Clinical laboratory, Shenzhen Children's Hospital, No. 7019, Yitian Road, Shenzhen, Guangdong, 518038, People's Republic of China.
Division of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, Guangdong, 518038, People's Republic of China.
BMC Cancer. 2019 Jul 10;19(1):679. doi: 10.1186/s12885-019-5898-4.
Although the prognosis of chronic myeloid leukemia (CML) has dramatically improved, the pathogenesis of CML remains elusive. Studies have shown that sustained phosphorylation of AKT1 plays a crucial role in the proliferation of CML cells. Evidence indicates that in tongue cancer cells, FAM168A, also known as tongue cancer resistance-associated protein (TCRP1), can directly bind to AKT1 and regulate AKT1/NFκB signaling pathways. This study aimed to investigate the role of FAM168A in regulation of AKT1/NFκB signaling pathway and cell cycle in CML.
FAM168A interference was performed, and the expression and phosphorylation of FAM168A downstream proteins were measured in K562 CML cell line. The possible roles of FAM168A in the proliferation of CML cells were investigated using in vitro cell culture, in vivo animal models and clinical specimens.
We found that the expression of FAM168A significantly increased in the peripheral blood mononuclear cells of CML patients, compared with normal healthy controls. FAM168A interference did not change AKT1 protein expression, but significantly decreased AKT1 phosphorylation, significantly increased IκB-α protein level, and significantly reduced nuclear NFκB protein level. Moreover, there was a significant increase of G2/M phase cells and Cyclin B1 level. Immunoprecipitation results showed that FAM168A interacts with breakpoint cluster region (BCR) -Abelson murine leukemia (ABL1) fusion protein and AKT1, respectively. Animal experiments confirmed that FAM168A interference prolonged the survival and reduced the tumor formation in mice inoculated with K562 cells. The results of clinical specimens showed that FAM168A expression and AKT1 phosphorylation were significantly elevated in CML patients.
This study demonstrates that FAM168A may act as a linker protein that binds to BCR-ABL1 and AKT1, which further mediates the downstream signaling pathways in CML. Our findings demonstrate that FAM168A may be involved in the regulation of AKT1/NFκB signaling pathway and cell cycle in CML.
虽然慢性髓性白血病（CML）的预后有了显著改善，但 CML 的发病机制仍不清楚。研究表明，AKT1 的持续磷酸化在 CML 细胞的增殖中起着关键作用。有证据表明，在舌癌细胞中，FAM168A，也称为舌癌耐药相关蛋白（TCRP1），可以直接与 AKT1 结合并调节 AKT1/NFκB 信号通路。本研究旨在探讨 FAM168A 在调节 CML 中 AKT1/NFκB 信号通路和细胞周期中的作用。
在 K562 CML 细胞系中进行 FAM168A 干扰，检测 FAM168A 下游蛋白的表达和磷酸化。通过体外细胞培养、体内动物模型和临床标本研究 FAM168A 对 CML 细胞增殖的可能作用。
我们发现 CML 患者外周血单个核细胞中 FAM168A 的表达明显高于正常健康对照者。FAM168A 干扰不改变 AKT1 蛋白表达，但明显降低 AKT1 磷酸化，明显增加 IκB-α 蛋白水平，明显降低核 NFκB 蛋白水平。此外，G2/M 期细胞和 Cyclin B1 水平明显增加。免疫沉淀结果表明，FAM168A 分别与断点簇区（BCR）-Abelson 鼠白血病（ABL1）融合蛋白和 AKT1 相互作用。动物实验证实，FAM168A 干扰可延长接种 K562 细胞的小鼠的存活时间并减少肿瘤形成。临床标本结果表明，CML 患者中 FAM168A 表达和 AKT1 磷酸化明显升高。
本研究表明，FAM168A 可能作为一种连接蛋白，与 BCR-ABL1 和 AKT1 结合，进一步介导 CML 中的下游信号通路。我们的研究结果表明，FAM168A 可能参与 CML 中 AKT1/NFκB 信号通路和细胞周期的调节。
