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-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.

胃癌是全球癌症相关死亡的最常见原因之一。肿瘤抑制因子早幼粒细胞白血病（PML）蛋白在胃癌中的表达降低或缺失，这与淋巴侵袭程度增加、更高的pTNM分期发展以及不良预后相关。在此，我们研究了晚期胃癌中肿瘤浸润淋巴细胞的程度与PML蛋白表达状态之间的关系。我们观察到，与PML阳性组织相比，在PML表达降低或缺失的胃癌组织中浸润的T细胞数量更多。在体外，从干扰素 - γ（IFN - γ）刺激的胃癌细胞系获得的培养上清液对T细胞迁移的影响程度也受PML表达的影响。在PML水平降低的胃癌组织中，干扰素 - γ诱导蛋白10（IP - 10 / CXCL10）的表达增加。此外，在存在IFN - γ的情况下，Pml基因敲除和基因敲低细胞均显示出IP - 10 mRNA和蛋白表达增强。PML基因敲低增加了IFN - γ介导的信号转导和转录激活因子 - 1（STAT - 1）与IP - 10启动子的结合，导致IP - 10基因转录升高。相反，PML IV蛋白表达抑制了IP - 10启动子的激活。基于这些结果，我们提出胃癌细胞中PML蛋白表达的缺失通过增强STAT - 1活性促进IP - 10转录，进而促进肿瘤区域内的淋巴细胞迁移。