He Changyu, Wang Zhenqiang, Zhang Li, Yang Liyun, Li Jianfang, Chen Xuehua, Zhang Jun, Chang Qing, Yu Yingyan, Liu Bingya, Zhu Zhenggang
Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Otolaryngology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Oncotarget. 2017 Jul 18;8(29):46818-46833. doi: 10.18632/oncotarget.17473.
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.
前B细胞白血病同源盒1（PBX1）最初被鉴定为人类白血病中的一种原癌基因。尽管已证明这种蛋白质有助于细胞发育和肿瘤发生，但PBX1在胃癌（GC）中的作用仍不清楚。在本研究中，我们观察到与相邻正常组织相比，GC组织中PBX1的表达增加。PBX1表达水平的这种增加与HOXB9 mRNA表达呈负相关，并且还与恶性肿瘤和转移相关。PBX1在体外和体内均促进GC细胞的增殖和转移。这些现象还伴随着上皮-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所必需的。该分析还表明，TALE同源结构域第一个螺旋中的Phe252残基参与了后者的疏水结合反应。来自PBX1突变体的体外数据表明，当Phe252残基失去疏水性时，PBX1不能通过诱导EMT促进GC细胞的肿瘤发生。该残基的存在可能对于促进与六肽基序的疏水结合至关重要。这些发现表明，PBX1可能是GC治疗的潜在靶点，并且本研究提供了一个平台来阐明支撑PBX1在GC肿瘤发生中作用的分子机制。
