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The inhibitory effects of AR/miR-190a/YB-1 negative feedback loop on prostate cancer and underlying mechanism.

Xu S, Wang T, Song W, Jiang T, Zhang F, Yin Y, Jiang SW, Wu K, Yu Z, Wang C, Chen K - Sci Rep (2015)

Bottom Line: MiR-190a belongs to the small noncoding RNA family and has an important role in breast cancer metastasis.Moreover, we examined the expression of miR-190a and observed a significant decrease in human prostate cancers.Reduced expression of miR-190a was inversely correlated to AR levels of prostate cancer patients, and patients with higher miR-190a expression in their tumor have improved tumor-free survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Gynecology, Shanghai First Matenity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.

ABSTRACT
Prostate cancer at advanced stages including metastatic and castration-resistant cancer remains incurable due to the lack of effective therapies. MiR-190a belongs to the small noncoding RNA family and has an important role in breast cancer metastasis. However, it is still unknown whether miR-190a plays a role in prostate cancer development. Herein, we first observed AR/miR-190a/YB-1 forms an auto-regulatory negative feedback loop in prostate cancer: miR-190a expression was down-regulated by AR activation; YB-1 functions are as an AR activator; miR-190a inhibited AR expression and transactivation through direct binding to 3'UTR of YB-1 gene. MiR-190a contributes the human prostate cancer cell growth through AR-dependent signaling. Moreover, we examined the expression of miR-190a and observed a significant decrease in human prostate cancers. Reduced expression of miR-190a was inversely correlated to AR levels of prostate cancer patients, and patients with higher miR-190a expression in their tumor have improved tumor-free survival. Taken together, our findings identified a biochemical and functional link between miR-190a with reduced expression in advanced prostate cancer, YB-1 and AR signaling in prostate cancer.

No MeSH data available.


Related in: MedlinePlus

MiR-190a-mediated suppression of AR expression and transactivation requires miR-190a binding to the 3′-UTR of YB-1 gene.(a) YB-1 is a potential target of miR-190a. The miR-190a targeting sites in 3′UTRs of human YB-1 are shown. (b,c) Luciferase/Renila activity level of 3′ UTR luciferase reporters of YB-1 in LNCaP and 22Rv1 cells at 48 hours after transfection. (d) LNCaP cells with stable overexpression of miR-190a and YB-1 knockdown. YB-1 and AR protein levels were determined by Western blot. (e) LNCaP cells with stable overexpression of miR-190a and YB-1. YB-1 and AR protein levels determined by Western blot. (f) LNCaP cells transiently transfected with miR-190a and/or YB-1 while treated with 10 nm DHT. PSA-Luc was assessed for AR activity. (g) Schematic representation of the AR/miR-190a/YB-1 negative feedback loop.
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f4: MiR-190a-mediated suppression of AR expression and transactivation requires miR-190a binding to the 3′-UTR of YB-1 gene.(a) YB-1 is a potential target of miR-190a. The miR-190a targeting sites in 3′UTRs of human YB-1 are shown. (b,c) Luciferase/Renila activity level of 3′ UTR luciferase reporters of YB-1 in LNCaP and 22Rv1 cells at 48 hours after transfection. (d) LNCaP cells with stable overexpression of miR-190a and YB-1 knockdown. YB-1 and AR protein levels were determined by Western blot. (e) LNCaP cells with stable overexpression of miR-190a and YB-1. YB-1 and AR protein levels determined by Western blot. (f) LNCaP cells transiently transfected with miR-190a and/or YB-1 while treated with 10 nm DHT. PSA-Luc was assessed for AR activity. (g) Schematic representation of the AR/miR-190a/YB-1 negative feedback loop.

Mentions: Our previous study demonstrated that miR-190a inhibited YB-1 and AR expression. In order to validate bioinformatics analysis, which indicated that only YB-1 was a potential target of miR-190a (Fig. 4a), we performed luciferase assays using reporters containing wild-type YB-1 3′-UTR and mutant defective for miR-190a binding (Fig. 4a). As shown in Fig. 4b,c, overexpression of miR-190a inhibited YB-1 wild-type, but not mutant luciferase reporter activities in LNCaP and 22Rv1 cells, indicating that miR-190a specifically targets YB-1 through direct 3′-UTR binding.


