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

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 24; pp. 7140 - 7150
• Main Authors: Chang, Wei-Min, Lin, Yuan-Feng, Su, Chia-Yi, Peng, Hsuan-Yu, Chang, Yu-Chan, Lai, Tsung-Ching, Wu, Guan-Hsun, Hsu, Yuan-Ming, Chi, Li-Hsing, Hsiao, Jenn-Ren, Chen, Chi-Long, Chang, Jang-Yang, Shieh, Yi-Shing, Hsiao, Michael, Shiah, Shine-Gwo
• Format: Journal Article
• Language: English
• Published: United States 15.12.2016
• Subjects: Animals; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Chromatin Immunoprecipitation; Core Binding Factor Alpha 1 Subunit - metabolism; Down-Regulation; Female; Gene Expression Regulation, Neoplastic - physiology; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Humans; In Situ Hybridization; Inhibin-beta Subunits - metabolism; Lymphatic Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs - biosynthesis; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Signal Transduction - physiology; Squamous Cell Carcinoma of Head and Neck; Tissue Array Analysis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-1188

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. ©2016 AACR.