Double-negative feedback loop between ZEB2 and miR-145 regulates epithelial-mesenchymal transition and stem cell properties in prostate cancer cells

Abstract

The invasion and metastasis of tumors are triggered by an epithelial to mesenchymal transition (EMT), which is regulated by microRNAs (miRNAs). EMT also promotes malignant tumor progression and the maintenance of the stem cell property, which endows cancer cells with the capabilities of self-renewal and immortalized proliferation. The transcriptional repressor zinc-finger E-box binding homeobox 2 (ZEB2), as an EMT activator, might be an important promoter of metastasis in some tumors. Here, we report that ZEB2 directly represses the transcription of miR-145, which is a strong repressor of EMT. In turn, ZEB2 is also a direct target of miR-145. Further, our findings show that the downregulation of ZEB2 not only represses invasion, migration, EMT, and the stemness of prostate cancer (PCa) cells, but also suppresses the capability of PC-3 cells to invade bone in vivo. Importantly, the expression level of ZEB2 as revealed by immunohistochemical analysis is positively correlated to bone metastasis, the serum free PSA level, the total PSA level, and the Gleason score in PCa patients and is negatively correlated with miR-145 expression in primary PCa specimens. Thus, our findings demonstrate a double-negative feedback loop between ZEB2 and miR-145 and indicate that the ZEB2/miR-145 double-negative feedback loop plays a significant role in the control of EMT and stem cell properties during the bone metastasis of PCa cells. These results suggest that the double-negative feedback loop between ZEB2 and miR-145 contributes to PCa progression and metastasis and might have therapeutic relevance for the bone metastasis of PCa.

Double‐negative feedback loop between long non‐coding RNA TUG1 and miR‐145 promotes epithelial to mesenchymal transition and radioresistance in human bladder cancer cells

“…MiR-145 is a regulator of EMT during cancer progression. MiR-145 is often down-regulated in cancer tissues and restoration of miR-145 suppressed cancer cell invasion by reversing the EMT phenotype [12,28]. MiR-145 acts as a tumor suppressor in bladder cancer [29].…”

“…Since miR-145 was involved in EMT process in cancer cells [12], we asked whether the effect of TUG1 on cell invasion was mediated by miR-145. Fig.…”

miRNAs as novel biomarkers in the management of prostate cancer

“…markers, such as vimentin, and up-regulating epithelial markers, such as E-cadherin, by directly targeting ZEB1 and ZEB2, which is a direct target of miR-145, too [57,58] (Figure 3). Ren et al [59] reported that ZEB2 also represses the transcription of miR-145, creating a double-negative feedback loop between ZEB2 and miR-145, which is a key in the control of EMT and stem cell properties during the bone metastasis of PCa. Besides, upregulation of miR-21 in PCa also plays an important role in EMT (Figure 3) by decreasing the BTG2 levels, initiating thus the acquisition of luminal markers and EMT [60,61].…”

An exclusive cellular and molecular network governs intestinal smooth muscle cell differentiation in vertebrates

“…Among them we found foxo1a, also predicted to be a target in zebrafish. Another gene was zeb2, which has recently been shown to be a direct target of miR-145 (Ren et al, 2014). Within the ZEB gene family in zebrafish, zeb1a has a predicted miR-145 target site.…”