JAK3/STAT5 signaling-triggered upregulation of PIK3CD contributes to gastric carcinoma development

Gastric cancer (GC) is one of the most common solid cancers with high incidence and mortality worldwide. Chronic gastritis and consequent inflammatory microenvironment is known as a major cause leading to gastric carcinogenesis. Here we report that PIK3CD that encodes p110 delta, a catalytic subunit of the class IA PI3Ks, is overexpressed and tumorigenic in GC and associated with tumor inflammatory microenvironment. By investigating the data from TCGA database and our immunohistochemical staining and quantitative real-time PCR results from clinical samples, we found PIK3CD exhibits higher expression level in GC tissues compared with adjacent non-tumorous stomach tissues. Genetic silencing of PIK3CD in GC cells retards proliferation and migration in vitro and tumorigenicity and metastasis in vivo. In contrast, enhanced expression of PIK3CD promotes these phenotypes in vitro. Furthermore, pharmacological inhibition of PIK3CD could reduce GC cell viability and colony formation capacities. More importantly, we reveal a relevant mechanism that PIK3CD, but not PIK3CA and PIK3CB, is transcriptionally regulated by the pro-inflammatory IL2/JAK3/STAT5 axis and tumor-infiltrating immune cells such as lymphocytes. These observations may setup a new crosstalk between tumor inflammatory microenvironment, IL2/JAK3/STAT5 signaling and PI3K/AKT signaling. Targeting PIK3CD may be a promising therapy strategy for GC. The molecular mechanism diagram of contribution of PIK3CD in gastric cancer development. The pro-inflammatory IL2/JAK3/STAT5 axis upregulates PIK3CD expression by modulating PIK3CD transcription, then PI3K/Akt signaling is activated and promotes gastric carcinoma growth and migration. image