MUC20 overexpression predicts poor prognosis and enhances EGF-induced malignant phenotypes via activation of the EGFR–STAT3 pathway in endometrial cancer
Highlights
► MUC20 is an independent prognostic factor for poor survival in patients with endometrial cancer. ► Forced expression of MUC20 increases malignant properties of endometrial cancer cells in vitro and in vivo. ► MUC20 enhances EGF-triggered EGFR–STAT3 signaling pathway.
Introduction
Endometrial cancer (EC) is the second most common gynecological malignancy in Taiwan, and its incidence has increased dramatically over the last decade. Most patients with EC have no clinical evidence of extrauterine spread and have a 5-year survival of more than 80% [1], [2]. In contrast to patients with early stage EC, patients with metastatic EC have a poor prognosis with a median survival of 8–16 months despite multimodality treatments including combination chemotherapy [3]. To further improve on outcome for patients with this disease, physicians need to identify high-risk patients and develop new treatment strategies to provide the best long-term survival.
Mucins are highly glycosylated proteins expressed by various epithelial cells. Mucins are categorized into: membrane-bound mucins (MUC1, MUC3A, MUC4, MUC12, MUC13, MUC15, MUC16, MUC17, MUC20, and MUC21) and secreted mucins (MUC2, MUC5AC, MUC5B, MUC6, MUC7, MUC8, and MUC19) [4]. Mucins not only provide a protective barrier for the epithelium but also serve as sensors of the external environment to transmit signals into cells. Altered expression of membrane-bound mucins often accompanies tumor progression and modulates many cellular properties, such as proliferation, migration, and invasion [4], [5], [6], [7], [8], [9], [10], [11], [12]. A recently identified membrane-bound mucin MUC20 is highly expressed in kidney and moderately in placenta, colon, lung, prostate, and liver [13]. MUC20 in kidney cells has been demonstrated to be a negative regulator in the HGF-induced Grb2-Ras pathway [14]. The over-production of MUC20 is associated with renal injuries [13].
Epidermal growth factor receptor (EGFR) is a membrane-bound receptor tyrosine kinase that belongs to the ErbB subfamily. On ligand binding, EGFRs initiate activation of a series of cellular signal transduction pathways that regulate cell growth, migration, and invasion. The EGFR shows altered expression in a variety of human cancers, including carcinomas of the lung, breast, head and neck, and bladder as well as ovary [15]. In addition to AKT and ERK, signal transducer and activator of transcription 3 (STAT3) is an important downstream signaling molecule of EGFR. STAT3 has been demonstrated to be critically involved in almost all aspects of tumorigenesis, including cell cycle progression, tumor invasion and metastasis, immune system evasion, and tumor angiogenesis [16], [17], [18], [19].
Although mucins play crucial roles in tumor development, no association of MUC20 with cancer has been reported. In this study, we evaluated MUC20 expression to determine its prognostic significance in patients with EC. Furthermore, we analyzed functions of MUC20 in EC cells and the underlying mechanisms to provide novel insights into the pathogenesis of EC.
Section snippets
Patient samples
Following written consent obtained from patients before sample collection and approval by our Institutional Review Board, paraffin-embedded archived tissue blocks from 66 patients with endometrioid EC and 31 patients with non-endometrioid (18 serous, 8 clear cell, and 5 mucinous) EC who had undergone surgery at the National Taiwan University Hospital between 2001 and 2009 were selected for the study. A chart review was performed in order to abstract clinicopathologic information.
Immunohistochemistry
MUC20 is frequently overexpressed in EC
The immunostaining intensity of MUC20 in normal (n = 16) and cancerous (n = 97) endometrial tissues was scored from 0 to 3 (Fig. 1A). For analysis of correlation with clinicopathologic characteristics, the expression of MUC20 was classified into two levels, namely, low (SI < 6) and high (SI ≥ 6). Our data showed that high levels of MUC20 expression were not found in normal endometrial tissues, whereas there was 43% (42/97) for EC tissues (Fig. 1B). We also found that MUC20 was differentially expressed
Discussion
EC is a heterogeneous tumor. The clinicopathologic and molecular data suggest the existence of two distinct types of EC [25], [28], [29]. Type I EC comprises the endometrioid adenocarcinomas and type II EC is that of non-endometrioid histology, in particular serous or clear-cell morphology. Herein, we demonstrated that MUC20 was overexpressed in either type I or type II EC specimens compared with the normal endometrial tissues. Moreover, MUC20 overexpression was significantly correlated with
Conflict of interest statement
The authors declare that they have no conflicts of interest.
Acknowledgments
This work was supported by the National Taiwan University Hospital 99M-1442, 100M-1703, and 101M-1941 (to Dr. Chen CH) and the National Science Council NSC98-2320-B-002-032-MY3 (to Dr. Huang MC).
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