EZH2在人脂肪肉瘤的表达情况及EZH2抑制剂抗人脂肪肉瘤效果及机制研究

摘要 目的：探索组蛋白H3K27me3甲基转移酶EZH2在人脂肪瘤、高分化脂肪肉瘤和去分化脂肪肉瘤的表达情况及EZH2酶活性小分子抑制剂GSK126对人脂肪肉瘤细胞系SW872的影响,并初步探索其可能机制。方法：筛选脂肪瘤、高分化脂肪肉瘤和去分化脂肪肉瘤患者术后活检标本共计23例,其中脂肪瘤7例,高分化脂肪肉瘤9例,去分化脂肪肉瘤7例,制成组织芯片,免疫组化染色检测EZH2的蛋白表达情况。体外培养SW872 脂肪肉瘤细胞系,采用CCK-8 法检测不同浓度GSK126对细胞生存的抑制作用,流式细胞技术检测细胞凋亡情况,Realtime PCR法检测细胞的凋亡与抗凋亡（Caspase-1、Caspase-3、Caspase-7、Caspase-9、Bcl-2、Bag-3）、血管生成（VEGF-α）、干性（CD133、CD44、CD24）相关基因的表达,Western blot 检测内质网应激相关蛋白Bip和ATF4蛋白的表达量。结果：EZH2在去分化脂肪肉瘤的表达高于高分化脂肪肉瘤,在良性脂肪瘤中的阳性表达少见（均P＜0.05）。EZH2酶活性抑制剂GSK126对SW872 细胞的存活有明显的抑制作用,给药后细胞凋亡率增加（P＜0.05）,凋亡相关基因Caspase-1、Caspase-3、Caspase-7、Caspase-9均表达增强（均P＜0.05）,血管生成基因VEGF-?琢表达降低（P＜0.01）,干性基因CD133表达降低（P＜0.01）,其余基因表达无明显差别。GSK126组的内质网应激相关蛋白Bip和ATF4蛋白的表达增加。结论：EZH2蛋白表达量与脂肪肉瘤细胞分化程度呈负相关,EZH2有望成为脂肪肉瘤的生物学标志物及恶性程度标志物。EZH2抑制剂可能成为脂肪肉瘤潜在的化疗药物,可能通过增强内质网应激发挥作用。     

Clinico-molecular study of dedifferentiation in well-differentiated liposarcoma

Well-differentiated liposarcoma (WD) acquires fully malignant potential when the histological progression named dedifferentiation occurs. This progression is supposed to occur in a time-dependent manner but this is still a debated issue. Clinically, the prediction of dedifferentiation for WD is very important from the therapeutic point of view. To identify genes that are predictive of dedifferentiation and to understand the mechanism of dedifferentiation, we investigated clinical information of 50 cases and studied the gene expression profiles of 36 lipomatous tumors using cDNA microarray. The clinical study showed that the dedifferentiation did not always seem to occur in a time-dependent manner. Interestingly, from the gene expression study, unsupervised hierarchical clustering analysis of well-differentiated lesions obtained from dedifferentiated liposarcoma (DD) cases that were indistinguishable from WD pathologically showed a clearly distinct gene expression pattern from WD. Using the pattern-matching program, 1687 genes including 487 known genes were identified, which discriminated WD cases from well-differentiated lipomatous lesions obtained from DD cases. These results suggest that the dedifferentiation may arise from different types of WD that could be distinguished from gene expression profiling but could hardly be classified by the pathological studies.     

CT和MRI鉴定腹膜后间隙脂肪肉瘤与组织病理学特征相关

本研究选取2012年1月至2018年1月在我院治疗的腹膜后间隙脂肪肉瘤患者33例,分析患者术前CT、MRI图像及术后病理结果,旨在探讨不同类型腹膜后间隙脂肪肉瘤病理学及影像学特征。研究结果表明:33例患者中术后病理诊断为高分化脂肪肉瘤19例,去分化脂肪肉瘤7例,黏液性脂肪肉瘤7例;不同病理分型脂肪肉瘤病灶大小比较差异无统计学意义(p>0.05);高分化脂肪肉瘤其CT密度同皮下脂肪,CT值-10～-110 Hu,肿瘤内可见不规则增厚的间隔;去分化脂肪肉瘤部分区域呈脂肪密度(CT值-70～30 Hu),部分区域呈软组织肿块(CT值为30～50 Hu);黏液性脂肪肉瘤CT密度接近水,增强扫描时肿块呈网状、片状、延迟强化,CT值20～40 Hu;高分化脂肪肉瘤MRI信号同皮下脂肪;黏液性脂肪肉瘤MRI呈长T1,长T2信号,与水相似;CT和MRI诊断腹膜后间隙脂肪瘤准确率分别为69.70%和73.33%,差异比较无统计学意义(p>0.05)。本研究得出初步结论,不同病理类型腹膜后间隙脂肪肉瘤的CT、MRI表现有所差异;CT和MRI术前诊断腹膜后间隙脂肪肉瘤准确性相似。