Cancer Research UK Beatson Institute, Bearsden, Glasgow, UK.
Academic Unit of Surgery, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK.
J Pathol. 2018 Jul;245(3):337-348. doi: 10.1002/path.5086. Epub 2018 May 28.
N-WASP (WASL) is a widely expressed cytoskeletal signalling and scaffold protein also implicated in regulation of Wnt signalling and homeostatic maintenance of skin epithelial architecture. N-WASP mediates invasion of cancer cells in vitro and its depletion reduces invasion and metastatic dissemination of breast cancer. Given this role in cancer invasion and universal expression in the gastrointestinal tract, we explored a role for N-WASP in the initiation and progression of colorectal cancer. While deletion of N-wasp is not detectably harmful in the murine intestinal tract, numbers of Paneth cells increased, indicating potential changes in the stem cell niche, and migration up the crypt-villus axis was enhanced. Loss of N-wasp promoted adenoma formation in an adenomatous polyposis coli (Apc) deletion model of intestinal tumourigenesis. Thus, we establish a tumour suppressive role of N-WASP in early intestinal carcinogenesis despite its later pro-invasive role in other cancers. Our study highlights that while the actin cytoskeletal machinery promotes invasion of cancer cells, it also maintains normal epithelial tissue function and thus may have tumour suppressive roles in pre-neoplastic tissues. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
N-WASP（WASL）是一种广泛表达的细胞骨架信号转导和支架蛋白，也与 Wnt 信号转导的调节和皮肤上皮结构的动态平衡维持有关。N-WASP 介导体外癌细胞的侵袭，其缺失可降低乳腺癌的侵袭和转移扩散。鉴于其在癌症侵袭中的作用以及在胃肠道中的普遍表达，我们探讨了 N-WASP 在结直肠癌发生和发展中的作用。虽然 N-wasp 在小鼠肠道中缺失并不明显有害，但 Paneth 细胞数量增加，表明干细胞龛位可能发生变化，隐窝-绒毛轴向上的迁移增强。在结直肠肿瘤发生的腺瘤性结肠息肉病（Apc）缺失模型中，N-wasp 的缺失促进了腺瘤的形成。因此，尽管 N-WASP 在其他癌症中具有促进侵袭的后期作用，但我们确立了 N-WASP 在早期肠道癌变中的肿瘤抑制作用。我们的研究强调，尽管肌动蛋白细胞骨架机制促进了癌细胞的侵袭，但它也维持了正常的上皮组织功能，因此在癌前组织中可能具有肿瘤抑制作用。
