Research ArticleCD147 and AGR2 expression promote cellular proliferation and metastasis of head and neck squamous cell carcinoma
Highlights
► We investigated AGR2 in head and neck squamous cell carcinoma for the first time. ► We explored the relationship between AGR2 and CD147 for the first time. ► AGR2 and CD147 appear to co-localize in head and squamous cell carcinoma samples. ► Knockdown of both AGR2 and CD147 reduced migration and invasion in vitro. ► Knockdown of both AGR2 and CD147 decreased metastasis in vivo.
Introduction
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a propensity for invasion and metastasis. Despite advances in treatment modalities, the prognosis remains poor and survival rates have failed to improve. Contributing to treatment challenges is the underlying complexities of the disease pathogenesis, which remains largely unknown. Furthermore, the ability of HNSCC cells to migrate and invade results in significant regional and distant metastasis and poor patient survival. Limiting the ability of oncogenic cells to regionally and distantly metastasize would improve disease control and outcomes.
In order for an oncogenic cell to migrate and invade, it requires the capability of anchorage-independent growth, the means to break down the components of the extracellular matrix and basement membrane and the ability to promote the formation of new blood vessels [1], [2], [3], [4]. These requirements can all be facilitated by CD147, also known as extracellular matrix metalloproteinase inducer, a cell membrane bound glycoprotein expressed by several different types of oncogenic cells [5], [6], [7], [8], [9], [10]. CD147 allows for oncogenic cells to interact with supporting cells, such as fibroblasts and endothelial cells, resulting in increased expression of matrix metalloproteinases (MMP) and hyaluronan and upregulation of vascular endothelial growth factor [5], [9], [10], [11]. As a result, CD147 promotes tumor growth, metastasis and drug resistance [5], [6], [7], [12], [13], [14], [15].
CD147 is highly expressed in squamous cell carcinomas arising from several anatomical sites, including the head and neck, esophagus, lungs and gastrointestinal track [6], [7], [16], [17], [18], [19], [20]. Previous investigations have found high levels of CD147 expression in HNSCC and its expression correlated with tumor progression and lymphatic metastasis [6], [7], [12], [17]. We previously investigated the role of CD147 in HNSCC cell invasion and found CD147 expression by HNSCC cells resulted in increased MMP production by fibroblast and subsequent collagen degradation [8].
The tumor microenvironment also contains the secreted peptide AGR2. Elevation of AGR2 expression has been found in malignancies arising from a variety of anatomical sites, including the esophagus, breast, prostate, pancreas, lung and ovaries [21], [22], [23], [24], [25], [26], [27], [28], [29]. Furthermore, AGR2 was found to enhance breast cancer metastasis in xenografts [30]. While the exact function of AGR2 is, for the most part, unknown, it is believed that AGR2 acts as a chaperone, guiding misfolded proteins out of the cell [31], [32]. Several investigations into tumor progression have found AGR2 has a role in promoting cell migration and invasion [21], [22], [30], [33]. To this end we investigated if there was a link between these proteins, CD147 and AGR2, and metastasis of HNSCC cells.
Section snippets
Clinical tissue specimens
A retrospective review of patients with HNSCC (n=20) was performed following Institutional Review Board approval at the University of Alabama at Birmingham. Tumor histology was confirmed by the pathology department.
Cell lines and tissue culture
Two human HNSCC tumor cell lines were studied: FADU (ATCC; Manassas, VA) and OSC-19 (Jeffrey Myers, The University of Texas M. D. Anderson Cancer Center, Houston, Texas). The cells were obtained, grown, and maintained in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal
CD147 and AGR2 expression and localization in HNSCC specimens
To evaluate the expression patterns of CD147 and AGR2 in HNSCC, immunofluorescence analysis of clinical tissue specimens was performed. CD147 expression was primarily membranous, while AGR2 immunoreactivity was predominately cytoplasmic (Fig. 1) [22]. Approximately half of the oncogenic cells demonstrated CD147 expression (48.8±7.6%) while close to a third demonstrated AGR2 immunoreactivity (34.5±6.4%). Furthermore, consistent with previous findings, CD147 expression was primarily on oncogenic
Discussion
There is limited understanding of the pathogenesis which allows head and neck oncogenic cells to metastasize. Previous investigations by our lab and others, have found CD147 is highly expressed in HNSCC and plays a role in oncogenic cell invasion [6], [8], [10], [12], [15], [16], [17], [19], [39], [40]. Furthermore, CD147 expression levels have been found to correlate with progression of disease, prognosis and lymph node metastasis in HNSCC [6], [12], [16]. However, its effect on regional and
Conflicts of interest
The authors have no potential conflicts of interest to disclose.
Acknowledgment
This study was supported jointly by grants for the National Institute of Health (R01CA142637-01 and 2T32CA091078-09). The funding source had no role in experimental design or manuscript composition.
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