Abstract
Esophageal squamous cell carcinoma (ESCC) is increasing in incidence, but the knowledge of the genetic underpinnings of this disease remains limited. In this study, we identified the tetraspanin cell surface receptor uroplakin 1A (UPK1A) as a candidate tumor suppressor gene (TSG), and we investigated its function and mechanism in ESCC cells. UPK1A downregulation occurred in 68% of primary ESCCs examined, where it was correlated significantly with promoter hypermethylation (P < 0.05). Ectopic expression of UPK1A in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, and tumor formation in nude mice. Mechanistic investigations suggested that these effects may be mediated by inhibiting nuclear translocation of β-catenin and inactivation of its downstream targets, including cyclin-D1, c-jun, c-myc, and matrix metalloproteinase 7 (MMP7). Cell cycle arrest elicited by UPK1A at the G(1)-S checkpoint was associated with downregulation of cyclin D1 and cyclin-dependent kinase 4, whereas metastasis suppression was associated with reduction of MMP7. These findings were consistent with evidence derived from clinical samples, where UPK1A downregulation was correlated with lymph node metastasis (P = 0.009), stage (P = 0.015), and overall survival (P < 0.0001). Indeed, multivariate cyclooxygenase regression analysis showed that UPK1A was an independent prognostic factor for overall survival. Taken together, our findings define a function for UPK1A as an important TSG in ESCC development.
Highlights
Esophageal cancer is one of the most common malignancies and has been ranked as the sixth leading cause of cancer death over the world [1]
uroplakin 1A (UPK1A) is frequently downregulated in esophageal squamous cell carcinoma (ESCC) Semiquantitative reverse transcription-PCR (RT-PCR) was used to study the expression of UPK1A in nine ESCC cell lines and 100 pairs of primary ESCC tumors and their corresponding nontumorous tissues
The results showed that absent expression of UPK1A was detected in 68 of 100 primary ESCC tissues (Fig. 1A) and five of nine ESCC cell lines (Fig. 1B)
Summary
Esophageal cancer is one of the most common malignancies and has been ranked as the sixth leading cause of cancer death over the world [1]. Throughout the world, the major type of esophageal cancer is esophageal squamous cell carcinoma (ESCC). The incidence ratio of ESCC in China varies widely compared with other common cancers, wherein the high- and low-risk regions can be as high as 500:1 [2]. More than 50% of ESCC cases occurred in Asia, wherein Linzhou and the nearby countries in Henan province of Northern China have the highest incidence in the world [3, 4]. Like other types of cancers, the development of ESCC is be-. To have a better understanding of ESCC, it is important to identify these key genes, elucidate their roles, and discover new biomarkers for improving clinical management
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