Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer
Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer
复制标题
靶向 NEK2 通过抑制宫颈癌中的 Wnt1/β-catenin 信号通路损害肿瘤发生和放射抗性
DOI：
10.1186/s13046-020-01659-y
复制
发表时间：
2020-09-10
影响因子：
11.3
通讯作者：
Xu, Shuangbing
中科院分区：
文献类型：
--
作者：
Xu, Tie;Zeng, Yulan;Xu, Shuangbing
背景资料：NEK 2是一种参与有丝分裂的丝氨酸/苏氨酸激酶，在染色体不稳定性、肿瘤进展和转移中发挥重要作用，但其在宫颈癌放射抵抗中的作用尚不清楚。采用细胞生长和集落形成试验、EdU试验、凋亡试验以及体内小鼠模型检测NEK 2在肿瘤发生中的作用。应用γ-H2 AX和Rad 51灶形成、中性彗星试验和克隆形成细胞存活试验测定宫颈癌细胞的放射敏感性。进行RNA-seq以鉴定NEK 2的下游效应子。结果：NEK 2蛋白在宫颈癌组织中呈高表达，其表达水平与宫颈癌的临床分期和淋巴结转移密切相关。此外，我们提供的证据表明，NEK 2的耗竭损害肿瘤的发生，并提高宫颈癌的放射敏感性。使用RNA测序，我们确定Wnt 1作为NEK 2的关键下游效应子。NEK 2的敲低下调Wnt 1的mRNA和蛋白水平，从而抑制Wnt/β-连环蛋白信号通路的激活。更重要的是，所观察到的后果引起的NEK 2耗尽在宫颈癌细胞中可以部分救出Wnt 1 overexpression.Conclusions：我们的研究结果表明，NEK 2激活Wnt/β-catenin信号通路，通过Wnt 1驱动肿瘤发生和宫颈癌的放射抗性，这表明NEK 2可能是一个有前途的靶点宫颈癌的放射增敏。
Background: NEK2, a serine/threonine kinase involved in mitosis, has been found to function in chromosome instability, tumor progression and metastasis, but its role in cervical cancer radioresistance remains unknown.Methods: We detected the protein levels of NEK2 in cervical carcinoma tissues and paired paracarcinoma tissues by immunohistochemistry. The roles of NEK2 in oncogenesis were examined using cell growth and colony formation assays, EdU assay, apoptosis assay as well as in vivo mouse model. gamma-H2AX and Rad51 foci formation, neutral comet assay and clonogenic cell survival assay were applied to determine the radiosensitivity of cervical cancer cells. RNA-seq was performed to identify the downstream effector of NEK2. The gene expression levels were measured by Real-time PCR.Results: We report that NEK2 protein level is overexpressed and correlated with the tumor stage and lymph node metastasis in cervical cancer tissues. Furthermore, we provided evidence that depletion of NEK2 impairs oncogenesis and enhances radiosensitivity in cervical cancer. Using RNA sequencing, we identify Wnt1 as a key downstream effector of NEK2. Knockdown of NEK2 downregulates the mRNA and protein levels of Wnt1, thereby inhibiting the activation of the Wnt/beta-catenin signaling pathway. More importantly, the observed consequences induced by NEK2 depletion in cervical cancer cells can be partially rescued by Wnt1 overexpression.Conclusions: Our results demonstrate that NEK2 activates the Wnt/beta-catenin signaling pathway via Wnt1 to drive oncogenesis and radioresistance in cervical cancer, indicating that NEK2 may be a promising target for the radiosensitization of cervical cancer.