Xie Qiang, Zhao Shilei, Liu Wenzhi, Cui Yanwei, Li Fengzhou, Li Zhuoshi, Guo Tao, Yu Wendan, Guo Wei, Deng Wuguo, Gu Chundong
Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Lung Cancer Diagnosis, and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Front Oncol. 2021 Dec 15;11:702491. doi: 10.3389/fonc.2021.702491. eCollection 2021.
Abnormal expression of the transcription factor Y-box-binding protein-1 (YBX1) is associated with the proliferation, migration, aggressiveness, and stem-like properties of various cancers. These characteristics contribute to the tumorigenesis and metastasis of cancer. We found that the expression levels of Mucin-1 (MUC1) and YBX1 were positively correlated in lung adenocarcinoma cells and lung adenocarcinoma tissue. Our retrospective cohort study of 176 lung adenocarcinoma patients after surgery showed that low expression of both YBX1 and MUC1 was an independent predictor of the prognosis and recurrence of lung adenocarcinoma. In lung adenocarcinoma cells, the silencing/overexpression of YBX1 caused a simultaneous change in MUC1, and MUC1 overexpression partially reversed the decreased tumor cell migration, aggressiveness, and stemness caused by YBX1 silencing. Moreover, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays proved that MUC1 was the downstream target of YBX1 and that YBX1 bound to the -1480~-1476 position in the promoter region of MUC1 to regulate its transcription. Furthermore, in mouse xenograft models and a lung cancer metastasis model, MUC1, which is downstream of YBX1, partially reversed the decreased number and size of tumors caused by YBX1 silencing. In conclusion, our findings indicated a novel mechanism by which YBX1 promotes the stemness and metastasis of lung adenocarcinoma by targeting MUC1 and provided a combination approach for diagnosis different from traditional single tumor biomarkers to predict patient prognosis and provide clinical treatment targets.
转录因子Y盒结合蛋白1（YBX1）的异常表达与多种癌症的增殖、迁移、侵袭性及干细胞样特性相关。这些特性促成了癌症的发生和转移。我们发现，在肺腺癌细胞和肺腺癌组织中，黏蛋白1（MUC1）与YBX1的表达水平呈正相关。我们对176例肺腺癌术后患者进行的回顾性队列研究表明，YBX1和MUC1的低表达是肺腺癌预后和复发的独立预测指标。在肺腺癌细胞中，YBX1的沉默/过表达导致MUC1同时发生变化，且MUC1过表达部分逆转了YBX1沉默所致的肿瘤细胞迁移、侵袭性及干性的降低。此外，染色质免疫沉淀（ChIP）和双荧光素酶报告基因检测证明，MUC1是YBX1的下游靶点，且YBX1与MUC1启动子区域的-1480~-1476位结合以调控其转录。此外，在小鼠异种移植模型和肺癌转移模型中，作为YBX1下游靶点的MUC1部分逆转了YBX1沉默所致的肿瘤数量减少和肿瘤体积减小。总之，我们的研究结果表明了一种新机制，即YBX1通过靶向MUC1促进肺腺癌的干性和转移，并提供了一种有别于传统单一肿瘤生物标志物的联合诊断方法，以预测患者预后并提供临床治疗靶点。
