC cells to 5-FU and oxaliplatin, suggesting that it can be a target for chemoresistance.•miR-567 functions as a suppressor in GC progression and may serve as a novel prognostic and therapeutic biomarker for GC.•miR-567 directly targeted PIK3AP1 to inactivate PI3K/AKT/c-Myc and regulated its own expression.•These findings uncover a plausible mechanism for AKT/PI3K signalling activation in cancer progression.