Inhibition of stathmin1 accelerates the metastatic process.
Inhibition of stathmin1 accelerates the metastatic process.
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DOI：
10.1158/0008-5472.can-12-1158
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发表时间：
2012-10-15
期刊：
影响因子：
11.2
通讯作者：
Kasper S
中科院分区：
文献类型：
--
作者：
Williams K;Ghosh R;Giridhar PV;Gu G;Case T;Belcher SM;Kasper S
癌蛋白STMN1(STMN1)在大多数(如果不是全部)上皮源性癌症中上调，因此STMN1被认为是癌症治疗的靶点。然而，它在肿瘤转移中的作用尚未被研究。在这里，我们第一次报道，STMN1强烈抑制正常上皮细胞和癌细胞的转移行为。最初，STMN1的缺失会影响细胞间的黏附。其次是上皮细胞向间充质样细胞的转变，通过p38的协同激活和转化生长因子-β的非依赖和依赖机制，增加细胞迁移和转移。相反，表达STMN1可以恢复细胞间的黏附并逆转转移级联反应。从良性到未分化腺癌的原代前列腺上皮细胞培养的临床活检表明，EMT样细胞出现时，癌细胞仍然是器官受限的，并且它们的出现是肿瘤阶段特有的。此外，与非EMT细胞相比，原代EMT样细胞在体外和体内都表现出转移行为。这些观察预测，使用STMN1作为通用治疗靶点可能会加速转移。相反，可能存在肿瘤分期特定的“机会之窗”，其中需要保存STMN1的表达以抑制转移性疾病的出现。
The oncoprotein Stathmin 1 (STMN1) is upregulated in most, if not all, cancers of epithelial cell origin; therefore STMN1 is considered a target for cancer therapy. However its role during metastasis has not been investigated. Here we report for the first time that STMN1 strongly inhibits metastatic behavior in both normal epithelial and cancerous epithelial cells. Initially, loss-of-STMN1 compromises cell-cell adhesion. This is followed by epithelial-to-mesenchymal-like transition (EMT), increased cell migration, and metastasis via cooperative activation of p38 and through TGF-β-independent and dependent mechanisms. In contrast, expressing STMN1 restores cell-cell adhesion and reverses the metastatic cascade. Primary prostate epithelial cell cultures from benign to undifferentiated adenocarcinoma clinical biopsies demonstrate that EMT-like cells arise while the cancer is still organ-confined and that their emergence is tumor-stage specific. Furthermore, primary EMT-like cells exhibit metastatic behavior both in vitro and in vivo as compared to their non-EMT counterpart. These observations predict that using STMN1 as a generic therapeutic target might accelerate metastasis. Instead, there may be a tumor stage-specific “window-of-opportunity” in which conserving STMN1 expression is required to inhibit emergence of metastatic disease.