MUC1 induces metastasis in esophageal squamous cell carcinoma by upregulating matrix metalloproteinase 13

Abstract

Esophagus squamous cell carcinoma (ESCC) is one of the most deadly malignances because of its high frequency of metastasis. Given the associations of MUC1 with ESCC and tumor metastasis, we explored a potential role of MUC1 in ESCC metastasis. Among 40 ESCC and 20 paired normal tissue specimens examined, we found a significant increase of MUC1 expression in ESCC and more importantly, that expression of MUC1 and MMP13 are strongly correlated in patients who had lymph node metastasis. Studies with cell models indicated that overexpression of MUC1 upregulates the expression of MMP13, leading to increased cell migration. In support of a mode of transcriptional regulation, promoter analysis revealed that MUC1 stimulates MMP13 expression through the Runx-2-binding site. The link of MUC1 to cell motility was further confirmed by the finding that depletion of MUC1 resulted in reduced expression of MMP13 and cell migration, invasion and adhesion. Moreover, the loss of cell metastatic potential was rescued by overexpression of MMP13 completely. Collectively, our findings indicate that MUC1 contributes to ESCC metastasis by stimulating MMP13 expression, suggesting MUC1 as a novel diagnostic biomarker and therapeutic target in ESCC. Esophageal squamous cell carcinoma (ESCC) frequently exhibits extensive local invasion or regional lymph node metastasis at the time of initial diagnosis; therefore, it is one of the most common aggressive diseases with poor outcome. 1 Tumor invasion and metastasis involve degradation of different components of the extracellular matrix and require the actions of proteolytic enzymes, such as matrix metalloproteinases (MMPs), which are produced either by the tumor cells or surrounding stromal cells.2,3 MMP13 is a highly regulated zinc-dependent endopeptidase and has been reported to be associated with vascular invasion and lymph node metastasis in ESCC. 4 Mechanisms involved in regulation of MMP13 in ESCC are likely complex and poorly understood.Mucins are high-molecular-weight glycoproteins that have been identified as markers of adverse prognosis and as attractive therapeutic targets.5 MUC1, one of transmembrane mucins, is normally expressed in esophageal epithelium.Patients with MUC1 high expression often appear with advanced stage or lymph node metastasis suggesting correlation of the MUC1 expression and the invasion or metastasis of ESCC.6 In this study, we investigated the expression of MUC1 and MMP13 in ESCC patients and the potential functional relationship in tumor metastasis and prognosis. MATERIALS AND METHODS Tissue Sample CollectionA total of 40 paraffin-embedded archival specimens of primary ESCC cases were enrolled in this study: 20 with lymph node metastasis and 20 without lymph node metastasis. A total of 20 paired normal esophageal tissue specimens distant from the cancerous lesion in patients without lymph node metastasis were used as control. These patients did not receive any preoperative adjuvant radiation or chemotherapy.

Effects of matrix metalloproteinase 13 on vascular smooth muscle cells migration via Akt–ERK dependent pathway

“…Although many reports demonstrate that MMP13 is involved in the migration and invasion of various tumor and non-tumor cell types, including esophageal squamous cell carcinoma, cutaneous squamous cell carcinoma, and endothelial cells (Lopez-Rivera et al, 2005;Xu et al, 2012;Ye et al, 2011), the role of MMP13 in migratory VSMCs has been unclear. Our finding that Ang II treatment resulted in a significant increase of MMP13 expression in RAoSMCs is similar to a previous report in which Ang II induced production of MMP3 and MMP13 via the AT 1 receptor in osteoblasts (Nakai et al, 2013).…”

“…(Meierjohann et al, 2010;Pan et al, 2011;Yu et al, 2011). The metastasis of esophageal squamous cell carcinoma induced by MUC1, one of the transmembrane mucins, was reported to be mediated by upregulation of MMP13 expression (Ye et al, 2011). Non-tumor endothelial cell migration is also mediated by MMP13 via nitric oxide activation (Lopez-Rivera et al, 2005).…”

Significance of MUC1 expression in biopsy specimens of submucosal invasive gastric carcinoma: The association with lymph node metastasis

“…However, MUC1 is overexpressed in metastatic disease and becomes localized throughout the cell (16). In numerous types of tumors, MUC1 expression was reported to be correlated with aggressiveness, metastatic disease and poor prognosis (9)(10)(11)(12)(13)16,18). MUC1 expression was reported to accelerate tumor invasion and metastasis via the impairment of E-cadherin (10), decrease the binding of p120 catenin to E-cadherin (18), upregulate matrix metalloproteinase 13 expression (13) and activate Wnt/β-catenin abnormally (9).…”

“…ESD guidelines were previously based on hematoxylin and eosin staining; however, numerous studies have reported that the expression of cell adhesion molecules, cell surface molecules, membrane-associated mucin phenotypes and collagen phenotypes are associated with lymph node metastasis and prognosis of carcinomas in multiple organs (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Mucin 1, cell surface associated (MUC1) is a transmembrane member of the mucin family and has been reported to be associated with metastatic progression (16).…”

Is carcinoma a mesenchymal disease? The role of the stromal microenvironment in carcinogenesis

“…65 Up-regulation of MMP-13 is associated with the development of metastases in oesophageal squamous cell carcinoma. 69 MMP-9 may also regulate angiogenesis, perhaps by releasing VEGF from the extracellular matrix and making it more available to endothelial cells; 50 and yet overexpression of MMP-9 was found to be associated with improved survival in organ-confined prostate cancer; 70 clearly it is not a case of 'one biomarker fits all'. Interestingly, it has been suggested that the relatively better prognosis in Lynch syndrome-associated cancers may in part be explained by the finding that expression of MMP-1 and -9 is lower in these tumours than in their sporadic counterparts, resulting in less efficient matrix degradation of the peritumoural stroma which would facilitate tumour cell migration.…”