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Cancer Res. 2016 Dec 15;76(24):7140-7150. Epub 2016 Oct 19.

Dysregulation of RUNX2/Activin-A Axis upon miR-376c Downregulation Promotes Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma.

Chang WM1,2,3, Lin YF4, Su CY3, Peng HY2, Chang YC3, Lai TC3, Wu GH2, Hsu YM2, Chi LH3,5,6, Hsiao JR7, Chen CL8,9, Chang JY2,10, Shieh YS11,12, Hsiao M13,14, Shiah SG15,12.

Author information

1
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
2
National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
3
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
4
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
5
The PhD Program for Translational Medicine, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
6
Division of Oral and Maxillofacial Surgery, Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan.
7
Department of Otolaryngology, Head and Neck Collaborative Oncology Group and National Cheng-Kung University Hospital, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
8
Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
9
Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
10
Department of Internal Medicine, National Cheng-Kung University Hospital, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
11
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan. davidssg@nhri.org.tw mhsiao@gate.sinica.edu.tw ndmcyss@ndmctsgh.edu.tw.
12
Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
13
Genomics Research Center, Academia Sinica, Taipei, Taiwan. davidssg@nhri.org.tw mhsiao@gate.sinica.edu.tw ndmcyss@ndmctsgh.edu.tw.
14
Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
15
National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. davidssg@nhri.org.tw mhsiao@gate.sinica.edu.tw ndmcyss@ndmctsgh.edu.tw.

Abstract

Epigenetic correlates of the head and neck cancer may illuminate its pathogenic roots. Through a gene set enrichment analysis, we found that the oncogenic transcription factor RUNX2 is widely upregulated in the head and neck squamous cell carcinoma (HNSCC) with lymph node metastasis, where it also predicts poor prognosis in patients with HNSCC. Enforced expression of ectopic RUNX2 promoted the metastatic capabilities of HNSCC, whereas RUNX2 silencing inhibited these features. Mechanistic investigations showed that manipulating levels of activin A (INHBA) could rescue or compromise the RUNX2-mediated metastatic capabilities of HNSCC cells. Furthermore, we found that miR-376c-3p encoded within the 3'-untranslated region of RUNX2 played a pivotal role in regulating RUNX2 expression in highly metastatic HNSCC cells, where it was downregulated commonly. Restoring miR-376c expression in this setting suppressed expression of RUNX2/INHBA axis along with metastatic capability. Clinically, we observed an inverse relationship between miR-376c-3p expression and the RUNX2/INHBA axis in HNSCC specimens. In summary, our results defined a novel pathway in which dysregulation of the RUNX2/INHBA axis due to miR-376c downregulation fosters lymph node metastasis in HNSCC. Cancer Res; 76(24); 7140-50.

PMID:
27760788
DOI:
10.1158/0008-5472.CAN-16-1188
[Indexed for MEDLINE]
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