HOXB9 induction of mesenchymal-to-epithelial transition in gastric carcinoma is negatively regulated by its hexapeptide motif
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Qing Chang1,2,*, Li Zhang1,4,*, Changyu He1, Baogui Zhang1, Jun Zhang2, Bingya Liu1, Naiyan Zeng3, Zhenggang Zhu1
1Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2Department of Clinical Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
3Department of Pathology and Pathophysiology, Key laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
4Current Address: Department of Gastrointestinal Surgery, Guizhou Provincial People's Hospital, Guiyang, China
*These authors have contributed equally to this work
Naiyan Zeng, e-mail: [email protected]
Zhenggang Zhu, e-mail: [email protected]
Keywords: HOXB9, hexapeptide, gastric carcinoma, mesenchymal-to-epithelial transition
Received: April 17, 2015 Accepted: October 13, 2015 Published: October 23, 2015
HOXB9, a transcription factor, plays an important role in development. While HOXB9 has been implicated in tumorigenesis and metastasis, its mechanisms are variable and its role in gastric carcinoma (GC) remains unclear. In the present study, we demonstrated that the expression of HOXB9 decreased in gastric carcinoma and was associated with malignancy and metastasis. Re-expression of HOXB9 in gastric cell lines resulted in the suppression of cell proliferation, migration, and invasion, which was accompanied by the induction of mesenchymal-to-epithelial transition (MET). Comparative sequence analysis and examination of a HOXB9 structural model indicated that three sites might possibly be involved in MET regulation. The in vitro study of HOXB9 mutants showed that these were unable to inhibit MET induction. However, when overexpressing a HOXB9 mutant lacking the hexapeptide motif, a more potent MET induction and tumor suppression was observed compared to that of the wild-type, indicating that the presence of the hexapeptide motif reduced HOXB9 MET induction and tumor suppression activity. Therefore, the results of the present study suggested that HOXB9 is a tumor suppressor in gastric carcinoma, and its activity was controlled by different regulatory mechanisms such as the hexapeptide motif as a “brake” in this case. The results of these regulatory effects could lead to either oncogenic or tumor suppressive roles of HOXB9, depending on the context of the particular type of cancer involved.
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