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A dual yet opposite growth-regulating function of miR-204 and its target XRN1 in prostate adenocarcinoma cells and neuroendocrine-like prostate cancer cells.

Ding M, Lin B, Li T, Liu Y, Li Y, Zhou X, Miao M, Gu J, Pan H, Yang F, Li T, Liu XY, Li R - Oncotarget (2015)

Bottom Line: Androgen-responsive genes involved in PCa progression including NED remain largely unknown.Importantly, overexpression of miR-204 and knockdown of XRN1 inhibited AR expression in PCa cells.Repression of miR-34a, a known AR-targeting miRNA, contributes AR expression by XRN1.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
Androgen deprivation therapy in prostate cancer (PCa) causes neuroendocrine differentiation (NED) of prostatic adenocarcinomas (PAC) cells, leading to recurrence of PCa. Androgen-responsive genes involved in PCa progression including NED remain largely unknown. Here we demonstrated the importance of androgen receptor (AR)-microRNA-204 (miR-204)-XRN1 axis in PCa cell lines and the rat ventral prostate. Androgens downregulate miR-204, resulting in induction of XRN1 (5'-3' exoribonuclease 1), which we identified as a miR-204 target. miR-204 acts as a tumor suppressor in two PAC cell lines (LNCaP and 22Rv1) and as an oncomiR in two neuroendocrine-like prostate cancer (NEPC) cell lines (PC-3 and CL1). Importantly, overexpression of miR-204 and knockdown of XRN1 inhibited AR expression in PCa cells. Repression of miR-34a, a known AR-targeting miRNA, contributes AR expression by XRN1. Thus we revealed the AR-miR-204-XRN1-miR-34a positive feedback loop and a dual function of miR-204/XRN1 axis in prostate cancer.

No MeSH data available.


Related in: MedlinePlus

miR-204 expression is down-regulated by AR signalingA. Relative miR-204 levels as measured by RT-qPCR in LNCaP cells in the presence and absence R1881 (1.0 nM). B. Silencing of AR up-regulates miR-204 expression in LNCaP cells and 22Rv1 cells. Shown are RT-PCR results. C. The effect of exogenously-expressed AR on miR-204 expression in PC-3 cells. Shown are miR-204 RT-PCR results in PC-3 cells transfected with AR (PC-3-AR) and control vector (PC-3-vector). D. Immunoblotting analysis of expression of NSE and CgA in LNCaP cells and CL1 cells. E. Relative levels of miR-204 in untreated PCa cell lines as indicated. The levels of miR-204 were normalized to the levels measured in LNCaP cells. Bar, mean±SEM; * p<0.05, **p<0.01, n=3.
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Figure 1: miR-204 expression is down-regulated by AR signalingA. Relative miR-204 levels as measured by RT-qPCR in LNCaP cells in the presence and absence R1881 (1.0 nM). B. Silencing of AR up-regulates miR-204 expression in LNCaP cells and 22Rv1 cells. Shown are RT-PCR results. C. The effect of exogenously-expressed AR on miR-204 expression in PC-3 cells. Shown are miR-204 RT-PCR results in PC-3 cells transfected with AR (PC-3-AR) and control vector (PC-3-vector). D. Immunoblotting analysis of expression of NSE and CgA in LNCaP cells and CL1 cells. E. Relative levels of miR-204 in untreated PCa cell lines as indicated. The levels of miR-204 were normalized to the levels measured in LNCaP cells. Bar, mean±SEM; * p<0.05, **p<0.01, n=3.

Mentions: To study the possible impact of androgen on the miR's expression in PAC cells, we first used a miRNA array to compare miR expression of LNCaP cells in the presence and absence of androgen treatment. miR-204 was one of several miRs that was down-regulated by androgen (Supplementary Table 2). Consistent with this, our results showed that miR-204 levels increased gradually after the LNCaP cells were incubated in the medium with charcoal-stripped FBS that was depleted of androgen (Fig. 1A). Subsequently, after the synthetic androgen analog R1881was added to the culture at 48 and 72 hours post androgen withdrawal, the level of miR-204 expression decreased when compared to the control (Fig. 1A). Furthermore, when an AR-siRNA was transfected into 22Rv1 (an androgen-independent but androgen responsive PAC cell line [30]) and LNCaP cells, miR-204 expression increased by 2.51 folds and 2.12 folds, respectively, compared to those cells transfected with control GFP-siRNA (Fig. 1B). Together, these results indicate that androgen down-regulates miR-204 in PAC cells.


