Open Access Research article

Matrix metalloproteinase 12 is induced by heterogeneous nuclear ribonucleoprotein K and promotes migration and invasion in nasopharyngeal carcinoma

I-Che Chung1, Lih-Chyang Chen2, An-Ko Chung3, Mei Chao4, Hsin-Yi Huang3, Chuen Hsueh15, Ngan-Ming Tsang6, Kai-Ping Chang7, Ying Liang1, Hsin-Pai Li14* and Yu-Sun Chang13*

Author Affiliations

1 Molecular Medicine Research Center, Chang Gung University, 259 Wen-Hwa Ist Road, Taoyuan, Kwei-shan 333, Taiwan

2 Department of Medicine, Mackay Medical College, No.46, Sec.3, Zhong-Zheng Rd, New Taipei City, San-Zhi Dist 252, Taiwan

3 Graduate Institute of Biomedical Sciences, Chang Gung University, 259 Wen-Hwa Ist Road, Taoyuan, Kwei-shan 333, Taiwan

4 Department of Microbiology and Immunology, Chang Gung University, 259 Wen-Hwa Ist Road, Taoyuan, Kwei-shan 333, Taiwan

5 Departments of Pathology, Chang Gung Memorial Hospital at Lin-Kou, 5, Fu-Ching St, Taoyuan, Kwei-Shan 333, Taiwan

6 Departments of Radiation Oncology, Chang Gung Memorial Hospital at Lin-Kou, 5, Fu-Ching St, Taoyuan, Kwei-Shan 333, Taiwan

7 Departments of Otolaryngology, Chang Gung Memorial Hospital at Lin-Kou, 5, Fu-Ching St, Taoyuan, Kwei-Shan 333, Taiwan

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BMC Cancer 2014, 14:348  doi:10.1186/1471-2407-14-348

Published: 20 May 2014

Abstract

Background

Overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a DNA/RNA binding protein, is associated with metastasis in nasopharyngeal carcinoma (NPC). However, the mechanisms underlying hnRNP K-mediated metastasis is unclear. The aim of the present study was to determine the role of matrix metalloproteinase (MMP) in hnRNP K-mediated metastasis in NPC.

Methods

We studied hnRNP K-regulated MMPs by analyzing the expression profiles of MMP family genes in NPC tissues and hnRNP K-knockdown NPC cells using Affymetrix microarray analysis and quantitative RT-PCR. The association of hnRNP K and MMP12 expression in 82 clinically proven NPC cases was determined by immunohistochemical analysis. The hnRNP K-mediated MMP12 regulation was determined by zymography and Western blot, as well as by promoter, DNA pull-down and chromatin immunoprecipitation (ChIP) assays. The functional role of MMP12 in cell migration and invasion was demonstrated by MMP12-knockdown and the treatment of MMP12-specific inhibitor, PF-356231.

Results

MMP12 was overexpressed in NPC tissues, and this high level of expression was significantly correlated with high-level expression of hnRNP K (Pā€‰=ā€‰0.026). The levels of mRNA, protein and enzyme activity of MMP12 were reduced in hnRNP K-knockdown NPC cells. HnRNP K interacting with the region spanning āˆ’42 to āˆ’33 bp of the transcription start site triggered transcriptional activation of the MMP12 promoter. Furthermore, inhibiting MMP12 by MMP12 knockdown and MMP12-specific inhibitor, PF-356231, significantly reduced the migration and invasion of NPC cells.

Conclusions

Overexpression of MMP12 was significantly correlated with hnRNP K in NPC tissues. HnRNP K can induce MMP12 expression and enzyme activity through activating MMP12 promoter, which promotes cell migration and invasion in NPC cells. In vitro experiments suggest that NPC metastasis with high MMP12 expression may be treated with PF-356231. HnRNP K and MMP12 may be potential therapeutic markers for NPC, but additional validation studies are warranted.

Keywords:
hnRNP K; MMP12; Migration; Invasion; Nasopharyngeal carcinoma