Center for Gastric Cancer, National Cancer Center, Gyeonggi, Republic of Korea.
Int J Cancer. 2015 Feb 15;136(4):810-20. doi: 10.1002/ijc.29056. Epub 2014 Jul 7.
The importance of PPARγ (peroxisome proliferator-activated receptor γ) in gastric cancer (GC) is unclear. We investigated the role of PPARγ in GC cell lines and an animal model, and its prognostic significance of PPARγ in GC patients. We controlled PPARγ and galectin-9 expression by using siRNAs and lentiviral constructs. Interaction between PPARγ and galectin-9 was evaluated using luciferase and chromatin immunoprecipitation assays. PPARγ expression in GCs was determined by immunohistochemical staining of tissue microarrays and survival analysis was done. Overexpression of PPARγ was accompanied by increased galectin-9. Enhanced PPARγ or galectin-9 expression increased E-cadherin expression; decreased expression of N-cadherin, fibronectin, snail, twist and slug and reduced cell invasion and migration. PPARγ bound to the galectin-9 promoter region. Galectin-9 activity increased in PPARγ-overexpressing cells but decreased in PPARγ siRNA-treated cells. In a zebrafish xenograft model, the number of migrated cancer cells and number of fish with AGS cells in the tail vein were reduced in PPARγ-overexpressing GC cells. PPARγ was expressed in 462 of the 688 patients (69.2%) with GC. In 306 patients with intestinal-type GC, those with PPARγ-positive tumors had lower overall and cancer-specific mortalities than those with PPARγ-negative tumors. PPARγ expression was an independent prognostic factor for overall and GC-specific mortality in patients with intestinal-type GC (adjusted hazard ratio, 0.42; 95% CI, 0.22-0.81). PPARγ inhibits cell invasion, migration and epithelial-mesenchymal transition through upregulation of galectin-9 in vitro and in vivo.
过氧化物酶体增殖物激活受体 γ（PPARγ）在胃癌（GC）中的作用尚不清楚。我们研究了 PPARγ 在 GC 细胞系和动物模型中的作用及其在 GC 患者中的预后意义。我们使用 siRNA 和慢病毒构建体来控制 PPARγ 和半乳糖凝集素-9 的表达。使用荧光素酶和染色质免疫沉淀测定评估 PPARγ 和半乳糖凝集素-9 之间的相互作用。通过组织微阵列的免疫组织化学染色确定 GC 中的 PPARγ 表达，并进行生存分析。PPARγ 的过表达伴随着半乳糖凝集素-9 的增加。增强的 PPARγ 或半乳糖凝集素-9 表达增加了 E-钙黏蛋白的表达；减少了 N-钙黏蛋白、纤维连接蛋白、蜗牛、twist 和 slug 的表达，并减少了细胞侵袭和迁移。PPARγ 与半乳糖凝集素-9 启动子区域结合。在过表达 PPARγ 的细胞中，半乳糖凝集素-9 的活性增加，但在 PPARγ siRNA 处理的细胞中则减少。在斑马鱼异种移植模型中，过表达 PPARγ 的 GC 细胞中迁移的癌细胞数量和尾部静脉中 AGS 细胞的鱼数减少。在 688 例 GC 患者中，有 462 例（69.2%）表达 PPARγ。在 306 例肠型 GC 患者中，PPARγ 阳性肿瘤患者的总生存率和癌症特异性死亡率均低于 PPARγ 阴性肿瘤患者。PPARγ 表达是肠型 GC 患者总生存率和 GC 特异性死亡率的独立预后因素（调整后的危险比，0.42；95%CI，0.22-0.81）。PPARγ 通过体外和体内上调半乳糖凝集素-9 抑制细胞侵袭、迁移和上皮-间充质转化。