A dual yet opposite growth-regulating function of miR-204 and its target XRN1 in prostate adenocarcinoma cells and neuroendocrine-like prostate cancer cells.

Ding M, Lin B, Li T, Liu Y, Li Y, Zhou X, Miao M, Gu J, Pan H, Yang F, Li T, Liu XY, Li R - Oncotarget (2015)

miR-204 expression is down-regulated by AR signalingA. Relative miR-204 levels as measured by RT-qPCR in LNCaP cells in the presence and absence R1881 (1.0 nM). B. Silencing of AR up-regulates miR-204 expression in LNCaP cells and 22Rv1 cells. Shown are RT-PCR results. C. The effect of exogenously-expressed AR on miR-204 expression in PC-3 cells. Shown are miR-204 RT-PCR results in PC-3 cells transfected with AR (PC-3-AR) and control vector (PC-3-vector). D. Immunoblotting analysis of expression of NSE and CgA in LNCaP cells and CL1 cells. E. Relative levels of miR-204 in untreated PCa cell lines as indicated. The levels of miR-204 were normalized to the levels measured in LNCaP cells. Bar, mean±SEM; * p<0.05, **p<0.01, n=3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4480709&req=5

Figure 1: miR-204 expression is down-regulated by AR signalingA. Relative miR-204 levels as measured by RT-qPCR in LNCaP cells in the presence and absence R1881 (1.0 nM). B. Silencing of AR up-regulates miR-204 expression in LNCaP cells and 22Rv1 cells. Shown are RT-PCR results. C. The effect of exogenously-expressed AR on miR-204 expression in PC-3 cells. Shown are miR-204 RT-PCR results in PC-3 cells transfected with AR (PC-3-AR) and control vector (PC-3-vector). D. Immunoblotting analysis of expression of NSE and CgA in LNCaP cells and CL1 cells. E. Relative levels of miR-204 in untreated PCa cell lines as indicated. The levels of miR-204 were normalized to the levels measured in LNCaP cells. Bar, mean±SEM; * p<0.05, **p<0.01, n=3.
Mentions: To study the possible impact of androgen on the miR's expression in PAC cells, we first used a miRNA array to compare miR expression of LNCaP cells in the presence and absence of androgen treatment. miR-204 was one of several miRs that was down-regulated by androgen (Supplementary Table 2). Consistent with this, our results showed that miR-204 levels increased gradually after the LNCaP cells were incubated in the medium with charcoal-stripped FBS that was depleted of androgen (Fig. 1A). Subsequently, after the synthetic androgen analog R1881was added to the culture at 48 and 72 hours post androgen withdrawal, the level of miR-204 expression decreased when compared to the control (Fig. 1A). Furthermore, when an AR-siRNA was transfected into 22Rv1 (an androgen-independent but androgen responsive PAC cell line [30]) and LNCaP cells, miR-204 expression increased by 2.51 folds and 2.12 folds, respectively, compared to those cells transfected with control GFP-siRNA (Fig. 1B). Together, these results indicate that androgen down-regulates miR-204 in PAC cells.

Bottom Line: Androgen-responsive genes involved in PCa progression including NED remain largely unknown.Importantly, overexpression of miR-204 and knockdown of XRN1 inhibited AR expression in PCa cells.Repression of miR-34a, a known AR-targeting miRNA, contributes AR expression by XRN1.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
Androgen deprivation therapy in prostate cancer (PCa) causes neuroendocrine differentiation (NED) of prostatic adenocarcinomas (PAC) cells, leading to recurrence of PCa. Androgen-responsive genes involved in PCa progression including NED remain largely unknown. Here we demonstrated the importance of androgen receptor (AR)-microRNA-204 (miR-204)-XRN1 axis in PCa cell lines and the rat ventral prostate. Androgens downregulate miR-204, resulting in induction of XRN1 (5'-3' exoribonuclease 1), which we identified as a miR-204 target. miR-204 acts as a tumor suppressor in two PAC cell lines (LNCaP and 22Rv1) and as an oncomiR in two neuroendocrine-like prostate cancer (NEPC) cell lines (PC-3 and CL1). Importantly, overexpression of miR-204 and knockdown of XRN1 inhibited AR expression in PCa cells. Repression of miR-34a, a known AR-targeting miRNA, contributes AR expression by XRN1. Thus we revealed the AR-miR-204-XRN1-miR-34a positive feedback loop and a dual function of miR-204/XRN1 axis in prostate cancer.

No MeSH data available.


Related in: MedlinePlus