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Abstract
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.
Highlights
Gastric cancer is one of the most frequent causes of cancer-related deaths worldwide
It is known that tumor suppressor promyelocytic leukemia (PML) protein expression is reduced or abolished in gastric cancer, and that this is associated with more extensive lymphatic invasion, higher pTNM staging, and unfavorable prognosis, suggesting that PML loss is linked to carcinogenesis and gastric carcinoma progression [2]
Loss of PML protein is associated with increased infiltration of CD8+ T-cells into advanced gastric carcinoma tissue Immunohistochemical staining for PML and CD8 was performed to explore whether the extent of lymphocyte infiltration was associated with PML expression status in advanced gastric cancer
Summary
Gastric cancer is one of the most frequent causes of cancer-related deaths worldwide. Recent advances in genetics have facilitated the detection of events occurring during the course of gastric carcinogenesis, including activation of oncogenes, silencing of tumor suppressor genes, and mutation of genes involved in DNA repair [1]. Among these genetic events, it is known that tumor suppressor promyelocytic leukemia (PML) protein expression is reduced or abolished in gastric cancer, and that this is associated with more extensive lymphatic invasion, higher pTNM staging, and unfavorable prognosis, suggesting that PML loss is linked to carcinogenesis and gastric carcinoma progression [2]. In addition to reports focusing on the tumor suppressor role played by PML, several studies have confirmed that the protein acts as a transcriptional regulator, via association with the co-activator CREB-binding protein; co-repressors including HDAC, N-CoR, and mSin3A; and the transcription factors Nur, AP-1, myc, p53, and STAT-1a [10,11,12,13,14,15,16,17]
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