Zou Juntao, Lin Yang, Hu Min, Wan Mengzhi, Tan Xinyu, Xu Xinping, Xu Fei
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, No. 1519, Dongyue Avenue, Dongxin Township, Nanchang County, Nanchang 330006, Jiangxi, China.
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, No. 1519, Dongyue Avenue, Dongxin Township, Nanchang County, Nanchang 330006, Jiangxi, China.
Pathol Res Pract. 2022 Oct;238:154083. doi: 10.1016/j.prp.2022.154083. Epub 2022 Aug 22.
Small cell lung cancer (SCLC) is characterized by a high proliferative rate, a strong predilection for early metastasis and poor prognosis. Novel SCLC biomarkers are urgently required to improve current diagnostic and treatment modalities. MYCN encodes the proto-oncogene N-Myc that is overexpressed in SCLC, but its downstream effectors are poorly characterized. Here, we investigated the role of the N-Myc/Skp2/p27 axis during SCLC progression.
Immunohistochemistry (IHC) and western blotting were performed to evaluate N-Myc/Skp2/p27 expression. SCLC cell apoptosis was investigated through TUNEL staining. Wound healing and transwell assays were performed to detect the migratory and invasive potential of SCLC cells. N-Myc and Skp2 binding was confirmed through luciferase reporter and ChIP assays. Xenograft models were developed to investigate the function of Skp2 during SCLC tumor growth in vivo.
N-Myc and Skp2 were overexpressed in SCLC, whilst p27 expression was suppressed. Skp2 facilitated SCLC progression by protecting cells from apoptosis and facilitating cell migration and invasion. N-Myc was found to bind to the promoter region of Skp2 to enhance its expression. Skp2 enhanced tumor growth in vivo through the suppression of p27. Skp2 silencing reversed the pro-oncogenic effects of N-myc in SCLC tumors.
We show that N-Myc enhances Skp2 to regulate p27 expression during SCLC progression. We therefore highlight the N-Myc/Skp2/p27 axis as a novel diagnostic and much-needed therapeutic target in SCLC.
小细胞肺癌（SCLC）的特征是增殖率高、早期转移倾向强且预后差。迫切需要新型SCLC生物标志物来改善当前的诊断和治疗方式。MYCN编码原癌基因N-Myc，其在SCLC中过表达，但其下游效应分子的特征尚不明确。在此，我们研究了N-Myc/Skp2/p27轴在SCLC进展过程中的作用。
采用免疫组织化学（IHC）和蛋白质印迹法评估N-Myc/Skp2/p27的表达。通过TUNEL染色研究SCLC细胞凋亡情况。进行伤口愈合和Transwell实验以检测SCLC细胞的迁移和侵袭能力。通过荧光素酶报告基因和染色质免疫沉淀实验证实N-Myc与Skp2的结合。建立异种移植模型以研究Skp2在SCLC体内肿瘤生长过程中的功能。
N-Myc和Skp2在SCLC中过表达，而p27表达受到抑制。Skp2通过保护细胞免于凋亡并促进细胞迁移和侵袭来促进SCLC进展。发现N-Myc与Skp2的启动子区域结合以增强其表达。Skp2通过抑制p27增强体内肿瘤生长。Skp2沉默逆转了N-myc在SCLC肿瘤中的促癌作用。
我们表明，在SCLC进展过程中，N-Myc增强Skp2以调节p27表达。因此，我们强调N-Myc/Skp2/p27轴是SCLC中一种新型的诊断和急需的治疗靶点。
