核仁与纺锤体相关蛋白 1 通过激活 Wnt/β-连环蛋白信号通路促进宫颈癌的转移。
Nucleolar and spindle associated protein 1 promotes metastasis of cervical carcinoma cells by activating Wnt/β-catenin signaling.
机构信息
State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
Department of Obstetrics Gynecology, The First Pepole's Hospital, Foshan, Guangdong, China.
出版信息
J Exp Clin Cancer Res. 2019 Jan 24;38(1):33. doi: 10.1186/s13046-019-1037-y.
BACKGROUND
The primary obstacle to treat cervical cancer is its high prevalence of metastasis, which severely affects patients' quality of life and survival time. Nucleolar and spindle associated protein 1 (NUSAP1) has been implicated in the development, progression, and metastasis in several types of cancer. However, its oncogenic role in cervical cancer remains unclear.
METHODS
Western blot assay and immunohistochemistry were used to determine the expression of NUSAP1 in 21 clinical fresh Cervical cancer tissues and 233 clinicopathologically characterized cervical cancer specimens. The biological roles of NUSAP1 in the metastasis of cervical cancer were investigated both in vitro by EMT, Side population analysis and Transwell assays and so on, and in vivo using a mouse 4w model of hematogenous metastasis and lymph node metastasis. Bioinformatics analysis, luciferase reporter analysis, immunoprecipitation and immunoblotting of nuclear and cytoplasmic cellular fractions were applied to discern and examine the relationshipbetween NUSAP1 and its potential targets.
RESULTS
The results demonstrated that NUSAP1 was upregulated in cervical cancer cells and tissues, correlated positively with metastasis and poor clinical outcome of patients. High expression of NUSAP1 promoted metastasis by enhancing cancer stem cell (CSC) traits and epithelial-mesenchyme transition (EMT) progression, while silencing of NUSAP1 reduced CSC traits and EMT progression. Mechanistically, upregulation of NUSAP1 induced SUMOylation of TCF4 via interacting with SUMO E3 ligase Ran-binding protein 2 (RanBP2) and hyperactivated Wnt/β-catenin signaling in cervical cancer cells. Additionally, NUSAP1-induced cervical cancer cells metastasis and the cancer stem cell phenotype were abrogated with the Wnt/β-catenin signaling inhibitor XAV-939 treatment. Importantly, co-therapy of conventional treatment and XAV-939 will provide a novel and effective treatment for NUSAP1-ovexpressed cervical cancer patients.
CONCLUSIONS
Our results demonstrate thatNUSAP1 upregulation contributes to metastasis of cervical cancer by promoting CSC properties and EMT via Wnt/β-catenin signaling and XAV-939 might serve as a potential tailored therapeutic option for patients with NUSAP1-ovexpressed cervical cancer.
背景
治疗宫颈癌的主要障碍是其高转移性，这严重影响了患者的生活质量和生存时间。核仁纺锤体相关蛋白 1（NUSAP1）已被证实与多种癌症的发生、发展和转移有关。然而，其在宫颈癌中的致癌作用尚不清楚。
方法
Western blot 检测和免疫组化分析了 21 例新鲜宫颈癌组织和 233 例临床病理特征明确的宫颈癌标本中 NUSAP1 的表达。通过 EMT、侧群分析和 Transwell 等体外实验以及小鼠 4w 血行转移和淋巴结转移模型，研究了 NUSAP1 在宫颈癌转移中的作用。应用生物信息学分析、荧光素酶报告分析、免疫沉淀和核质细胞分数免疫印迹等方法，探讨和检验 NUSAP1 与其潜在靶标的关系。
结果
结果表明，NUSAP1 在宫颈癌细胞和组织中上调，与转移和患者不良临床结局呈正相关。NUSAP1 的高表达通过增强癌症干细胞（CSC）特征和上皮-间充质转化（EMT）进展促进转移，而 NUSAP1 的沉默则降低 CSC 特征和 EMT 进展。机制上，NUSAP1 通过与 SUMO E3 连接酶 Ran 结合蛋白 2（RanBP2）相互作用，诱导 TCF4 的 SUMO 化，从而激活宫颈癌细胞中的 Wnt/β-catenin 信号通路。此外，用 Wnt/β-catenin 信号抑制剂 XAV-939 处理可阻断 NUSAP1 诱导的宫颈癌细胞转移和癌干细胞表型。重要的是，常规治疗联合 XAV-939 治疗可为 NUSAP1 过表达的宫颈癌患者提供一种新的有效治疗方法。
结论
我们的研究结果表明，NUSAP1 的上调通过促进 Wnt/β-catenin 信号通路中的 CSC 特性和 EMT 促进宫颈癌的转移，XAV-939 可能成为 NUSAP1 过表达的宫颈癌患者潜在的靶向治疗选择。
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