microRNA-218 inhibits prostate cancer cell growth and promotes apoptosis by repressing TPD52 expression

doi:10.1016/j.bbrc.2014.12.026

Biochemical and Biophysical Research Communications

Volume 456, Issue 3, 16 January 2015, Pages 804-809

https://doi.org/10.1016/j.bbrc.2014.12.026 Get rights and content

Highlights

•
miR-218 expression is downregulated in prostate cancer.
•
miR-218 inhibits prostate tumor cells proliferation partially through promoting apoptosis.
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miR-218 targets TPD52 by binding to its 3′-UTR.
•
miR-218 suppresses prostate cancer cell growth through inhibiting TPD52 expression.

Abstract

The tumor protein D52 (TPD52) is an oncogene overexpressed in prostate cancer (PC) due to gene amplification. Although the oncogenic effect of TPD52 is well recognized, how its expression is regulated is still not clear. This study tried to explore the regulative role of miR-218, a tumor suppressing miRNA on TPD52 expression and prostate cancer cell proliferation. We found the expression of miR-218 was significantly lower in PC specimens. Based on gain and loss of function analysis, we found miR-218 significantly inhibit cancer cell proliferation by inducing apoptosis. These results strongly suggest that miR-218 plays a tumor suppressor role in PC cells. In addition, our data firstly demonstrated that miR-218 directly regulates oncogenic TPD52 in PC3 cells and the miR-218-TPD52 axis can regulate growth of this prostate cancer cell line. Knockdown of TPD52 resulted in significantly increased cancer cell apoptosis. Clearly understanding of oncogenic TPD52 pathways regulated by miR-218 might be helpful to reveal new therapeutic targets for PC.

Introduction

Prostate cancer (PC) is the most common male malignancy and accounts for about 10% of all male cancer-related deaths across the world [1]. Most of the PC patients are responsive to androgen-deprivation therapy (ADT) in first treatment. However, a large proportion of the cancer cases develop castration-resistance and distant metastasis, which is the leading cause of death [2]. Thus, clear understanding of the molecular mechanisms of PC development and metastasis is beneficial for development of effective therapy.

The tumor protein D52 (TPD52) is an oncogene overexpressed in prostate cancer due to gene amplification [3]. Previous studies found TPD52 transcript levels were significantly higher in high- versus low-grade localized prostate cancers [4]. Its expression was also closely related to development of systemic progression within 5 years [5]. In cell line models, increased TPD52 led to increased proliferation and colony formation and significantly higher expression of phospho Akt (pSer 473) in LnCaP cells [6], [7], [8]. Increased TPD52 is also associated with higher LnCaP cell migration [6]. Besides, TPD52 is an upstream mediator of the mitochondrial apoptotic reaction. Transient knockdown of TPD52 increased cell death of both LnCaP and C4-2, two prostate cancer cell lines [6], [7], [8]. Therefore, TPD52 plays a quite critical role in survival, proliferation, migration, and invasion of prostate cancer cells.

Although the oncogenic effect of TPD52 is well recognized, how its expression is regulated is still not quite clear. microRNAs (miRNAs) are a set of endogenous small (19–22 bases in length) non-coding RNA. They can regulate the gene expression by inhibiting translation or cleaving RNA transcripts in a sequence specific manner [9]. Approximately 80% of the TPD52 transcript was originally identified as 3′-untranslated region (3′-UTR) [10], which usually contains targeting sequence of miRNA [11]. Previous studies observed that TPD52 is a target of miR-34a [12] in colorectal cancer cells and a target of miR-224 in prostate cancer cell [13]. However, whether other miRNAs are involved in regulating TPD52 in prostate cancer is not clear.

This study firstly reported TPD52 is a downstream target of miR-218, a tumor suppressing miRNA in several cancers [14], [15]. Through repressing TPD52 expression, miR-218 could inhibit prostate cancer growth and promote apoptosis.

Section snippets

Human prostate tissue specimens

All human tissue based studies were proved by the ethics committee of Xinxiang Medical University and all participants were recruited from the first affiliated hospital of Xinxiang Medical University. Men who were suspected of having PC due to elevated serum prostate-specific antigen (PSA) levels were possible candidates of this study. A pair of 10 cores of prostate specimens were obtained from each patient at the same region by using transrectal ultrasound guided prostate biopsy. The paired

miR-218 expression is downregulated in prostate cancer

miR-218 expression in 46 prostate cancer patients (cancer tissue, adjacent normal tissue and serum) and in 25 normal controls (normal tissue and serum) were quantified by qRT-TPCR analysis. Generally, in prostate cancer patients, miR-218 expression was significantly lower in cancer tissues than in adjacent normal tissue (Fig. 1A). In addition, compared with normal controls, cancer cases also had significantly lower miR-218 expression in both cancer tissue (p < 0.001) and serum (p < 0.01) (Fig. 1B

Discussion

In the current study, we found the expression of miR-218 was significantly lower in PC specimens. Based on gain and loss of function analysis, we found miR-218 significantly inhibit cancer cell proliferation by inducing apoptosis. These results strongly suggest that miR-218 plays a tumor suppressor role in PC cells. In fact, the suppressing effect of miR-218 was also observed in several type of cancers, including oral cancer [16], nasopharyngeal cancer [17] liver cancer [15] and bladder cancer

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Citation Excerpt :
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View full text

microRNA-218 inhibits prostate cancer cell growth and promotes apoptosis by repressing TPD52 expression

Highlights

Abstract

Introduction

Section snippets

Human prostate tissue specimens

miR-218 expression is downregulated in prostate cancer

Discussion

Cancer Treat. Rev.

Cell

FEBS Lett.

Neoplasia

Cancer statistics

CA Cancer J. Clin.

Overexpression, amplification, and androgen regulation of TPD52 in prostate cancer

Cancer Res.

Gene expression pathways of high grade localized prostate cancer

Prostate

A tissue biomarker panel predicting systemic progression after PSA recurrence post-definitive prostate cancer therapy

PLoS ONE

Altered expression of tumor protein D52 regulates apoptosis and migration of prostate cancer cells

FEBS J.

PrLZ expression is associated with the progression of prostate cancer LNCaP cells

Mol. Carcinog.

PC-1/PrLZ contributes to malignant progression in prostate cancer

Cancer Res.