Oncotarget

Research Papers:

A hydrophobic residue in the TALE homeodomain of PBX1 promotes epithelial-to-mesenchymal transition of gastric carcinoma

Changyu He, Zhenqiang Wang, Li Zhang, Liyun Yang, Jianfang Li, Xuehua Chen, Jun Zhang, Qing Chang _, Yingyan Yu, Bingya Liu and Zhenggang Zhu

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Oncotarget. 2017; 8:46818-46833. https://doi.org/10.18632/oncotarget.17473

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Abstract

Changyu He1,*, Zhenqiang Wang1,*, Li Zhang1, Liyun Yang2, Jianfang Li1, Xuehua Chen1, Jun Zhang3, Qing Chang4, Yingyan Yu1, Bingya Liu1 and Zhenggang Zhu1

1 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

2 Department of Otolaryngology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

3 Department of Clinical Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

4 Clinical Research Center, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China

* These authors have contributed equally to this work

Correspondence to:

Qing Chang, email:

Zhenggang Zhu, email:

Keywords: PBX1, gastric carcinoma, epithelial-to-mesenchymal transition, tumorigenesis, hydrophobic binding

Received: October 24, 2016 Accepted: April 12, 2017 Published: April 27, 2017

Abstract

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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