Abstract
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.
Highlights
Oral cancer is a major subgroup of head and neck cancers and remains a common malignancy worldwide [1]
To explore the clinical value of Carbonic anhydrase IX (CAIX) in patients with malignant tumors, we analyzed CAIX mRNA expression in data sets from The Cancer Genome Atlas (TCGA) and found that most CAIX transcripts were overexpressed in carcinoma tissues compared with noncancerous tissues (Figure 1A)
Because cell invasion and metastasis are often associated with the enhanced expression of MMPs [21,22,23,24], we examined the effect of CAIX on expression of MMP family by using real-time polymerase chain reaction (PCR)
Summary
Oral cancer is a major subgroup of head and neck cancers and remains a common malignancy worldwide [1]. In Taiwan, oral cancer is the fourth leading cause of cancer death and is associated with increasing morbidity and mortality rates [2, 3]. Despite technological advancement in treatment modalities and diagnosis, the 5-year survival rate of oral cancer patients has not significantly improved during the last half century [4]. The overall survival rate of oral cancer patients is relatively low due to metastasis and recurrence [5, 6]. CAIX supplies bicarbonate ions for the neutralization of intracellular pH and provides protons for the acidification of the extracellular microenvironment, which contribute to promoting cell survival and proliferation, reducing cell adhesion, activating proteases that degrade the extracellular matrix (ECM), and increasing cell migration and invasion [11,12,13,14]
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