College of Pharmacy, Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China.
Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, P.R. China.
Oncol Rep. 2021 Mar;45(3):1044-1058. doi: 10.3892/or.2020.7918. Epub 2020 Dec 30.
As a potential oncogene, nucleolar and spindle‑associated protein 1 (NUSAP1) is involved in the regulation of tumor cell proliferation, metastasis and drug resistance. However, the role of NUSAP1 in non‑small cell lung cancer (NSCLC) remains unclear. The present study aimed to investigate the biological function and underlying molecular mechanisms of NUSAP1 in NSCLC. NUSAP1 expression was measured in NSCLC tissues and cell lines via immunohistochemistry and western blotting, respectively. NSCLC cell lines stably inhibiting NUSAP1 were established to investigate its effects on cell proliferation, colony formation and invasion, and on in vivo tumorigenicity. Additionally, the upstream and downstream mechanisms of NUSAP1 in regulating NSCLC progression were investigated. The results indicated that NUSAP1 expression was upregulated in NSCLC tissues and cell lines. High NUSAP1 expression was associated with tumor size, TNM stage, lymph node metastasis and poor patient survival, whereas knockdown of NUSAP1 inhibited NSCLC cell proliferation, colony formation and invasion. Furthermore, downregulation of NUSAP1 decreased the growth of NSCLC xenografts in vivo. In addition, myocyte enhancer factor 2D (MEF2D) directly targeted the NUSAP1 promoter, thereby enhancing the mRNA and protein expression levels of NUSAP1. Moreover, the results demonstrated that MEF2D expression was upregulated in NSCLC tissues and was positively correlated with NUSAP1 expression. MEF2D‑knockdown decreased NSCLC cell proliferation, colony formation and invasion. NUSAP1 upregulation reversed the effects of MEF2D‑knockdown on NSCLC progression. Furthermore, it was observed that MEF2D‑knockdown inhibited the accumulation and nuclear translocation of β‑catenin, thereby repressing the activation of the Wnt/β‑catenin signaling pathway in NSCLC cells, whereas NUSAP1 upregulation rescued the effects of MEF2D‑knockdown on the activation of the Wnt/β‑catenin signaling pathway. In conclusion, the findings of the present study indicated that the MEF2D/NUSAP1 signaling pathway promoted NSCLC progression by inducing the activation of Wnt/β‑catenin signaling, and this novel mechanism may represent a potential treatment target for patients with NSCLC.
作为一个潜在的癌基因，核仁纺锤体相关蛋白 1（NUSAP1）参与肿瘤细胞增殖、转移和耐药性的调节。然而，NUSAP1 在非小细胞肺癌（NSCLC）中的作用尚不清楚。本研究旨在探讨 NUSAP1 在 NSCLC 中的生物学功能和潜在的分子机制。通过免疫组织化学和蛋白质印迹法分别测量 NSCLC 组织和细胞系中的 NUSAP1 表达。建立稳定抑制 NUSAP1 的 NSCLC 细胞系，以研究其对细胞增殖、集落形成和侵袭以及体内致瘤性的影响。此外，还研究了 NUSAP1 调节 NSCLC 进展的上下游机制。结果表明，NUSAP1 在 NSCLC 组织和细胞系中表达上调。NUSAP1 高表达与肿瘤大小、TNM 分期、淋巴结转移和患者生存不良有关，而 NUSAP1 敲低抑制 NSCLC 细胞增殖、集落形成和侵袭。此外，下调 NUSAP1 可减少 NSCLC 异种移植瘤在体内的生长。此外，肌细胞增强因子 2D（MEF2D）直接靶向 NUSAP1 启动子，从而增强 NUSAP1 的 mRNA 和蛋白表达水平。此外，研究结果表明，MEF2D 在 NSCLC 组织中表达上调，与 NUSAP1 表达呈正相关。MEF2D 敲低可降低 NSCLC 细胞增殖、集落形成和侵袭。NUSAP1 上调逆转了 MEF2D 敲低对 NSCLC 进展的影响。此外，观察到 MEF2D 敲低抑制 β-连环蛋白的积累和核易位，从而抑制 NSCLC 细胞中 Wnt/β-连环蛋白信号通路的激活，而 NUSAP1 上调挽救了 MEF2D 敲低对 Wnt/β-连环蛋白信号通路激活的影响。总之，本研究结果表明，MEF2D/NUSAP1 信号通路通过诱导 Wnt/β-连环蛋白信号通路的激活促进 NSCLC 进展，这一新机制可能成为 NSCLC 患者的潜在治疗靶点。
