He Weiling, He Shanyang, Wang Zuo, Shen Hongwei, Fang Wenfeng, Zhang Yang, Qian Wei, Lin Millicent, Yuan Jinglun, Wang Jinyang, Huang Wenhua, Wang Liantang, Ke Zunfu
Department of Gastrointestinal Surgery, Guangzhou, 510080, Province Guangdong, Peoples' Republic of China.
Gynecology, and the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, Peoples' Republic of China.
BMC Cancer. 2015 Mar 8;15:107. doi: 10.1186/s12885-015-1124-1.
Non-small cell lung cancer (NSCLC) is a highly metastatic cancer with limited therapeutic options, so development of novel therapies that target NSCLC is needed. During the early stage of metastasis, the cancer cells undergo an epithelial-mesenchymal transition (EMT), a phase in which Wnt/β-catenin signaling is known to be involved. Simultaneously, AEG-1 has been demonstrated to activate Wnt-mediated signaling in some malignant tumors.
Human NSCLC cell lines and xenograft of NSCLC cells in nude mice were used to investigate the effects of AEG-1 on EMT. EMT or Wnt/β-catenin pathway-related proteins were characterized by western blot, immunofluorescence and immunohistochemistry.
In the present study, we demonstrated that astrocyte elevated gene-1(AEG-1) ectopic overexpression promoted EMT, which resulted from the down-regulation of E-cadherin and up-regulation of Vimentin in lung cancer cell lines and clinical lung cancer specimens. Using an orthotopic xenograft-mouse model, we also observed that AEG-1 overexpression in human carcinoma cells led to the development of multiple lymph node metastases and elevated mesenchymal markers such as Vimentin, which is a characteristic of cells in EMT. Furthermore, AEG-1 functioned as a critical protein in the regulation of EMT by directly targeting multiple positive regulators of the Wnt/β-catenin signaling cascade, including GSK-3β and CKIδ. Notably, overexpression of AEG-1 in metastatic cancer tissues was closely associated with poor survival of NSCLC patients.
These results reveal the critical role of AEG-1 in EMT and suggest that AEG-1 may be a prognostic biomarker and its targeted inhibition may be utilized as a novel therapy for NSCLC.
非小细胞肺癌（NSCLC）是一种具有高度转移性且治疗选择有限的癌症，因此需要开发针对NSCLC的新型疗法。在转移的早期阶段，癌细胞会经历上皮-间质转化（EMT），已知Wnt/β-连环蛋白信号通路参与这一阶段。同时，已证明AEG-1在某些恶性肿瘤中可激活Wnt介导的信号通路。
使用人NSCLC细胞系和NSCLC细胞在裸鼠中的异种移植模型来研究AEG-1对EMT的影响。通过蛋白质免疫印迹、免疫荧光和免疫组织化学对EMT或Wnt/β-连环蛋白通路相关蛋白进行表征。
在本研究中，我们证明星形胶质细胞上调基因-1（AEG-1）的异位过表达促进了EMT，这是由肺癌细胞系和临床肺癌标本中E-钙黏蛋白的下调和波形蛋白的上调所致。使用原位异种移植小鼠模型，我们还观察到人癌细胞中AEG-1的过表达导致多个淋巴结转移的发生，并使波形蛋白等间充质标志物升高，波形蛋白是EMT细胞的一个特征。此外，AEG-1通过直接靶向Wnt/β-连环蛋白信号级联的多个正向调节因子，包括糖原合成酶激酶-3β（GSK-3β）和酪蛋白激酶Iδ（CKIδ），在EMT的调节中发挥关键蛋白的作用。值得注意的是，转移性癌组织中AEG-1的过表达与NSCLC患者的不良生存密切相关。
这些结果揭示了AEG-1在EMT中的关键作用，并表明AEG-1可能是一种预后生物标志物，其靶向抑制可作为NSCLC的一种新型治疗方法。
