Dysregulation of RUNX2/activin-A axis upon miR-376c downregulation promotes lymph node metastasis in head and neck squamous cell carcinoma

Wei Min Chang, Yuan Feng Lin, Chia Yi Su, Hsuan Yu Peng, Yu Chan Chang, Tsung Ching Lai, Guan Hsun Wu, Yuan Ming Hsu, Li Hsing Chi, Jenn Ren Hsiao, Chi Long Chen, Jang Yang Chang, Yi Shing Shieh, Michael Hsiao, Shine Gwo Shiah

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7140-7150
Number of pages11
JournalCancer Research
Volume76
Issue number24
DOIs
Publication statusPublished - 2016 Dec 15

Fingerprint

Down-Regulation
Lymph Nodes
Neoplasm Metastasis
3' Untranslated Regions
Head and Neck Neoplasms
Carcinoma, squamous cell of head and neck
activin A
Epigenomics
Transcription Factors
Genes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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. / Dysregulation of RUNX2/activin-A axis upon miR-376c downregulation promotes lymph node metastasis in head and neck squamous cell carcinoma. In: Cancer Research. 2016 ; Vol. 76, No. 24. pp. 7140-7150.
@article{0e3663b152db41cca98d558b79330af9,
title = "Dysregulation of RUNX2/activin-A axis upon miR-376c downregulation promotes lymph node metastasis in head and neck squamous cell carcinoma",
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.",
author = "Chang, {Wei Min} and Lin, {Yuan Feng} and Su, {Chia Yi} and Peng, {Hsuan Yu} and Chang, {Yu Chan} and Lai, {Tsung Ching} and Wu, {Guan Hsun} and Hsu, {Yuan Ming} and Chi, {Li Hsing} and Hsiao, {Jenn Ren} and Chen, {Chi Long} and Chang, {Jang Yang} and Shieh, {Yi Shing} and Michael Hsiao and Shiah, {Shine Gwo}",
year = "2016",
month = "12",
day = "15",
doi = "10.1158/0008-5472.CAN-16-1188",
language = "English",
volume = "76",
pages = "7140--7150",
journal = "Cancer Research",
issn = "0008-5472",
number = "24",

}

Chang, WM, Lin, YF, Su, CY, Peng, HY, Chang, YC, Lai, TC, Wu, GH, Hsu, YM, Chi, LH, Hsiao, JR, Chen, CL, Chang, JY, Shieh, YS, Hsiao, M & Shiah, SG 2016, 'Dysregulation of RUNX2/activin-A axis upon miR-376c downregulation promotes lymph node metastasis in head and neck squamous cell carcinoma', Cancer Research, vol. 76, no. 24, pp. 7140-7150. https://doi.org/10.1158/0008-5472.CAN-16-1188

Dysregulation of RUNX2/activin-A axis upon miR-376c downregulation promotes lymph node metastasis in head and neck squamous cell carcinoma. / 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.

In: Cancer Research, Vol. 76, No. 24, 15.12.2016, p. 7140-7150.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dysregulation of RUNX2/activin-A axis upon miR-376c downregulation promotes lymph node metastasis in head and neck squamous cell carcinoma

AU - Chang, Wei Min

AU - Lin, Yuan Feng

AU - Su, Chia Yi

AU - Peng, Hsuan Yu

AU - Chang, Yu Chan

AU - Lai, Tsung Ching

AU - Wu, Guan Hsun

AU - Hsu, Yuan Ming

AU - Chi, Li Hsing

AU - Hsiao, Jenn Ren

AU - Chen, Chi Long

AU - Chang, Jang Yang

AU - Shieh, Yi Shing

AU - Hsiao, Michael

AU - Shiah, Shine Gwo

PY - 2016/12/15

Y1 - 2016/12/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85006944248&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006944248&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-16-1188

DO - 10.1158/0008-5472.CAN-16-1188

M3 - Article

C2 - 27760788

AN - SCOPUS:85006944248

VL - 76

SP - 7140

EP - 7150

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 24

ER -