《Nature》：EMT是怎样被调节的

生物谷

在原肠胚形成、伤口愈合和癌症扩散过程中，上皮细胞积极抑制细胞与细胞间的粘附，表现出侵略行为。这种受调节的表现型转变被称为EMT（上皮细胞-间叶细胞转变）。要了解身体各部分是怎么形成的、伤口是怎么愈合的、以及癌症是怎么扩散的，需要回答的一个重要问题是EMT是怎样被调节的。现在，对原肠胚形成过程中 EMT的分子机制所做的一项研究表明，LIVI（一种据报道与乳腺癌有关的锌运输蛋白）是一种关键分子，通过连接调节蛋白STAT3 和 Snail来调节EMT。

Nature \ 429, 298 - 302 (20 May 2004); doi:10.1038/nature02545
Nature AOP, published online 5 May 2004

Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer

SUSUMU YAMASHITA^1,2,*, CHIEMI MIYAGI^2,*, TOSHIYUKI FUKADA^2,3, NAOFUMI KAGARA², YONG-SUK CHE¹ & TOSHIO HIRANO^1,2,3

¹ Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan
² Department of Molecular Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
³ Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan
* These authors contributed equally to this work

Correspondence and requests for materials should be addressed to T.H. (hirano@molonc.med.osaka-u.ac.jp). The zebrafish LIV1 cDNA sequence has been deposited in the GenBank database under accession number AB126260.

Vertebrate gastrulation is a critical step in the establishment of body plan. During gastrulation, epithelial-mesenchymal transition (EMT) occurs. EMT is one of the central events of embryonic development, organ and tissue regeneration, and cancer metastasis. Signal transducers and activators of transcription (STATs) mediate biological actions such as cell proliferation, differentiation and survival in response to cytokines and growth factors, in a variety of biological processes. STATs are also important in EMT during gastrulation, organogenesis, wound healing and cancer progression. We previously showed that STAT3 is activated in the organizer during zebrafish gastrulation and its activity is essential for gastrulation movements. The requirement for STAT3 is cell-autonomous for the anterior migration of gastrula organizer cells, and non-cell-autonomous for the convergence of neighbouring cells. The molecular mechanisms of STAT's action in EMT, however, are unknown. Here we identify LIV1, a breast-cancer-associated zinc transporter protein, as a downstream target of STAT3 that is essential and sufficient for STAT3's cell-autonomous role in the EMT of zebrafish gastrula organizer cells. Furthermore, we demonstrate that LIV1 is essential for the nuclear localization of zinc-finger protein Snail, a master regulator of EMT. These results establish a molecular link between STAT3, LIV1 and Snail in EMT.