Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.
EMBO Mol Med. 2012 Dec;4(12):1294-307. doi: 10.1002/emmm.201201486. Epub 2012 Nov 6.
Elevated levels of nuclear β-catenin are associated with higher rates of survival in patients with melanoma, raising questions as to how ß-catenin is regulated in this context. In the present study, we investigated the formal possibility that the secretion of WNT ligands that stabilize ß-catenin may be regulated in melanoma and thus contributes to differences in ß-catenin levels. We find that WLS, a conserved transmembrane protein necessary for WNT secretion, is decreased in both melanoma cell lines and in patient tumours relative to skin and to benign nevi. Unexpectedly, reducing endogenous WLS with shRNAs in human melanoma cell lines promotes spontaneous lung metastasis in xenografts in mice and promotes cell proliferation in vitro. Conversely, overexpression of WLS inhibits cell proliferation in vitro. Activating β-catenin downstream of WNT secretion blocks the increased cell migration and proliferation observed in the presence of WLS shRNAs, while inhibiting WNT signalling rescues the growth defects induced by excess WLS. These data suggest that WLS functions as a negative regulator of melanoma proliferation and spontaneous metastasis by activating WNT/β-catenin signalling.
核β-连环蛋白水平升高与黑色素瘤患者的生存率较高有关，这引发了一个问题，即在这种情况下β-连环蛋白是如何被调控的。在本研究中，我们研究了一种可能性，即稳定β-连环蛋白的 WNT 配体的分泌可能在黑色素瘤中受到调控，从而导致β-连环蛋白水平的差异。我们发现，WLS 是一种保守的跨膜蛋白，对于 WNT 的分泌是必需的，与皮肤和良性痣相比，在黑色素瘤细胞系和患者肿瘤中均减少。出乎意料的是，用 shRNA 减少人黑色素瘤细胞系中的内源性 WLS 会促进异种移植小鼠肺转移的自发性发生，并促进体外细胞增殖。相反，WLS 的过表达抑制体外细胞增殖。WNT 分泌下游的β-连环蛋白激活会阻止在存在 WLS shRNA 时观察到的细胞迁移和增殖增加，而抑制 WNT 信号转导会挽救由过量 WLS 引起的生长缺陷。这些数据表明，WLS 通过激活 WNT/β-连环蛋白信号转导，作为黑色素瘤增殖和自发转移的负调控因子发挥作用。
