Activin A balance regulates epithelial invasiveness and tumorigenesis
Activin A balance regulates epithelial invasiveness and tumorigenesis
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DOI：
10.1038/labinvest.2014.97
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发表时间：
2014-10-01
影响因子：
5
通讯作者：
Andl, Claudia D.
中科院分区：
文献类型：
--
作者：
Le Bras, Gregoire F.;Loomans, Holli A.;Andl, Claudia D.
激活素A（Act A）是TGF β超家族的成员。Act A和TGF β具有多个共同的下游靶点，并且已被描述为在其细胞内信号传导级联和功能中合并。我们以前已经证明，协调损失的E-钙粘蛋白和TGF β受体II（T β RII）的结果在上皮细胞的侵袭。当在三维器官型重建培养物中生长时，表达E-cadherin和T β RII的显性阴性突变体的食管角质形成细胞在功能性T β RII不存在的情况下显示激活的Smad 2。然而，我们可以表明，增加的Act A分泌水平能够诱导Smad 2磷酸化。生长因子的分泌可以激活自分泌和旁分泌信号，从而影响上皮区室与周围微环境之间的串扰。我们表明，治疗与Act A拮抗剂卵泡抑素或与中和Act A抗体可以增加细胞侵袭器官型培养成纤维细胞和MMP依赖性的方式。类似地，用shRNA抑制Act A增加体内细胞侵袭和肿瘤发生。因此，我们得出结论，保持一个微妙的平衡的Act A的表达是至关重要的食管微环境中的稳态。
Activin A (Act A) is a member of the TGF beta superfamily. Act A and TGF beta have multiple common downstream targets and have been described to merge in their intracellular signaling cascades and function. We have previously demonstrated that coordinated loss of E-cadherin and TGF beta receptor II (T beta RII) results in epithelial cell invasion. When grown in three-dimensional organotypic reconstruct cultures, esophageal keratinocytes expressing dominant-negative mutants of E-cadherin and T beta RII showed activated Smad2 in the absence of functional T beta RII. However, we could show that increased levels of Act A secretion was able to induce Smad2 phosphorylation. Growth factor secretion can activate autocrine and paracrine signaling, which affects crosstalk between the epithelial compartment and the surrounding microenvironment. We show that treatment with the Act A antagonist Follistatin or with a neutralizing Act A antibody can increase cell invasion in organotypic cultures in a fibroblast- and MMP-dependent manner. Similarly, suppression of Act A with shRNA increases cell invasion and tumorigenesis in vivo. Therefore, we conclude that maintaining a delicate balance of Act A expression is critical for homeostasis in the esophageal microenvironment.