Abstract
Simple SummaryThe Derlin-1 protein, encoded by DERL1, is located in the endoplasmic reticulum membrane and is responsible for the unfolded protein response. Derlin-1 has recently drawn lots of attention with regard to cancer pathogenesis. The purpose of this study is to examine its role and molecular mechanism in upper tract urothelial carcinoma (UTUC). The protein levels of Derlin-1 in human UTUC specimens are observed by immunohistochemistry. Derlin-1 overexpression is evidently associated with cancer stage, distant metastasis, recurrence, and poor prognosis in patients with UTUC. In an in vitro study, the knockdown of Derlin-1 represses, while over-expression of Derlin-1 increases migration and invasion of UTUC cells significantly. We identify the microRNA-375-3p (miR-375-3p) as one of the potential candidate microRNAs and then examine the relationship between Derlin-1 and miR-375-3p. The dual-luciferase reporter assay confirms that miR-375-3p directly targets Derlin-1. Furthermore, we reveal that miR-375-3p modulate Derlin-1 and epithelial–mesenchymal transition (EMT) marker protein levels. However, the above effects are reversed by the restoration of Derlin-1. Our study clarifies that miR-375-3p represses invasion and migration by directly targeting Derlin-1 and regulating the expression of EMT-associated proteins in UTUC cells, suggesting Derlin-1 may act as a useful predictor of prognosis and that both Derlin-1 and miR-375-3p could be potential therapeutic targets in UTUC.Little is known regarding the molecular characterization of upper tract urothelial carcinoma (UTUC). Novel therapeutic targets and prognostic predictors are imminent. In the present study, we aim to examine the oncogenic function and molecular mechanism of Derlin-1 in UTUC. Derlin-1 overexpression is significantly associated with poor prognosis in patients with UTUC. In vitro, knockdown or over-expression of Derlin-1 markedly regulated UTUC cell invasion and migration. We further discovered miR-375-3p suppresses cell invasion and migration by inversely regulating Derlin-1 and blocking EMT in UTUC cells. Taking this together, miR-375-3p functions as a tumor suppressive microRNA by directly targeting Derlin-1 and blocking epithelial–mesenchymal transition (EMT) in UTUC.
Highlights
Upper tract urothelial carcinoma (UTUC) accounts for only 10% of all urothelial cancers worldwide, with a lack of available evidence on specific topics due to its rarity [1]
These results suggest that Derlin-1 enhances cell invasion and migration of upper tract urothelial carcinoma (UTUC) cells, which may be related to epithelial–mesenchymal transition (EMT)
For the first time, we implicated an oncogenic function of Derlin-1 in the progression of UTUC
Summary
Upper tract urothelial carcinoma (UTUC) accounts for only 10% of all urothelial cancers worldwide, with a lack of available evidence on specific topics due to its rarity [1]. The incidence of UTUC is exceptionally high in Taiwan, accounting for more than 30% of all urothelial cancers [2]. Over the past few decades, radical nephroureterectomy (RNU) has been considered the optimal treatment of choice for most patients with localized UTUC owing to the high proportion of high-grade tumors and advanced stages previously reported in large databases [5]. Even though considerable progress has been made in radiotherapy, chemotherapy, and novel immuno-oncology approaches to improve clinical outcomes, the overall survival of patients with UTUC remains unsatisfactory, which may result from some remarkable characteristics of urothelial carcinomas such as increased invasion and migration [6]. Because the prognosis of urothelial carcinoma depends on invasion depth and metastasis development, the exploration of additional novel molecules to inhibit the migration and invasion of urothelial carcinoma cells is deemed necessary [7]
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