The inhibitory effects of AR/miR-190a/YB-1 negative feedback loop on prostate cancer and underlying mechanism.

Xu S, Wang T, Song W, Jiang T, Zhang F, Yin Y, Jiang SW, Wu K, Yu Z, Wang C, Chen K - Sci Rep (2015)

MiR-190a-mediated suppression of AR expression and transactivation requires miR-190a binding to the 3′-UTR of YB-1 gene.(a) YB-1 is a potential target of miR-190a. The miR-190a targeting sites in 3′UTRs of human YB-1 are shown. (b,c) Luciferase/Renila activity level of 3′ UTR luciferase reporters of YB-1 in LNCaP and 22Rv1 cells at 48 hours after transfection. (d) LNCaP cells with stable overexpression of miR-190a and YB-1 knockdown. YB-1 and AR protein levels were determined by Western blot. (e) LNCaP cells with stable overexpression of miR-190a and YB-1. YB-1 and AR protein levels determined by Western blot. (f) LNCaP cells transiently transfected with miR-190a and/or YB-1 while treated with 10 nm DHT. PSA-Luc was assessed for AR activity. (g) Schematic representation of the AR/miR-190a/YB-1 negative feedback loop.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4551971&req=5

f4: MiR-190a-mediated suppression of AR expression and transactivation requires miR-190a binding to the 3′-UTR of YB-1 gene.(a) YB-1 is a potential target of miR-190a. The miR-190a targeting sites in 3′UTRs of human YB-1 are shown. (b,c) Luciferase/Renila activity level of 3′ UTR luciferase reporters of YB-1 in LNCaP and 22Rv1 cells at 48 hours after transfection. (d) LNCaP cells with stable overexpression of miR-190a and YB-1 knockdown. YB-1 and AR protein levels were determined by Western blot. (e) LNCaP cells with stable overexpression of miR-190a and YB-1. YB-1 and AR protein levels determined by Western blot. (f) LNCaP cells transiently transfected with miR-190a and/or YB-1 while treated with 10 nm DHT. PSA-Luc was assessed for AR activity. (g) Schematic representation of the AR/miR-190a/YB-1 negative feedback loop.
Mentions: Our previous study demonstrated that miR-190a inhibited YB-1 and AR expression. In order to validate bioinformatics analysis, which indicated that only YB-1 was a potential target of miR-190a (Fig. 4a), we performed luciferase assays using reporters containing wild-type YB-1 3′-UTR and mutant defective for miR-190a binding (Fig. 4a). As shown in Fig. 4b,c, overexpression of miR-190a inhibited YB-1 wild-type, but not mutant luciferase reporter activities in LNCaP and 22Rv1 cells, indicating that miR-190a specifically targets YB-1 through direct 3′-UTR binding.

Bottom Line: MiR-190a belongs to the small noncoding RNA family and has an important role in breast cancer metastasis.Moreover, we examined the expression of miR-190a and observed a significant decrease in human prostate cancers.Reduced expression of miR-190a was inversely correlated to AR levels of prostate cancer patients, and patients with higher miR-190a expression in their tumor have improved tumor-free survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Gynecology, Shanghai First Matenity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.

ABSTRACT
Prostate cancer at advanced stages including metastatic and castration-resistant cancer remains incurable due to the lack of effective therapies. MiR-190a belongs to the small noncoding RNA family and has an important role in breast cancer metastasis. However, it is still unknown whether miR-190a plays a role in prostate cancer development. Herein, we first observed AR/miR-190a/YB-1 forms an auto-regulatory negative feedback loop in prostate cancer: miR-190a expression was down-regulated by AR activation; YB-1 functions are as an AR activator; miR-190a inhibited AR expression and transactivation through direct binding to 3'UTR of YB-1 gene. MiR-190a contributes the human prostate cancer cell growth through AR-dependent signaling. Moreover, we examined the expression of miR-190a and observed a significant decrease in human prostate cancers. Reduced expression of miR-190a was inversely correlated to AR levels of prostate cancer patients, and patients with higher miR-190a expression in their tumor have improved tumor-free survival. Taken together, our findings identified a biochemical and functional link between miR-190a with reduced expression in advanced prostate cancer, YB-1 and AR signaling in prostate cancer.

No MeSH data available.


Related in: MedlinePlus