NEK2 regulates cellular proliferation and cabergoline sensitivity in pituitary adenomas.
NEK2 regulates cellular proliferation and cabergoline sensitivity in pituitary adenomas.
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NEK2 调节垂体腺瘤中的细胞增殖和卡麦角林敏感性
DOI：
10.7150/jca.52937
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发表时间：
2021
影响因子：
3.9
通讯作者：
Bian L
中科院分区：
文献类型：
--
作者：
Jian F;Sun Y;Sun Q;Zhang B;Bian L
目的：探讨NEK 2在泌乳素腺瘤中的作用及其机制。研究方法：我们对用多巴胺受体激动剂卡麦角林（CAB）处理的MMQ细胞系进行了RNA-seq，以鉴定参与泌乳素瘤进展和多巴胺受体激动剂（DA）敏感性的基因。然后选择NEK 2进行进一步研究。采用实时定量PCR、免疫印迹和免疫组织化学方法检测NEK 2在垂体腺瘤（PA）和正常垂体组织中的表达。我们使用功能获得和功能丧失测定来探索NEK 2在体内和体外细胞生长中的生物学作用。免疫共沉淀法也用于检测NEK 2和USP 7之间的结合。结果：在此，我们报道了NEK 2在泌乳素瘤，特别是多巴胺耐药的泌乳素瘤中上调。NEK 2过表达显著促进垂体瘤GH 3和MMQ细胞增殖，并降低细胞对CAB的敏感性。相反，敲低NEK 2抑制GH 3和MMQ细胞生长，并使细胞对CAB敏感。从机制上讲，NEK 2通过Wnt信号通路调节细胞增殖;此外，我们证明了USP 7与NEK 2相互作用，去泛素化并稳定NEK 2。结论：总的来说，我们的研究结果表明，NEK 2可能是一个潜在的治疗催乳素瘤的目标。
Objective: To identify critical roles played by NEK2 in prolactinomas and to clarify the corresponding underlying mechanisms. Methods: We performed RNA-seq on MMQ cell lines treated with the dopamine receptor agonist cabergoline (CAB) to identify genes involved in prolactinoma progression and dopamine receptor-agonist (DA) sensitivity. NEK2 was then selected for further study. The expression of NEK2 was examined using quantitative real-time PCR, western immunoblotting, and immunohistochemistry - both in pituitary adenomas (PA) and in normal pituitary tissue. We used gain-of-function and loss-of-function assays to explore the biologic roles of NEK2 in cell growth in vivo and in vitro. Co-immunoprecipitation was also used to detect the binding between NEK2 and USP7. Results: Herein, we reported that NEK2 was upregulated in prolactinomas, particularly dopamine-resistant prolactinomas. NEK2 overexpression significantly promoted pituitary tumor GH3 and MMQ cell proliferation, and it impaired cellular sensitivity to CAB. Conversely, knockdown of NEK2 inhibited GH3 and MMQ cell growth, and sensitized the cells to CAB. Mechanistically, NEK2 regulated cell proliferation via the Wnt-signaling pathway; and in addition, we demonstrated that USP7 interacted with, deubiquitylated, and stabilized NEK2. Conclusions: Collectively, our results suggest that NEK2 might be a potential therapeutic target for prolactinoma.
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