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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

Inverse correlation of miR-204 and XRN1 expression in the ventral prostates of ratsMale rats were injected with TP (s.c., 25mg/kg/day) for 1–3 weeks. Ventral prostates were removed from three rats at the indicated time and were used to measure levels of miR-204 using RT-qPCR (A) and XRN1 using immunoblotting analysis (C). Ventral prostates were isolated from the three castrated rats at various times after castration, as indicated, and were used to monitor miR-204 expression (B) and for immunoblotting analysis of XRN1 expression (C). The data were obtained from three independent assays (Bar, mean± SEM; * p<0.05; ** p<0.01, n=3). (D) Inverse correlation between miR-204 and XRN1 protein in ventral prostates of castrated rats. Bottom, The 33-bp sequences in the 3′-UTRs of rat XRN1 mRNA (from nt3731 to nt3763) and human XRN1 mRNA (from nt4619 to nt4651) including the base-pairs (underlined) complementary to seed sequence of miR-204.
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Figure 4: Inverse correlation of miR-204 and XRN1 expression in the ventral prostates of ratsMale rats were injected with TP (s.c., 25mg/kg/day) for 1–3 weeks. Ventral prostates were removed from three rats at the indicated time and were used to measure levels of miR-204 using RT-qPCR (A) and XRN1 using immunoblotting analysis (C). Ventral prostates were isolated from the three castrated rats at various times after castration, as indicated, and were used to monitor miR-204 expression (B) and for immunoblotting analysis of XRN1 expression (C). The data were obtained from three independent assays (Bar, mean± SEM; * p<0.05; ** p<0.01, n=3). (D) Inverse correlation between miR-204 and XRN1 protein in ventral prostates of castrated rats. Bottom, The 33-bp sequences in the 3′-UTRs of rat XRN1 mRNA (from nt3731 to nt3763) and human XRN1 mRNA (from nt4619 to nt4651) including the base-pairs (underlined) complementary to seed sequence of miR-204.

Mentions: We further measured levels of miR-204 in ventral prostates of rats that were injected with testosterone propionate (TP) (Fig. 4A) or castrated (Fig. 4B). Our results showed that miR-204 gradually decreased as the prostate index (gross weight of prostate/weight of whole animal ×100%) increased (Fig. 4A). However, castration dramatically increased expression of miR-204 (Fig. 4B). These results indicated that miR-204 is down-regulated by androgen in ventral prostates of rats. In contrast to miR-204, XRN1 was induced by androgen but inhibited by castration in rat ventral prostates (Fig. 4C). Given that XRN1 is a direct target of miR-204 (Fig. 3) and a miR-204-paring sequence was also identified in the 3′-UTR of rat XRN1 mRNA (Fig. 4D), the inverse relationship between miR-204 and XRN1 expression in ventral prostate of castrated rats (Fig. 4D) provided an evidence strongly supporting the presence of AR-miR-204-XRN1 axis in vivo.


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)

Inverse correlation of miR-204 and XRN1 expression in the ventral prostates of ratsMale rats were injected with TP (s.c., 25mg/kg/day) for 1–3 weeks. Ventral prostates were removed from three rats at the indicated time and were used to measure levels of miR-204 using RT-qPCR (A) and XRN1 using immunoblotting analysis (C). Ventral prostates were isolated from the three castrated rats at various times after castration, as indicated, and were used to monitor miR-204 expression (B) and for immunoblotting analysis of XRN1 expression (C). The data were obtained from three independent assays (Bar, mean± SEM; * p<0.05; ** p<0.01, n=3). (D) Inverse correlation between miR-204 and XRN1 protein in ventral prostates of castrated rats. Bottom, The 33-bp sequences in the 3′-UTRs of rat XRN1 mRNA (from nt3731 to nt3763) and human XRN1 mRNA (from nt4619 to nt4651) including the base-pairs (underlined) complementary to seed sequence of miR-204.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Inverse correlation of miR-204 and XRN1 expression in the ventral prostates of ratsMale rats were injected with TP (s.c., 25mg/kg/day) for 1–3 weeks. Ventral prostates were removed from three rats at the indicated time and were used to measure levels of miR-204 using RT-qPCR (A) and XRN1 using immunoblotting analysis (C). Ventral prostates were isolated from the three castrated rats at various times after castration, as indicated, and were used to monitor miR-204 expression (B) and for immunoblotting analysis of XRN1 expression (C). The data were obtained from three independent assays (Bar, mean± SEM; * p<0.05; ** p<0.01, n=3). (D) Inverse correlation between miR-204 and XRN1 protein in ventral prostates of castrated rats. Bottom, The 33-bp sequences in the 3′-UTRs of rat XRN1 mRNA (from nt3731 to nt3763) and human XRN1 mRNA (from nt4619 to nt4651) including the base-pairs (underlined) complementary to seed sequence of miR-204.
Mentions: We further measured levels of miR-204 in ventral prostates of rats that were injected with testosterone propionate (TP) (Fig. 4A) or castrated (Fig. 4B). Our results showed that miR-204 gradually decreased as the prostate index (gross weight of prostate/weight of whole animal ×100%) increased (Fig. 4A). However, castration dramatically increased expression of miR-204 (Fig. 4B). These results indicated that miR-204 is down-regulated by androgen in ventral prostates of rats. In contrast to miR-204, XRN1 was induced by androgen but inhibited by castration in rat ventral prostates (Fig. 4C). Given that XRN1 is a direct target of miR-204 (Fig. 3) and a miR-204-paring sequence was also identified in the 3′-UTR of rat XRN1 mRNA (Fig. 4D), the inverse relationship between miR-204 and XRN1 expression in ventral prostate of castrated rats (Fig. 4D) provided an evidence strongly supporting the presence of AR-miR-204-XRN1 axis in vivo.

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