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-γ-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-γ. PML knockdown increased IFN-γ-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.