DataSheet_3_NUF2 overexpression contributes to epithelial ovarian cancer progression via ERBB3-mediated PI3K-AKT and MAPK signaling axes.pdf

IntroductionNDC80 kinetochore complex component (NUF2) is upregulated and plays an important role in various human cancers. However, the function and mechanism of NUF2 in epithelial ovarian cancer (EOC) remain unclear.MethodsNUF2 expression was detected in EOC tissues and cell lines. The effects of NUF2 downregulation on cell proliferation, migration and invasion in EOC were analyzed by CCK-8 and Transwell assays. Meanwhile, the effect of NUF2 downregulation on tumor growth in vivo was determined by xenograft tumor models. The mechanisms by which NUF2 regulates EOC progression were detected by RNA sequencing and a series of in vitro assays.ResultsWe showed that NUF2 was significantly upregulated in EOC tissues and cell lines, and high NUF2 expression was associated with FIGO stage, pathological grade and poor EOC prognosis. NUF2 downregulation decreased cell proliferation, migration, invasion and tumor growth in nude mice. RNA sequencing studies showed that NUF2 knockdown inhibited several genes enriched in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT serine/threonine kinase (AKT) and mitogen-activated protein kinase (MAPK) signaling pathways. Erb-B2 receptor tyrosine kinase 3 (ERBB3) was the key factor involved in both of the above pathways. We found that ERBB3 silencing could inhibit EOC progression and repress activation of the PI3K-AKT and MAPK signaling pathways. Furthermore, the exogenous overexpression of ERBB3 partially reversed the inhibitory effects on EOC progression induced by NUF2 downregulation, while LY294002 and PD98059 partially reversed the effects of ERBB3 upregulation.ConclusionThese results showed that NUF2 promotes EOC progression through ERBB3-induced activation of the PI3K-AKT and MAPK signaling axes. These findings suggest that NUF2 might be a potential therapeutic target for EOC.

NDC80着丝粒复合物组分（NUF2）在多种人类癌症中表达上调，并发挥着至关重要的作用。然而，NUF2在子宫内膜癌（EOC）中的功能与作用机制尚不明确。研究方法中，我们检测了EOC组织和细胞系中的NUF2表达，并通过CCK-8和Transwell实验分析了NUF2下调对EOC细胞增殖、迁移和侵袭的影响。同时，通过异种移植肿瘤模型确定了NUF2下调对体内肿瘤生长的影响。通过RNA测序和一系列体外实验，我们揭示了NUF2调控EOC进展的机制。研究结果揭示了NUF2在EOC组织和细胞系中显著上调，且高表达NUF2与FIGO分期、病理分级和EOC预后不良相关。NUF2下调减少了裸鼠中的细胞增殖、迁移、侵袭和肿瘤生长。RNA测序研究表明，NUF2敲低抑制了富含磷脂酰肌醇-4,5-二磷酸3-激酶（PI3K）-丝氨酸/苏氨酸激酶（AKT）和丝裂原活化蛋白激酶（MAPK）信号通路的基因。Erb-B2受体酪氨酸激酶3（ERBB3）是参与上述两条通路的关键因素。我们发现，ERBB3的沉默可以抑制EOC进展并抑制PI3K-AKT和MAPK信号通路的激活。此外，外源性过表达ERBB3部分逆转了NUF2下调对EOC进展的抑制作用，而LY294002和PD98059部分逆转了ERBB3上调的效果。结论：这些结果表明，NUF2通过ERBB3诱导的PI3K-AKT和MAPK信号轴的激活促进EOC进展。这些发现表明，NUF2可能成为EOC的潜在治疗靶点。