Loss of the Promyelocytic Leukemia Protein in Gastric Cancer: Implications for IP-10 Expression and Tumor-Infiltrating Lymphocytes

Gastric cancer is one of the most common causes of cancer-related mortality worldwide. Expression of the tumor suppressor, promyelocytic leukemia (PML) protein, is reduced or abolished in gastric carcinomas, in association with an increased level of lymphatic invasion, development of higher pTNM staging, and unfavorable prognosis. Herein, we investigated the relationship between the extent of tumor-infiltrating lymphocytes and the status of PML protein expression in advanced gastric carcinoma. We observed higher numbers of infiltrating T-cells in gastric carcinoma tissues in which PML expression was reduced or abolished, compared to tissues positive for PML. The extent of T-cell migration toward culture supernatants obtained from interferon-gamma (IFN-gamma-stimulated gastric carcinoma cell lines was additionally affected by expression of PML in vitro. Interferon-gamma-inducible protein 10 (IP-10/CXCL10) expression was increased in gastric carcinoma tissues displaying reduced PML levels. Moreover, both Pml knockout and knockdown cells displayed enhanced IP-10 mRNA and protein expression in the presence of IFN-gamma. PML knockdown increased IFN-gamma-mediated Signal Transducer and Activator of Transcription-1 (STAT-1) binding to the IP-10 promoter, resulting in elevated transcription of the IP-10 gene. Conversely, PML IV protein expression suppressed IP-10 promoter activation. Based on these results, we propose that loss of PML protein expression in gastric cancer cells contributes to increased IP-10 transcription via enhancement of STAT-1 activity, which, in turn, promotes lymphocyte trafficking within tumor regions.