Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β-SMAD3 pathway in non-small cell lung adenocarcinoma
Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β-SMAD3 pathway in non-small cell lung adenocarcinoma
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DOI：
10.1073/pnas.1407074111
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发表时间：
2014-09-09
影响因子：
11.1
通讯作者：
Verde, Pasquale
中科院分区：
文献类型：
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作者：
Risolino, Maurizio;Mandia, Nadia;Verde, Pasquale
Pre-B-cell leukemia homeobox（Pbx）-regulating protein-1（Prep 1）是一种普遍存在的同源异型蛋白，参与早期发育、基因组稳定性、胰岛素敏感性和造血。以前，我们已经表明，Prep 1是一个单倍不足的肿瘤抑制因子，通过与髓细胞亲合性整合位点1竞争结合到共同的异源二聚体伙伴Pbx 1来抑制肿瘤转化。上皮-间充质转化（EMT）由响应于旁分泌因子（诸如TGF-β）的前侵袭性转录因子的复杂网络控制。在这里，我们表明，除了抑制原发性肿瘤生长，PREP 1是一种新的EMT诱导剂和促转移转录因子。在人非小细胞肺癌（NSCLC）细胞中，PREP 1过表达足以触发EMT，而PREP 1下调则抑制TGF-β诱导EMT。PREP 1通过诱导小母体抗十肢瘫痪同源物3（SMAD 3）核转位来调节细胞对TGF-β的敏感性，所述机制至少部分依赖于PREP 1介导的SMAD 3第一内含子中的调节元件的反式激活。沿着PBX 1的稳定和积累，PREP 1诱导多种激活蛋白1组分的表达，包括前侵袭性Fos相关抗原1（FRA-1）癌蛋白。FRA-1和PBX 1都是肺肿瘤细胞中PREP 1引发的间质变化所必需的。最后，我们发现PREP 1诱导的间充质转化与过表达PREP 1的细胞显著增加的肺定植相关。因此，我们已经检测到PREP 1在各种实体瘤（包括NSCLC）的大量人脑转移瘤中的积累。这些发现指出了PREP 1同源异型蛋白在控制TGF-β途径、EMT和NSCLC转移中的新作用。
Pre-B-cell leukemia homeobox (Pbx)-regulating protein-1 (Prep1) is a ubiquitous homeoprotein involved in early development, genomic stability, insulin sensitivity, and hematopoiesis. Previously we have shown that Prep1 is a haploinsufficient tumor suppressor that inhibits neoplastic transformation by competing with myeloid ecotropic integration site 1 for binding to the common heterodimeric partner Pbx1. Epithelial-mesenchymal transition (EMT) is controlled by complex networks of proinvasive transcription factors responsive to paracrine factors such as TGF-beta. Here we show that, in addition to inhibiting primary tumor growth, PREP1 is a novel EMT inducer and prometastatic transcription factor. In human non-small cell lung cancer (NSCLC) cells, PREP1 overexpression is sufficient to trigger EMT, whereas PREP1 down-regulation inhibits the induction of EMT in response to TGF-beta. PREP1 modulates the cellular sensitivity to TGF-beta by inducing the small mothers against decapentaplegic homolog 3 (SMAD3) nuclear translocation through mechanisms dependent, at least in part, on PREP1-mediated transactivation of a regulatory element in the SMAD3 first intron. Along with the stabilization and accumulation of PBX1, PREP1 induces the expression of multiple activator protein 1 components including the proinvasive Fos-related antigen 1 (FRA-1) oncoprotein. Both FRA-1 and PBX1 are required for the mesenchymal changes triggered by PREP1 in lung tumor cells. Finally, we show that the PREP1-induced mesenchymal transformation correlates with significantly increased lung colonization by cells overexpressing PREP1. Accordingly, we have detected PREP1 accumulation in a large number of human brain metastases of various solid tumors, including NSCLC. These findings point to a novel role of the PREP1 homeoprotein in the control of the TGF-beta pathway, EMT, and metastasis in NSCLC.