CDCA8 induced by NF-YA promotes hepatocellular carcinoma progression by regulating the MEK/ERK pathway.
CDCA8 induced by NF-YA promotes hepatocellular carcinoma progression by regulating the MEK/ERK pathway.
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DOI：
10.1186/s40164-022-00366-y
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发表时间：
2023-01-13
影响因子：
10.9
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Chen, Erbao;He, Yu;Jiang, Jing;Yi, Jing;Zou, Zhilin;Song, Qiuzi;Ren, Qingqi;Lin, Zewei;Lu, Yi;Liu, Jikui;Zhang, Jian
肝细胞癌（HCC）是最致命的恶性肿瘤之一。细胞分裂周期相关8 （CDCA8）是肿瘤中重要的多因子调控因子。然而，其在HCC中的上下游靶点和作用尚不清楚。利用癌症基因组图谱数据集（TCGA）进行全面的生物信息学分析，以探索新的核心癌基因。我们使用qRT-PCR定量了HCC肿瘤中的CDCA8水平。采用细胞计数试剂盒-8 （CCK-8）法、5-乙基-2′-脱氧尿苷（EdU）法、克隆形成法和Transwell法检测HCC细胞的增殖、迁移和侵袭能力。建立原位肿瘤模型和尾静脉模型，观察CDCA8在体内的抑制作用。利用RNA测序研究了CDCA8的作用机制。采用组织芯片免疫组化染色评估CDCA8的预后价值。CDCA8在HCC的发展过程中被确定为一种新的癌基因。无论是在公开数据集还是在我们的队列中，CDCA8的高表达都是HCC预后恶化的独立预测因子。我们发现CDCA8敲低通过抑制MEK/ERK途径抑制HCC细胞增殖、集落形成和迁移。此外，CDCA8缺乏显著抑制肿瘤的发生和转移。新一代测序和实验室验证表明，CDCA8沉默抑制了TPM3、NECAP2和USP13的表达。此外，NA-YA过表达上调CDCA8的表达。CDCA8敲低可减弱nf - ya介导的体外细胞侵袭。NF-YA单独表达或与CDCA8联合表达被证实为患者生存的重要独立危险因素。我们的研究结果表明，CDCA8单独表达或与NF-YA联合表达可促进癌症进展，并可作为HCC患者新的潜在治疗靶点。在线版本包含补充材料，可在10.1186/s40164-022-00366-y获得。
Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors. Cell division cycle associated 8 (CDCA8) is an important multifactorial regulator in cancers. However, its up and downstream targets and effects in HCC are still unclear. A comprehensive bioinformatics analysis was performed using The Cancer Genome Atlas dataset (TCGA) to explore novel core oncogenes. We quantified CDCA8 levels in HCC tumors using qRT-PCR. HCC cell’s proliferative, migratory, and invasive abilities were detected using a Cell Counting Kit-8 (CCK-8) assay, 5-ethynyl-2′-deoxyuridine (EdU) assay, clone formation, and a Transwell assay. An orthotopic tumor model and tail vein model were constructed to determine the effects of CDCA8 inhibition in vivo. The mechanism underlying CDCA8 was investigated using RNA sequencing. The prognostic value of CDCA8 was assessed with immunohistochemical staining of the tissue microarrays. CDCA8 was identified as a novel oncogene during HCC development. The high expression of CDCA8 was an independent predictor for worse HCC outcomes both in publicly available datasets and in our cohort. We found that CDCA8 knockdown inhibited HCC cell proliferation, colony formation, and migration by suppressing the MEK/ERK pathway in vitro. Moreover, CDCA8 deficiency significantly inhibited tumorigenesis and metastasis. Next-generation sequencing and laboratory validation showed that CDCA8 silencing inhibited the expression of TPM3, NECAP2, and USP13. Furthermore, NA-YA overexpression upregulated the expression of CDCA8. CDCA8 knockdown could attenuate NF-YA-mediated cell invasion in vitro. The expression of NF-YA alone or in combined with CDCA8 were validated as significant independent risk factors for patient survival. Our findings revealed that the expression of CDCA8 alone or in combined with NF-YA contributed to cancer progression, and could serve as novel potential therapeutic targets for HCC patients. The online version contains supplementary material available at 10.1186/s40164-022-00366-y.
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