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β(2)‐adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog‐Gli1 signaling activation

BACKGROUND: Considerable evidence suggests that the sympathetic nervous system, mainly via adrenergic signaling, contributes to prostate cancer (PCa) progression. However, the underlying molecular mechanisms remain unknown. METHODS: The expression level of β(2)‐adrenergic receptor (β(2)‐AR) in tissu...

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Autores principales: Zhang, Mi, Wang, Qianhui, Sun, Xueqing, Yin, Qingqing, Chen, Jinying, Xu, Linhui, Xu, Chen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540401/
https://www.ncbi.nlm.nih.gov/pubmed/32894788
http://dx.doi.org/10.1002/pros.24060
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author Zhang, Mi
Wang, Qianhui
Sun, Xueqing
Yin, Qingqing
Chen, Jinying
Xu, Linhui
Xu, Chen
author_facet Zhang, Mi
Wang, Qianhui
Sun, Xueqing
Yin, Qingqing
Chen, Jinying
Xu, Linhui
Xu, Chen
author_sort Zhang, Mi
collection PubMed
description BACKGROUND: Considerable evidence suggests that the sympathetic nervous system, mainly via adrenergic signaling, contributes to prostate cancer (PCa) progression. However, the underlying molecular mechanisms remain unknown. METHODS: The expression level of β(2)‐adrenergic receptor (β(2)‐AR) in tissue microarray was evaluated by immunohistochemistry. The effects of isoproterenol (ISO) or Sonic Hedgehog (Shh) signaling inhibitor on tumor growth were analyzed in proliferation and colony formation assays. The apoptosis of cells was analyzed by flow cytometry. Small hairpin RNA‐based knockdown of β(2)‐AR or Gli1 was validated by Western blot analysis and real‐time PCR. Effects of β(2)‐AR on prostate carcinogenesis in vivo were observed in a mouse xenograft model. The expression levels of the indicated proteins in xenograft tissues were evaluated by immunohistochemistry. Expression levels of Shh signaling components and downstream proteins were assessed by immunoblotting. RESULTS: We determined that β(2)‐AR was expressed at significantly higher levels in carcinoma than in normal prostate tissues. β(2)‐AR signaling also played an essential role in sustaining PCa cell proliferation in vivo and in vitro. We also found that inhibition of Shh signaling or knockdown of Gli1 expression significantly restrained ISO‐induced cell proliferation in vitro. ISO alleviated the apoptosis induced by suppressing or knocking down of Gli1. The β(2)‐AR agonist ISO upregulated the transcription and protein expression of target genes of Shh signaling, including c‐Myc, Cyclin D1, and VEGFA. Conversely, knocking down β(2)‐AR markedly suppressed the expression of Shh components in vivo and in vitro. In Gli1 knockdown cells, ISO failed to increase the expression of target genes of Shh signaling. CONCLUSIONS: In this study, we uncovered an important role of β(2)‐AR signaling in regulating the Shh pathway activity in PCa tumorigenesis and provide further insight into the mechanism of the involvement of the Hh signaling pathway. Furthermore, given the efficacy of β(2)‐adrenergic modulation on PCa, our study might also add evidence for potential therapeutic options of β‐blockers for PCa.
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spelling pubmed-75404012020-10-09 β(2)‐adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog‐Gli1 signaling activation Zhang, Mi Wang, Qianhui Sun, Xueqing Yin, Qingqing Chen, Jinying Xu, Linhui Xu, Chen Prostate Original Articles BACKGROUND: Considerable evidence suggests that the sympathetic nervous system, mainly via adrenergic signaling, contributes to prostate cancer (PCa) progression. However, the underlying molecular mechanisms remain unknown. METHODS: The expression level of β(2)‐adrenergic receptor (β(2)‐AR) in tissue microarray was evaluated by immunohistochemistry. The effects of isoproterenol (ISO) or Sonic Hedgehog (Shh) signaling inhibitor on tumor growth were analyzed in proliferation and colony formation assays. The apoptosis of cells was analyzed by flow cytometry. Small hairpin RNA‐based knockdown of β(2)‐AR or Gli1 was validated by Western blot analysis and real‐time PCR. Effects of β(2)‐AR on prostate carcinogenesis in vivo were observed in a mouse xenograft model. The expression levels of the indicated proteins in xenograft tissues were evaluated by immunohistochemistry. Expression levels of Shh signaling components and downstream proteins were assessed by immunoblotting. RESULTS: We determined that β(2)‐AR was expressed at significantly higher levels in carcinoma than in normal prostate tissues. β(2)‐AR signaling also played an essential role in sustaining PCa cell proliferation in vivo and in vitro. We also found that inhibition of Shh signaling or knockdown of Gli1 expression significantly restrained ISO‐induced cell proliferation in vitro. ISO alleviated the apoptosis induced by suppressing or knocking down of Gli1. The β(2)‐AR agonist ISO upregulated the transcription and protein expression of target genes of Shh signaling, including c‐Myc, Cyclin D1, and VEGFA. Conversely, knocking down β(2)‐AR markedly suppressed the expression of Shh components in vivo and in vitro. In Gli1 knockdown cells, ISO failed to increase the expression of target genes of Shh signaling. CONCLUSIONS: In this study, we uncovered an important role of β(2)‐AR signaling in regulating the Shh pathway activity in PCa tumorigenesis and provide further insight into the mechanism of the involvement of the Hh signaling pathway. Furthermore, given the efficacy of β(2)‐adrenergic modulation on PCa, our study might also add evidence for potential therapeutic options of β‐blockers for PCa. John Wiley and Sons Inc. 2020-09-07 2020-11-01 /pmc/articles/PMC7540401/ /pubmed/32894788 http://dx.doi.org/10.1002/pros.24060 Text en © 2020 The Authors. The Prostate published by Wiley Periodicals LLC This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Zhang, Mi
Wang, Qianhui
Sun, Xueqing
Yin, Qingqing
Chen, Jinying
Xu, Linhui
Xu, Chen
β(2)‐adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog‐Gli1 signaling activation
title β(2)‐adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog‐Gli1 signaling activation
title_full β(2)‐adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog‐Gli1 signaling activation
title_fullStr β(2)‐adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog‐Gli1 signaling activation
title_full_unstemmed β(2)‐adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog‐Gli1 signaling activation
title_short β(2)‐adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog‐Gli1 signaling activation
title_sort β(2)‐adrenergic receptor signaling drives prostate cancer progression by targeting the sonic hedgehog‐gli1 signaling activation
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540401/
https://www.ncbi.nlm.nih.gov/pubmed/32894788
http://dx.doi.org/10.1002/pros.24060
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