Department I of Internal Medicine, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Straße 21, Cologne, 50931, Germany.
Oncogene. 2018 May;37(20):2746-2756. doi: 10.1038/s41388-018-0158-7. Epub 2018 Mar 5.
LIN28B is a RNA-binding protein regulating predominantly let-7 microRNAs with essential functions in inflammation, wound healing, embryonic stem cells, and cancer. LIN28B expression is associated with tumor initiation, progression, resistance, and poor outcome in several solid cancers, including lung cancer. However, the functional role of LIN28B, especially in non-small cell lung adenocarcinomas, remains elusive. Here, we investigated the effects of LIN28B expression on lung tumorigenesis using LIN28B transgenic overexpression in an autochthonous KRAS-driven mouse model. We found that LIN28B overexpression significantly increased the number of CD44+/CD326+ tumor cells, upregulated VEGF-A and miR-21 and promoted tumor angiogenesis and epithelial-to-mesenchymal transition (EMT) accompanied by enhanced AKT phosphorylation and nuclear translocation of c-MYC. Moreover, LIN28B accelerated tumor initiation and enhanced proliferation which led to a shortened overall survival. In addition, we analyzed lung adenocarcinomas of the Cancer Genome Atlas (TCGA) and found LIN28B expression in 24% of KRAS-mutated cases, which underscore the relevance of our model.
LIN28B 是一种 RNA 结合蛋白，主要调节 let-7 微 RNA，在炎症、伤口愈合、胚胎干细胞和癌症中具有重要功能。LIN28B 的表达与几种实体瘤（包括肺癌）的肿瘤起始、进展、耐药和不良预后有关。然而，LIN28B 的功能作用，特别是在非小细胞肺腺癌中，仍然难以捉摸。在这里，我们使用 KRAS 驱动的自发肺腺癌小鼠模型中的 LIN28B 转基因过表达，研究了 LIN28B 表达对肺肿瘤发生的影响。我们发现，LIN28B 过表达显著增加了 CD44+/CD326+肿瘤细胞的数量，上调了 VEGF-A 和 miR-21，并促进了肿瘤血管生成和上皮间质转化（EMT），同时伴随着 AKT 磷酸化和 c-MYC 的核转位增强。此外，LIN28B 加速了肿瘤的起始和增殖，导致总生存期缩短。此外，我们分析了癌症基因组图谱（TCGA）中的肺腺癌，发现 24%的 KRAS 突变病例存在 LIN28B 表达，这突显了我们模型的相关性。
