MiR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1.

X Sun,P Luo,H Pei,J Zhang,Y Li,J Yu

doi:10.1093/jjco/hyv027

Abstract

Recent reports strongly suggest the profound role of miRNAs in cancer therapeutic response and progression, including invasion and metastasis. The sensitivity to therapy and invasion is the major obstacle for successful treatment in prostate cancer. We aimed to investigate the regulative effect of miR-128/zinc-finger E-box-binding homeobox 1 axis on prostate cancer cell chemosensitivity and invasion. The miR-128 expression pattern of prostate cancer cell lines and tissues was detected by real-time reverse transcriptase-polymerase chain reaction, while the mRNA and protein expression levels of zinc-finger E-box-binding homeobox 1 were measured by real-time reverse transcriptase-polymerase chain reaction and western blot assay, respectively. Dual-luciferase reporter gene assay was used to find the direct target of miR-128. Furthermore, prostate cancer cells were treated with miR-128 mimic or zinc-finger E-box-binding homeobox 1-siRNA, and then the cells' chemosensitivity and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transwell assay, respectively. We found miR-128 expression obviously decreased in prostate cancer tissues compared with paired normal tissues. Restored miR-128 expression sensitized prostate cancer cells to cisplatin and inhibited the invasion. Furthermore, there was an inverse expression pattern between miR-128 and zinc-finger E-box-binding homeobox 1 in prostate cancer cells and tissues, and zinc-finger E-box-binding homeobox 1 was identified as a direct target of miR-128 in prostate cancer. Knockdown of zinc-finger E-box-binding homeobox 1 expression efficiently sensitized prostate cancer cells to cisplatin and inhibited the invasion. However, ectopic zinc-finger E-box-binding homeobox 1 expression impaired the effects of miR-128 on chemosensitivity and invasion in prostate cancer cells. miR-128 functions as a potential cancer suppressor in prostate cancer progression and rational therapeutic strategies for prostate cancer would be developed based on miR-128/zinc-finger E-box-binding homeobox 1 axis.

Highlights

Prostate cancer (PCa) is one of the most common malignant cancers among males all over the world
We determined the effects of ectopic miR-128 expression on cell chemosensitivity and invasion using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and transwell assays, respectively. miR-128 mimic upregulated its expression levels 15.93 and 13.07-fold in DU-145 and LNCaP PCa cell lines, respectively (Fig. 1B)
It is well known that PCa is an epithelial malignant cancer characterized by frequent metastasis and chemoresistance [19]

Summary

Introduction

Prostate cancer (PCa) is one of the most common malignant cancers among males all over the world. Chemoresistance and invasion remain the main causes of treatment failure and mortality in PCa patients. Several reports point to the fact that some miRNAs played an important role in PCa chemosensitivity and invasion. MiR-130b exerts a suppressive effect on PCa metastasis by downregulating MMP2 [5]. MiR-34a inhibits PCa regeneration and metastasis by directly repressing CD44 [6]. MiR-200c increased sensitivity of PCa cells to paclitaxel, and miR-34a decreased the spread of PCa [7]. MiR125b promotes growth of prostatic xenograft tumors by downregulating three key pro-apoptotic genes, and PCa cells could be sensitized to chemotherapy through the inhibition of miR-125b [8,9]. MiR-616 induces androgen-independent growth of PCa cells by suppressing expression of tissue factor pathway inhibitor TFPI-2 [10] MiR125b promotes growth of prostatic xenograft tumors by downregulating three key pro-apoptotic genes, and PCa cells could be sensitized to chemotherapy through the inhibition of miR-125b [8,9]. miR-616 induces androgen-independent growth of PCa cells by suppressing expression of tissue factor pathway inhibitor TFPI-2 [10]

Methods

Results

Conclusion