CBX8 exhibits oncogenic properties and serves as a prognostic factor in hepatocellular carcinoma
CBX8 exhibits oncogenic properties and serves as a prognostic factor in hepatocellular carcinoma
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CBX8 具有致癌特性，可作为肝细胞癌的预后因素
DOI：
10.1038/s41419-018-1288-0
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发表时间：
2019-01-18
影响因子：
9
通讯作者：
He, Songqing
中科院分区：
文献类型：
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作者：
Tang, Bo;Tian, Yu;He, Songqing
Polycomb蛋白家族是一类在生理和病理过程中都起重要作用的蛋白，其家族成员Chromobox homolog 8 （CBX8）在多种肿瘤中调节细胞分化、衰老和细胞周期进程；然而，CBX8在肝细胞癌（HCC）中的作用和潜在机制很少报道。我们发现CBX8在临床HCC标本中的表达与患者生存率呈负相关。在HCC细胞中，我们发现CBX8的过度表达诱导了上皮-间质转化、侵袭性迁移和干细胞样特征，这些特征与小鼠肿瘤生长和转移增加有关。相反，CBX8沉默抑制具有高CBX8表达的HCC细胞的侵袭性表型。机制上，CBX8调节骨形态发生蛋白4 （BMP4）基因启动子中的H3K27me3， BMP4与BMP4的活性转录相关，从而激活Smads和丝裂原活化的蛋白激酶。BMP4表达逆转了CBX8沉默在抑制上皮-间质转化、干性和转移中的作用。我们的研究结果表明CBX8是HCC干细胞样和转移行为的关键驱动因素，并表征了其在调节BMP4表达中的作用。这些发现对靶向CBX8作为HCC预后和治疗的一种方法具有启示意义。
Polycomb group family is a class of proteins that have important roles in both physiological and pathological processes, and its family member Chromobox homolog 8 (CBX8) regulates cell differentiation, aging, and cell cycle progression in numerous carcinomas; however, the effects and underlying mechanisms of CBX8 in hepatocellular carcinoma (HCC) are rarely reported. We found that CBX8 expression in clinical HCC specimens correlates inversely with patient survival. In HCC cells, we found that enforced overexpression of CBX8 induces epithelial–mesenchymal transition, invasive migration, and stem cell-like traits, which are associated with increased tumor growth and metastasis in mice. Conversely, CBX8 silencing inhibits the aggressive phenotype of HCC cells that have high CBX8 expression. Mechanistically, CBX8 modulates H3K27me3 in the gene promoter of bone morphogenetic protein 4 (BMP4), which is associated with active BMP4 transcription and, consequently, the activation of Smads and mitogen-activated protein kinases. BMP4 expression reverses the effects of CBX8 silencing in inhibiting epithelial–mesenchymal transition, stemness, and metastasis. Our results establish CBX8 as a critical driver of HCC stem cell-like and metastatic behaviors and characterize its role in modulating BMP4 expression. These findings have implications for the targeting of CBX8 as an approach to HCC prognosis and treatment.