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目的研究过氧化物酶体增殖物激活受体γ(PPARγ)的激动剂罗格列酮(ROS)联用全反式维甲酸(ATRA)对人胃低分化黏液癌MGC-803细胞的裸鼠移植瘤血管生成的影响,并初步探讨其抗血管生成的可能机制。方法建立胃癌裸鼠移植瘤模型,荷瘤裸鼠随机分为荷瘤未用药组、ROS组(ROS 25 mg·kg~(-1)·2d~(-1))、ATRA联用ROS低剂量组(ROS 18 mg+ATRA 11 mg·kg~(-1)·2d~(-1))、中剂量组(ROS 30 mg+ATRA 11mg·kg~(-1)·2d~(-1))、高剂量组(ROS 50 mg+ATRA 11mg·kg~(-1)·2d~(-1))。用药40d后,观察各组裸鼠移植瘤体积变化及抑瘤率；利用免疫组化观察移植瘤中血管内皮生长因子(VEGF)的表达,对移植瘤中的微血管密度(MVD)进行计数,同时用RT-PCR技术观察VEGF及缺氧诱导因子-1α(HIF-1α)的表达。结果①ROS组能缩小瘤体体积,其与荷瘤未用药组比较差异有统计学意义(P＜0．01),ATRA联用ROS低剂量,与ROS组抑瘤率相当(P＞0．05),随着ROS剂量增加,抑瘤率增加,呈剂量依赖关系；②ROS组能抑制肿瘤新生血管生成,降低VEGF、HIF-1αmRNA的表达；ROS与ATRA联用,随着ROS剂量增加,抑制肿瘤新生血管生成、降低VEGF、HIF-1αmRNA的表达更明显(P＜0．05)。结论25mg·kg~(-1)·2d~(-1)ROS有一定抑瘤效果,ATRA与ROS联用可发挥协同抗肿瘤作用,其机制可能是通过蛋白酪氨酸磷酸酶基因(PTEN)途径抑制肿瘤血管生成,从而抑制肿瘤的生长。
Objective To investigate the effect of rosiglitazone (ROS), an agonist of peroxisome proliferator - activated receptor γ (PPARγ), on the proliferation of human gastric mucosa carcinoma MGC-803 cells with ATRA Xenograft tumor angiogenesis and to explore its possible mechanism of anti-angiogenesis. Methods The nude mice model of gastric cancer was established. The tumor-bearing nude mice were randomly divided into the tumor-bearing untreated group and ROS group (ROS 25 mg · kg -1 · 2 d -1). ATRA combined with low dose ROS Group (ROS 18 mg + ATRA 11 mg · kg -1 · 2 d -1) and middle dose group (ROS 30 mg + ATRA 11 mg · kg -1 · 2 d -1) , High dose group (ROS 50 mg + ATRA 11 mg · kg -1 · 2 d -1). After 40 days of treatment, the changes of tumor volume and tumor inhibition rate were observed in nude mice. The expression of vascular endothelial growth factor (VEGF) in the transplanted tumor was observed by immunohistochemistry, and the microvessel density (MVD) in the transplanted tumor was counted. The expression of VEGF and hypoxia-inducible factor-1α (HIF-1α) were observed by RT-PCR. Results (1) ROS decreased the volume of the tumor, which was significantly different from that of the untreated group (P <0.01). ATRA combined with low dose of ROS showed comparable inhibition rate with ROS (P> 0.05 ). With the increase of ROS dose, the tumor inhibition rate increased in a dose-dependent manner. ②ROS group could inhibit tumor angiogenesis and reduce the expression of VEGF and HIF-1αmRNA; ROS combined with ATRA, with the increase of ROS dose, Neovascularization reduced VEGF expression of HIF-1αmRNA (P <0.05). Conclusions 25 mg · kg -1 · · 2 d -1 ROS have antitumor effects. ATRA combined with ROS can exert a synergistic anti-tumor effect. The mechanism may be that protein tyrosine phosphatase (PTEN) Pathways inhibit tumor angiogenesis, thereby inhibiting tumor growth.