Overexpression of carbonic anhydrase IX induces cell motility by activating matrix metalloproteinase-9 in human oral squamous cell carcinoma cells
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Jia-Sin Yang1,2, Chiao-Wen Lin3,4, Yi-Hsien Hsieh5, Ming-Hsien Chien6,7, Chun-Yi Chuang8,9 and Shun-Fa Yang1,2
1Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
2Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
3Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
4Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
5Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
6Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
7Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
8School of Medicine, Chung Shan Medical University, Taichung, Taiwan
9Department of Otolaryngology, Chung Shan Medical University Hospital, Taichung, Taiwan
Shun-Fa Yang, email: [email protected]
Chun-Yi Chuang, email: [email protected]
Keywords: carbonic anhydrase, matrix metalloproteinase, metastasis, migration, OSCC
Received: July 02, 2017 Accepted: July 26, 2017 Published: August 12, 2017
Oral cancer is a solid malignant tumor that is prone to occur following hypoxia. There are no clear studies showing a link between hypoxia and oral carcinogenesis. Carbonic anhydrase IX (CAIX), which is a hypoxia-induced transmembrane protein, is highly expressed in various types of human cancer. However, the effects of CAIX on the metastasis of human oral cancer cells and the underlying molecular mechanisms have not been clarified. In this study, we observed that CAIX overexpression increased the migratory and invasive abilities of SCC-9 and SAS cells. In addition, CAIX overexpression increased the mRNA and protein expression of matrix metalloproteinase-9 (MMP-9) and the phosphorylation of focal adhesion kinase (FAK), steroid receptor coactivator (Src), and extracellular signal-regulated kinase 1/2 signaling proteins. CAIX overexpression also increased the binding capacity of nuclear factor-κB (NF-κB), c-Jun, and c-Fos on the MMP-9 gene promoter. In addition, treatment with MMP-9 short hairpin RNA, an MMP inhibitor (GM6001), an FAK mutant, or an MEK inhibitor (U0126) inhibited CAIX-induced cell motility in SCC-9 cells. Moreover, data sets from The Cancer Genome Atlas demonstrated that CAIX expression was significantly associated with advanced progression and poor survival in oral cancer. In conclusion, it can be inferred that CAIX overexpression induces MMP-9 gene expression, which consequently induces the metastasis of oral cancer cells.
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