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Mol Cancer. 2015 Apr 12;14:83. doi: 10.1186/s12943-015-0348-7.

Suppression of Aurora-A-FLJ10540 signaling axis prohibits the malignant state of head and neck cancer.

Chen CH1,2,3,4, Chang AY5, Li SH6, Tsai HT7,8,9, Shiu LY10, Su LJ11, Wang WL12,13,14, Chiu TJ15,16, Luo SD17,18, Huang TL19,20, Chien CY21,22,23.

Author information

1
Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. chench7@gmail.com.
2
Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan. chench7@gmail.com.
3
Kaohsiung Chang Gung Head and Neck Oncology Group, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. chench7@gmail.com.
4
Department of Applied Chemistry and Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Taoyuan, Taiwan. chench7@gmail.com.
5
Institute of Physiology, National Cheng Kung University, Tainan, Taiwan. aywchang@mail.ncku.edu.tw.
6
Departments of Hematology-Oncology, Chang Gung University College of Medicine, Kaohsiung, Taiwan. lee0624@cgmh.org.tw.
7
Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. thtsophia66@gmail.com.
8
Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan. thtsophia66@gmail.com.
9
Kaohsiung Chang Gung Head and Neck Oncology Group, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. thtsophia66@gmail.com.
10
Department of Medical Research, Cell Therapy and Research Center, E-Da Hospital, I-shou University, Kaohsiung, Taiwan. her2neu24@yahoo.com.tw.
11
Graduate Institute of Systems Biology and Bioinformatics, National Central University, Jhongli, Taiwan. sulijen@gmail.com.
12
Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan. wwenlung@gmail.com.
13
Kaohsiung Chang Gung Head and Neck Oncology Group, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. wwenlung@gmail.com.
14
Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. wwenlung@gmail.com.
15
Kaohsiung Chang Gung Head and Neck Oncology Group, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. chiutaijan@gmail.com.
16
Departments of Hematology-Oncology, Chang Gung University College of Medicine, Kaohsiung, Taiwan. chiutaijan@gmail.com.
17
Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan. rsd0323.tw@gmail.com.
18
Kaohsiung Chang Gung Head and Neck Oncology Group, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. rsd0323.tw@gmail.com.
19
Kaohsiung Chang Gung Head and Neck Oncology Group, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. victorhtl@yahoo.com.tw.
20
Departments of Hematology-Oncology, Chang Gung University College of Medicine, Kaohsiung, Taiwan. victorhtl@yahoo.com.tw.
21
Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. cychien3965@cgmh.org.tw.
22
Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan. cychien3965@cgmh.org.tw.
23
Kaohsiung Chang Gung Head and Neck Oncology Group, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. cychien3965@cgmh.org.tw.

Abstract

BACKGROUND:

Head and neck cancer (HNC) is a highly invasive cancer. Aurora-A has been reported for a number of malignancies. However, the identity of downstream effectors responsible for its aggressive phenotype in HNC remains underinvestigated.

METHODS:

The mRNA and protein expression levels of Aurora-A and FLJ10540 were assessed in HNC specimens and cell lines using RT-qPCR, western blot, Oncomine, and microarray database analysis. The downstream molecular mechanisms of Aurora-A were confirmed by RT-qPCR, western blot, luciferase reporter, confocal microscopy analyses, immunoprecipitation, colony formation, cell viability, and xenograft model. Cellular functions in response to Aurora-A-modulated downstream targets such as FLJ10540 and MMPs were examined in vitro and in vivo, including cell growth, motility and chemosensitivity. Aurora-A/FLJ10540/MMPs expression was determined in cancer and adjacent normal tissues from HNC patients by immunohistochemistry approach.

RESULTS:

In the current study, Aurora-A exhibited similar gene expression profiles with FLJ10540 by using accessibly public microarray and Oncomine database analysis, raising the possibility that these molecules might coordinately participate in cancer progression and metastasis of HNC. These two molecules connection were also examined in cell lines and tissues of HNC. Aurora-A overexpression could not only bind to the promoter of FLJ10540 to induce FLJ10540 expression, but also increase both mRNA and protein levels of MMP-7 and MMP-10 in HNC cells. Conversely, depletion of Aurora-A expression by using siRNA or Aurora-A kinase inhibitor, MLN8237, suppressed FLJ10540, MMP-7 and MMP-10 mRNA and protein expressions in vitro and in vivo. In addition, the FLJ10540-PI3K complex was destroyed by inhibition the Aurora-A kinase activity. Forced overexpression of FLJ10540 in Aurora-A-depleted or in MLN8237-treated HNC cells attenuated the effect on cytotoxicity to cisplatin. Elevated Aurora-A expression in HNC cells led to the characteristics of more aggressive malignancy, including enhanced chemoresistance and increased the abilities of proliferation, migration and invasion, which was required for FLJ10540/MMP-7 or FLJ10540/MMP-10 expressions. Finally, immunohistochemical analysis of human HNC specimens showed a significant positively correlation among Aurora-A, FLJ10540, MMP-7 and MMP-10 expressions.

CONCLUSION:

Together, our findings define a novel mechanism by which Aurora-A promotes cell malignancy, with potential implications for understanding the clinical action of Aurora-A.

PMID:
25889801
PMCID:
PMC4403844
DOI:
10.1186/s12943-015-0348-7
[Indexed for MEDLINE]
Free PMC Article

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