Interrogation of gender disparity uncovers androgen receptor as the transcriptional activator for oncogenic miR-125b in gastric cancer.
Ben LiuMeng ZhouXiangchun LiXining ZhangQinghua WangLuyang LiuMeng YangDa YangYan GuoQiang ZhangHong ZhengQiong WangLian LiXinlei ChuWei WangHaixin LiFengju SongYuan PanWei ZhangKe-Xin ChenPublished in: Cell death & disease (2021)
There is a male preponderance in gastric cancer (GC), which suggests a role of androgen and androgen receptor (AR). However, the mechanism of AR signaling in GC especially in female patients remains obscure. We sought to identify the AR signaling pathway that might be related to prognosis and examine the potential clinical utility of the AR antagonist for treatment. Deep learning and gene set enrichment analysis was used to identify potential critical factors associated with gender bias in GC (n = 1390). Gene expression profile analysis was performed to screen differentially expressed genes associated with AR expression in the Tianjin discovery set (n = 90) and TCGA validation set (n = 341). Predictors of survival were identified via lasso regression analyses and validated in the expanded Tianjin cohort (n = 373). In vitro and in vivo experiments were established to determine the drug effect. The GC gender bias was attributable to sex chromosome abnormalities and AR signaling dysregulation. The candidates for AR-related gene sets were screened, and AR combined with miR-125b was associated with poor prognosis, particularly among female patients. AR was confirmed to directly regulate miR-125b expression. AR-miR-125b signaling pathway inhibited apoptosis and promoted proliferation. AR antagonist, bicalutamide, exerted anti-tumor activities and induced apoptosis both in vitro and in vivo, using GC cell lines and female patient-derived xenograft (PDX) model. We have shed light on gender differences by revealing a hormone-regulated oncogenic signaling pathway in GC. Our preclinical studies suggest that AR is a potential therapeutic target for this deadly cancer type, especially in female patients.
Keyphrases
- poor prognosis
- signaling pathway
- end stage renal disease
- induced apoptosis
- newly diagnosed
- ejection fraction
- deep learning
- chronic kidney disease
- endoplasmic reticulum stress
- transcription factor
- mental health
- prognostic factors
- long non coding rna
- oxidative stress
- genome wide
- epithelial mesenchymal transition
- emergency department
- small molecule
- high throughput
- machine learning
- squamous cell carcinoma
- young adults
- risk assessment
- inflammatory response
- gas chromatography
- climate change
- heat shock
- electronic health record
- high resolution
- human health
- convolutional neural network
- nuclear factor
- simultaneous determination
- smoking cessation
- tandem mass spectrometry
- replacement therapy