WNT5A encodes two isoforms with distinct functions in cancers.
WNT5A encodes two isoforms with distinct functions in cancers.
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DOI：
10.1371/journal.pone.0080526
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Cappellen D
中科院分区：
文献类型：
--
作者：
Bauer M;Bénard J;Gaasterland T;Willert K;Cappellen D
WNT 5A是分泌型脂质修饰糖蛋白WNT家族的成员，是许多发育过程的关键调节因子，包括肢体形成、肺形态发生、肠伸长和乳腺发育。改变的WNT 5A表达与许多癌症相关。有趣的是，在某些类型的癌症中，如血液恶性肿瘤和结直肠癌，WNT 5A失活并发挥肿瘤抑制功能，而在其他癌症中，如黑色素瘤和胃癌，WNT 5A过表达并促进肿瘤进展。WNT 5A在癌症中实现这些不同活性的机制知之甚少。在这里，我们提供的证据表明，WNT 5A基因产生两种蛋白质亚型，WNT 5A-long（WNT 5A-L）和WNT 5A-short（WNT 5A-S）。氨基末端测序和WNT 5A-L特异性抗体证明成熟和分泌的同种型是不同的，WNT 5A-L携带额外的18个N末端氨基酸。生化分析表明，两种纯化的蛋白质在稳定性、疏水性和WNT/β-catenin信号传导活性方面相似。尽管如此，通过异位表达或敲除来调节这两种WNT 5A亚型，表明它们在癌细胞系中发挥不同的活性：WNT 5A-L抑制肿瘤细胞系的增殖，而WNT 5A-S促进其生长。最后，我们发现这两种WNT 5A亚型的表达在乳腺癌和宫颈癌以及最具侵袭性的神经母细胞瘤中发生了改变。在这些癌症中，WNT 5A-L经常被下调，而WNT 5A-S在相当一部分肿瘤中被发现过表达。总之，我们的研究提供了证据表明，WNT 5A在癌症中的不同活性可归因于两种WNT 5A亚型的产生。
WNT5A, a member of the WNT family of secreted lipid-modified glycoproteins, is a critical regulator of a host of developmental processes, including limb formation, lung morphogenesis, intestinal elongation and mammary gland development. Altered WNT5A expression has been associated with a number of cancers. Interestingly, in certain types of cancers, such as hematological malignancies and colorectal carcinoma, WNT5A is inactivated and exerts a tumor suppressive function, while in other cancers, such as melanoma and gastric carcinoma, WNT5A is overexpressed and promotes tumor progression. The mechanism by which WNT5A achieves these distinct activities in cancers is poorly understood. Here, we provide evidence that the WNT5A gene produces two protein isoforms, WNT5A-long (WNT5A-L) and WNT5A-short (WNT5A-S). Amino-terminal sequencing and a WNT5A-L specific antibody demonstrate that the mature and secreted isoforms are distinct, with WNT5A-L carrying an additional 18 N-terminal amino acids. Biochemical analysis indicates that both purified proteins are similar with respect to their stability, hydrophobicity and WNT/β-catenin signaling activity. Nonetheless, modulation of these two WNT5A isoforms, either through ectopic expression or knockdown, demonstrates that they exert distinct activities in cancer cell lines: while WNT5A-L inhibits proliferation of tumor cell lines, WNT5A-S promotes their growth. Finally, we show that expression of these two WNT5A isoforms is altered in breast and cervix carcinomas, as well as in the most aggressive neuroblastoma tumors. In these cancers, WNT5A-L is frequently down-regulated, whereas WNT5A-S is found overexpressed in a significant fraction of tumors. Altogether, our study provides evidence that the distinct activities of WNT5A in cancer can be attributed to the production of two WNT5A isoforms.
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