Guangdong Key Laboratory for Genome Stability & Disease Prevention and Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, 518060, People's Republic of China.
Department of Medicine/GI Division, Johns Hopkins University School of Medicine and Sidney Ki-mmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA.
Cell Death Dis. 2020 Oct 30;11(10):937. doi: 10.1038/s41419-020-03130-4.
Gastric cancer (GC) is the most common cancer throughout the world. Despite advances of the treatments, detailed oncogenic mechanisms are largely unknown. In our previous study, we investigated microRNA (miR) expression profiles in human GC using miR microarrays. We found miR-192/215 were upregulated in GC tissues. Then gene microarray was implemented to discover the targets of miR-192/215. We compared the expression profile of BGC823 cells transfected with miR-192/215 inhibitors, and HFE145 cells transfected with miR-192/-215 mimics, respectively. SET8 was identified as a proposed target based on the expression change of more than twofold. SET8 belongs to the SET domain-containing methyltransferase family and specifically catalyzes monomethylation of H4K20me. It is involved in diverse functions in tumorigenesis and metastasis. Therefore, we focused on the contributions of miR-192/215/SET8 axis to the development of GC. In this study, we observe that functionally, SET8 regulated by miR-192/215 is involved in GC-related biological activities. SET8 is also found to trigger oncogene-induced senescence (OIS) in GC in vivo and in vitro, which is dependent on the DDR (DNA damage response) and p53. Our findings reveal that SET8 functions as a negative regulator of metastasis via the OIS-signaling pathway. Taken together, we investigated the functional significance, molecular mechanisms, and clinical impact of miR-192/215/SET8/p53 in GC.
胃癌（GC）是全世界最常见的癌症。尽管治疗方法有所进步，但详细的致癌机制在很大程度上仍不清楚。在我们之前的研究中，我们使用miRNA 微阵列研究了人类 GC 中的 miRNA 表达谱。我们发现 miR-192/215 在 GC 组织中上调。然后进行基因微阵列以发现 miR-192/215 的靶标。我们比较了转染 miR-192/215 抑制剂的 BGC823 细胞和转染 miR-192/-215 模拟物的 HFE145 细胞的表达谱。根据两倍以上的表达变化，SET8 被确定为一个假定的靶标。SET8 属于 SET 结构域包含的甲基转移酶家族，特异性催化 H4K20me 的单甲基化。它参与肿瘤发生和转移中的多种功能。因此，我们专注于 miR-192/215/SET8 轴对 GC 发展的贡献。在这项研究中，我们观察到功能上，受 miR-192/215 调节的 SET8 参与了与 GC 相关的生物学活性。还发现 SET8 在体内和体外触发 GC 中的癌基因诱导的衰老（OIS），这依赖于 DDR（DNA 损伤反应）和 p53。我们的发现表明，SET8 通过 OIS 信号通路作为转移的负调节剂发挥作用。总之，我们研究了 miR-192/215/SET8/p53 在 GC 中的功能意义、分子机制和临床影响。
