Jiang Zheng, Li Xingang, Hu Jin, Zhou Wei, Jiang Yuquan, Li Gang, Lu Daru
Laboratory of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.
Neurosci Res. 2006 Dec;56(4):450-8. doi: 10.1016/j.neures.2006.09.006. Epub 2006 Oct 17.
LATS1 and LATS2 are tumor suppressor genes implicated in the regulation of cell cycle, but their methylation statuses are still unknown in human astrocytoma. Here, we found that the promoter hypermethylation frequencies of LATS1 and LATS1 were 63.66% (56/88) and 71.5% (63/88) in 88 astrocytomas by methylation-specific PCR. But no methylation of LATS1 and LATS2 promoter was detected in the 10 normal brain tissues. There was an increased methylation frequency of LATS1 and LATS2 with the malignant development of astrcytoma. By real-time PCR, the mRNA expression of LATS1 or LATS2 was detected significantly decreased in different pathological grade astrocytomas (P<0.05). And the mRNA levels of LATS1 and LATS2 in astrocytomas with hypermethylation were both significantly (P<0.01) lower than those without methylation. The methylation of LATS1 and LATS2 was detected in U251 and SHG-44 cell lines, and 5-aza-deoxycytidine could restore their expression to induce cell apoptosis. Our results suggested that LATS1 and LATS2 mRNA was down-regulated in astrocytoma by hypermethylation of the promoter. The methylation and mRNA expression of LATS1 and LATS2 may provide useful clues to the development of the diagnostic assays for astrocytoma. Our results also suggested that LATS1 and LATS2 may be a useful target for astrocytoma therapy.
LATS1和LATS2是参与细胞周期调控的肿瘤抑制基因，但它们在人类星形细胞瘤中的甲基化状态仍不清楚。在此，我们通过甲基化特异性PCR发现，在88例星形细胞瘤中，LATS1和LATS1的启动子高甲基化频率分别为63.66%（56/88）和71.5%（63/88）。但在10例正常脑组织中未检测到LATS1和LATS2启动子的甲基化。随着星形细胞瘤的恶性发展，LATS1和LATS2的甲基化频率增加。通过实时PCR检测发现，不同病理分级的星形细胞瘤中LATS1或LATS2的mRNA表达均显著降低（P<0.05）。而且，启动子发生高甲基化的星形细胞瘤中LATS1和LATS2的mRNA水平均显著低于未发生甲基化的肿瘤（P<0.01）。在U251和SHG-44细胞系中检测到LATS1和LATS2的甲基化，5-氮杂脱氧胞苷可恢复它们的表达以诱导细胞凋亡。我们的结果表明，LATS1和LATS2 mRNA在星形细胞瘤中因启动子高甲基化而下调。LATS1和LATS2的甲基化及mRNA表达可能为星形细胞瘤诊断检测方法的开发提供有用线索。我们的结果还表明，LATS1和LATS2可能是星形细胞瘤治疗的有用靶点。
