CD147 and AGR2 expression promote cellular proliferation and metastasis of head and neck squamous cell carcinoma

Abstract

The signaling pathways facilitating metastasis of head and neck squamous cell carcinoma (HNSCC) cells are not fully understood. CD147 is a transmembrane glycoprotein known to induce cell migration and invasion. AGR2 is a secreted peptide also known to promote cell metastasis. Here we describe their importance in the migration and invasion of HNSCC cells (FADU and OSC-19) in vitro and in vivo. In vitro, knockdown of CD147 or AGR2 decreased cellular proliferation, migration and invasion. In vivo, knockdown of CD147 or AGR2 expression decreased primary tumor growth as well as regional and distant metastasis.

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.