Original article
Prognostic significance of erythrocyte protein band 4.1-like5 expression in upper urinary tract urothelial carcinoma

https://doi.org/10.1016/j.urolonc.2017.04.008Get rights and content

Highlights

  • We observed high EPB4.1L5 expression in the invasive front of the UTUC.

  • High EPB4.1L5 score correlated with high grade and high tumor stage of patients with UTUC.

  • High EPB4.1L5 expression was related to patients׳ shorter survival.

Abstract

Objectives

The erythrocyte protein band 4.1-like5 (EPB4.1L5) regulates E-cadherin in cancer invasion and metastasis inducing epithelial-to-mesenchymal transition. This study aimed to investigate the biological significance of EPB4.1L5 in upper urinary tract urothelial carcinoma (UTUC).

Methods

Retrospective analysis of the clinical records of 165 patients with UTUC (Ta-4N0M0) subjected to radical nephroureterectomy and immunohistochemical examination of EPB4.1L5 expression in those tissues.

Results

The median follow-up period was 62.2 months (interquartile range = 77.0). The score of EPB4.1L5 significantly correlated with tumor grade, pathological T stage, and lymphovascular invasion (all P<0.001). The 5-year Kaplan-Meier recurrence-free survival and cancer-specific survival rates were 54.1% and 59.5% in patients with high EPB4.1L5 expression, compared with 81.6% and 87.2%, (all P<0.001) in their counterparts. Multivariate analyses revealed that high expression of EPB4.1L5 was one of the independent prognostic factors for tumor recurrence (P = 0.022, HR = 2.40) and cancer-specific survival (P = 0.015, HR = 2.94).

Conclusion

High EPB4.1L5 expression was related to worse clinical outcome in patients with UTUC. These results indicated that EPB4.1L5 could provide prognostic information in patients with UTUC regarding epithelial-to-mesenchymal transition.

Introduction

Upper urinary tract urothelial carcinoma (UTUC) is relatively rare, accounting for only 5% to 10% of all urothelial cancers [1], [2]. Radical nephroureterectomy with excision of the bladder cuff is the standard procedure for clinically localized UTUC. The prognosis of patients who undergo radical nephroureterectomy still remains poor because of the risk of local or distant recurrence even after curative surgery [3]. Many investigators have previously reported the possible predictors of tumor progression, including local or distant recurrences of UTUC [4], [5], [6], [7]. The clinicopathologic parameters of UTUC, such as tumor stage, histologic grade, and lymphovascular invasion (LVI), have been reported to be independent prognostic factors of clinical outcome following radical surgery [2], [4], [5], [6], [7], [8].

Epithelial-to-mesenchymal transition (EMT) is a key process in cancer development, progression, and metastasis [9], [10]. Tumor cells transform from a noninvasive to an invasive phenotype through a series of metastatic steps, whereby epithelial cells lose polarity and invade the lymphovasculature; especially necessary is disruption of E-cadherin-based cell-cell adhesion to allow cell detachment from their neighbors [11]. We previously demonstrated that erythrocyte protein band 4.1-like5 (EPB4.1L5) plays important roles in EMT and cell migration during mouse gastrulation [12]. EPB4.1L5 coordinates the down-regulation of E-cadherin-mediated cell-cell adhesion in a posttranscriptional manner by binding to p120ctn through its N-terminal FERM domain, inhibiting p120ctn-E-cadherin binding, and relocalizing E-cadherin into Rab5-positive vesicles (endocytosis) [12]. We recently reported that in clear cell renal cell carcinoma, EPB4.1L5 promotes EMT by binding AMAP1 through the Arf6 mesenchymal pathway [13]. Recently, researchers have reported that several transcription factors, such as Twist, Snail, Slug, SIP1, and E2A (E47/E12), play a significant role in EMT through regulation of E-cadherin [14], [15]. On the contrary, though it has been said that posttranscriptional events must also play vital roles in EMT, the mechanism of such events is not still largely investigated in detail [12], [13], [15], [16].

In this study, we examined the expression of EPB4.1L5 in UTUC specimens acquired by primary surgery and retrospectively investigated them to assess the prognostic significance of EPB4.1L5 in patients with UTUC.

Section snippets

Patient selection

The medical records of patients operated on between 1984 and 2007 and archived at Keio University Hospital (Shinjuku-ku, Tokyo, Japan) were, retrospectively, reviewed after obtaining Institutional Review Board approval. During this period, nephroureterectomy was performed for more than 200 patients with UTUC at Keio University Hospital. In our study population, we identified a total of 165 patients with UTUC (pTa-4N0M0) whose medical records could be used. The median follow-up of the whole

Patient characteristics

Table 1(A) shows the association of clinicopathological parameters with EPB4.1L5 expression in our study population. A total of 122 patients (73.9%) were men. The mean age of the patients was 66.4 years (range: 36–89 years). Pathologic analysis revealed 100 patients (60.6%) with tumors in the renal pelvis and 65 patients (39.4%) with tumors in the ureter. Tumor grade was low in 49 cases (29.7%) and high in 116 (70.3%). In 86 patients (52.1%), the disease was in pT2 stage or lower; 63 patients

Discussion

In this retrospective study, we evaluated the effect of EPB4.1L5 expression by immunohistochemistry in a series of patients with UTUC treated in a single center, and our result suggested that EPB4.1L5 expression, which was closely related to tumor grade, stage, and LVI, was one of the significant prognostic factors. High EPB4.1L5 expression was related to patients׳ shorter survival. As far as we know, this is the first study evaluating the prognostic value of EPB4.1L5 expression in patients

References (21)

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This work was supported in part by Grant-in-Aid for Young Scientists (JSPS KAKENHI Grant Number JP26861299 to T. K. and JP15K20111 to T. D.) from Japan Society for the Promotion of Science (JSPS), Japan.

1

These authors contributed equally.

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