Author:
Duan Yantao,Kong Pengfei,Huang Mingzhu,Yan Yonghao,Dou Yi,Huang Binhao,Guo Jing,Kang Wei,Zhu Caixia,Wang Yuyan,Zhou Donglei,Cai Qiliang,Xu Dazhi
Abstract
Abstract
Background
Helicobacter pylori (H pylori) infection is the primary cause of gastric cancer (GC). The role of Disabled-2 (DAB2) in GC remains largely unclear. This study aimed to investigate the role of DAB2 in H pylori-mediated gastric tumorigenesis.
Methods
We screened various datasets of GC to analyze DAB2 expression and cell signaling pathways. DAB2 expression was assessed in human GC tissue microarrays. H pylori infection in vivo and in vitro models were further explored. Immunostaining, immunofluorescence, chromatin immunoprecipitation, co-immunoprecipitation, Western blot, quantitative polymerase chain reaction, and luciferase reporter assays were performed in the current study.
Results
The bioinformatic analysis verified that DAB2 was 1 of the 8 genes contributed to tumorigenesis and associated with poor prognosis in GC. The median overall survival and disease-free survival rates in DAB2high group were significantly less than those in DAB2low group. These findings demonstrated that H pylori transcriptionally activated DAB2 expression via signal transducer and activator of transcription 3 (STAT3)-dependent pathway. By bioinformatics analysis and knockdown or overexpression of DAB2, we found that DAB2 upregulated Yes-associated protein 1 (YAP1) transcriptional activity. Mechanistically, DAB2 served as a scaffold protein for integrin beta 3 (ITGB3) and SRC proto-oncogene non-receptor tyrosine kinase (SRC), facilitated the phosphorylation of SRC, promoted the small GTPase ras homolog family member A (RHOA) activation and phosphorylation of YAP1, and ultimately enhanced the YAP1 transcriptional activity.
Conclusions
Altogether, these findings indicated that DAB2 is a key mediator in STAT3–regulated translation of YAP1 and plays crucial roles in H pylori-mediated GC development. DAB2 might serve as a novel therapeutic target for GC.
Publisher
Springer Science and Business Media LLC