A hydrophobic residue in the TALE homeodomain of PBX1 promotes epithelial-to-mesenchymal transition of gastric carcinoma.
A hydrophobic residue in the TALE homeodomain of PBX1 promotes epithelial-to-mesenchymal transition of gastric carcinoma.
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PBX1 TALE同源结构域中的疏水残基促进胃癌上皮间质转化
DOI：
10.18632/oncotarget.17473
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发表时间：
2017-07-18
期刊：
影响因子：
--
通讯作者：
Zhu Z
中科院分区：
文献类型：
--
作者：
He C;Wang Z;Zhang L;Yang L;Li J;Chen X;Zhang J;Chang Q;Yu Y;Liu B;Zhu Z
前b细胞白血病同源盒1 （PBX1）最初被确定为人类白血病的原癌基因。虽然该蛋白已被证明有助于细胞发育和肿瘤发生，但PBX1在胃癌（GC）中的作用尚不清楚。在本研究中，我们观察到与邻近正常组织相比，GC组织中PBX1的表达增加。PBX1表达水平的增加与HOXB9 mRNA表达呈负相关，并且与恶性肿瘤和转移有关。PBX1在体外和体内均能促进胃癌细胞的增殖和转移。这些现象还伴有上皮-间质转化（EMT）。此外，我们观察到PBX1促进肿瘤生长和血管生成因子的表达。PBX1- hox复合物的结构模型显示，PBX1与六肽基序之间的疏水结合可能是诱导EMT的必要条件。该分析还表明，TALE同位结构域第一螺旋上的Phe252残基参与了后一种疏水结合反应。来自PBX1突变体的体外数据表明，当Phe252残基失去疏水性时，PBX1不能通过EMT诱导GC细胞发生肿瘤。这种残基的存在很可能是促进与六肽基序的疏水结合所必需的。这些发现表明PBX1可能是胃癌治疗的潜在靶点，本研究为阐明PBX1在胃癌发生中的作用的分子机制提供了一个平台。
Pre-B-cell leukemia homeobox 1 (PBX1) was originally identified as a proto-oncogene in human leukemia. Although this protein has been shown to contribute to cellular development and tumorigenesis, the role of PBX1 in gastric carcinoma (GC) remains unclear. In this study, we observed increased expression of PBX1 in GC tissues compared with adjacent normal tissues. This increase in PBX1 expression levels negatively correlated with HOXB9 mRNA expression and was also associated with malignancy and metastasis. PBX1 promoted proliferation and metastasis of GC cells both in vitro and in vivo. These phenomena were also accompanied by epithelial-to-mesenchymal transition (EMT). Additionally, we observed that PBX1 promotes the expression of tumor growth and angiogenic factors. A structural model of the PBX1-HOX complex revealed that hydrophobic binding between PBX1 and the hexapeptide motif might be required for EMT induction. This analysis also demonstrated that the Phe252 residue in the first helix of the TALE homeodomain is involved in the latter hydrophobic binding reaction. In vitro data from PBX1 mutants suggest that PBX1 cannot promote tumorigenesis of GC cells via EMT induction when Phe252 residues lose hydrophobicity. It is likely that the presence of this residue is essential in facilitating hydrophobic binding with the hexapeptide motif. These findings suggest that PBX1 may be a potential target for GC treatment and this study provides a platform to elucidate the molecular mechanisms that underpin the role of PBX1 in GC tumorigenesis.
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