FAM122A supports the growth of hepatocellular carcinoma cells and its deletion enhances Doxorubicin-induced cytotoxicity
FAM122A supports the growth of hepatocellular carcinoma cells and its deletion enhances Doxorubicin-induced cytotoxicity
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FAM122A 支持肝细胞癌细胞的生长，其缺失增强了阿霉素诱导的细胞毒性。
DOI：
10.1016/j.yexcr.2019.111714
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发表时间：
2020-02-01
影响因子：
3.7
通讯作者：
Huang, Ying
中科院分区：
文献类型：
--
作者：
Zhou, Yong;Shi, Wen-Yang;Huang, Ying
FAM122A是一种在哺乳动物中高度保守的蛋白质，但到目前为止，其功能仍很不清楚。在本研究中，我们研究了FAM122A在肝细胞癌中的潜在作用。通过对来自RNA测序数据集的肝癌患者队列的分析，我们发现FAMI22A在肝癌患者中的表达水平显著上调。此外，与正常组织相比，部分肝细胞癌组织中也存在这种异常高表达的FAM122A蛋白。进一步，我们证明了CRISPR/Cas9介导的FAM122A基因敲除显著抑制了肝癌细胞的生长、克隆形成能力和异种移植，诱导了细胞周期停滞，并减少了增殖相关基因的表达。有趣的是，FAM122A缺失显著增强了多柔比星(Dox)的细胞毒性效应，多柔比星是一种用于肝癌患者标准化疗的药物。相反，FAM122A的过表达不仅促进了肝癌细胞的生长，而且抑制了Dox诱导的DNA损伤和细胞死亡。鉴于FAM122A以前被认为是PP2A的内源性抑制物，我们询问了FAM122A调节肝癌细胞生长是否与PP2A有关。结果表明，FAM122A对肝癌细胞的PP2A活性也有一定的调节作用，但PP2A抑制剂冈田酸对FAM122A缺失细胞生长和增殖的抑制作用不明显，提示FAM122A可能不依赖于对PP2A的调节作用而支持肝癌细胞的生长。总之，这些结果表明，FAM122A是维持肝癌细胞生长所必需的，它的消除与化疗相结合可能为肝癌患者提供一种潜在的新的治疗策略。
FAM122A is a highly conserved protein in mammals, however its function is still largely unknown so far. In this study, we investigated the potential role of FAM122A in hepatocellular carcinoma (HCC). By analyzing HCC patient cohorts from RNA sequencing datasets, we found the expression level of FAMI22A mRNA is significantly upregulated in HCC patients. Moreover, this abnormally higher expression pattern of FAM122A protein was also found in partial HCC tumor tissues, compared with the normal parts. Further, we demonstrated that CRISPR/Cas9-mediated FAM122A knockout significantly inhibits the growth, clonogenic potential and xenografts of HCC cells, induces cell cycle arrest and reduces the expression of proliferation-related genes. Interestingly, FAM122A deletion significantly enhances the cytotoxicity effect of Doxorubicin (Dox), a drug used in standard chemotherapy in HCC patients. In contrary, overexpression of FAM122A not only promotes HCC cell growth, but also inhibits Dox-induced DNA damage and cell death. Considering that FAM122A is previously identified as an endogenous inhibitor of PP2A, we asked whether FAM122A regulating HCC cell growth is associated with PP2A. The results showed FAM122A can also modulate PP2A activity in HCC cells although the modulated effect is relatively slight, however, treatment with a PP2A inhibitor okadaic acid did not rescue the inhibitory effects of cell growth and proliferation in FAM122A deletion cells, indicating that FAM122A may support HCC cell growth independent of its ability to modulate PP2A. Collectively, these results suggest that FAM122A is required for maintaining HCC cell growth, and its elimination combined with chemotherapy may represent a potential novel therapeutic strategy for HCC patients.