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Smoothened loss is a characteristic of neuroendocrine prostate cancer

PURPOSE: Hedgehog (Hh) signaling promotes castration‐resistant prostate cancer by supporting androgen‐independent prostate cancer cell development and growth; however, its role in neuroendocrine prostate cancer (NEPC) has not yet been explored. In this study, we assessed the expression of key genes...

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Autores principales: Wang, Lili, Li, Haiying, Li, Zhang, Li, Ming, Tang, Qi, Wu, Chunxiao, Lu, Zhiming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251989/
https://www.ncbi.nlm.nih.gov/pubmed/33955576
http://dx.doi.org/10.1002/pros.24122
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author Wang, Lili
Li, Haiying
Li, Zhang
Li, Ming
Tang, Qi
Wu, Chunxiao
Lu, Zhiming
author_facet Wang, Lili
Li, Haiying
Li, Zhang
Li, Ming
Tang, Qi
Wu, Chunxiao
Lu, Zhiming
author_sort Wang, Lili
collection PubMed
description PURPOSE: Hedgehog (Hh) signaling promotes castration‐resistant prostate cancer by supporting androgen‐independent prostate cancer cell development and growth; however, its role in neuroendocrine prostate cancer (NEPC) has not yet been explored. In this study, we assessed the expression of key genes involved in Hh signaling in prostate cancer and investigated the potential role of smoothened (SMO) in the pathogenesis of NEPC. METHODS: Six public datasets, each containing cases of prostate adenocarcinoma (AdPC) and NEPC, were analyzed to compare the differential messenger RNA (mRNA) expression of six classic Hh signaling genes. The SMO, synaptophysin, chromogranin A (CHGA) and androgen receptor (AR) proteins were evaluated in human tissues from 5 cases of NEPC, 2 cases of AdPC mixed with NEPC, 2 cases of AdPC with neuroendocrine differentiation and 22 cases of high‐grade AdPC as determined by an immunohistochemistry assay. Gene set enrichment analysis (GSEA) was performed to identify relevant genetic signatures associated with SMO expression based on the public datasets. Stable SMO‐knockdown LNCaP and C4‐2B cells were established with a lentiviral system, and the expression of SMO, Gli1, AR, prostate‐specific antigen (PSA), and REST was assessed by real‐time polymerase chain reaction and western blot. Secreted PSA in the conditioned medium was assessed by ELISA. Gli1 was ectopically expressed performed by the transfection of Gli1 complementary DNA into SMO‐knockdown LNCaP cells, and western blot was used to assess of AR and PSA expression. RESULTS: The mRNA level of SMO was dramatically downregulated in NEPC samples compared with AdPC samples in all 6 public datasets. SMO protein loss was observed in 100% of NEPC samples but in only 9% (2 of 22) of high‐grade AdPC samples. GSEA results showed that SMO loss was closely correlated with AR signaling activity. Stable SMO knockdown significantly attenuated AR signaling activity and suppressed AR expression, while Gli1 overexpression partially reversed the inhibitory effects of SMO knockdown on AR signaling activity and AR expression in LNCaP and C4‐2B cells. CONCLUSION: These results demonstrate that SMO loss is a characteristic of NEPC and that detecting SMO by IHC could aid pathologists in NEPC diagnosis. SMO loss may promote NEPC pathogenesis by modulating AR signaling.
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spelling pubmed-82519892021-07-07 Smoothened loss is a characteristic of neuroendocrine prostate cancer Wang, Lili Li, Haiying Li, Zhang Li, Ming Tang, Qi Wu, Chunxiao Lu, Zhiming Prostate Original Articles PURPOSE: Hedgehog (Hh) signaling promotes castration‐resistant prostate cancer by supporting androgen‐independent prostate cancer cell development and growth; however, its role in neuroendocrine prostate cancer (NEPC) has not yet been explored. In this study, we assessed the expression of key genes involved in Hh signaling in prostate cancer and investigated the potential role of smoothened (SMO) in the pathogenesis of NEPC. METHODS: Six public datasets, each containing cases of prostate adenocarcinoma (AdPC) and NEPC, were analyzed to compare the differential messenger RNA (mRNA) expression of six classic Hh signaling genes. The SMO, synaptophysin, chromogranin A (CHGA) and androgen receptor (AR) proteins were evaluated in human tissues from 5 cases of NEPC, 2 cases of AdPC mixed with NEPC, 2 cases of AdPC with neuroendocrine differentiation and 22 cases of high‐grade AdPC as determined by an immunohistochemistry assay. Gene set enrichment analysis (GSEA) was performed to identify relevant genetic signatures associated with SMO expression based on the public datasets. Stable SMO‐knockdown LNCaP and C4‐2B cells were established with a lentiviral system, and the expression of SMO, Gli1, AR, prostate‐specific antigen (PSA), and REST was assessed by real‐time polymerase chain reaction and western blot. Secreted PSA in the conditioned medium was assessed by ELISA. Gli1 was ectopically expressed performed by the transfection of Gli1 complementary DNA into SMO‐knockdown LNCaP cells, and western blot was used to assess of AR and PSA expression. RESULTS: The mRNA level of SMO was dramatically downregulated in NEPC samples compared with AdPC samples in all 6 public datasets. SMO protein loss was observed in 100% of NEPC samples but in only 9% (2 of 22) of high‐grade AdPC samples. GSEA results showed that SMO loss was closely correlated with AR signaling activity. Stable SMO knockdown significantly attenuated AR signaling activity and suppressed AR expression, while Gli1 overexpression partially reversed the inhibitory effects of SMO knockdown on AR signaling activity and AR expression in LNCaP and C4‐2B cells. CONCLUSION: These results demonstrate that SMO loss is a characteristic of NEPC and that detecting SMO by IHC could aid pathologists in NEPC diagnosis. SMO loss may promote NEPC pathogenesis by modulating AR signaling. John Wiley and Sons Inc. 2021-05-06 2021-06-15 /pmc/articles/PMC8251989/ /pubmed/33955576 http://dx.doi.org/10.1002/pros.24122 Text en © 2021 The Authors. The Prostate published by Wiley Periodicals LLC https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://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
Wang, Lili
Li, Haiying
Li, Zhang
Li, Ming
Tang, Qi
Wu, Chunxiao
Lu, Zhiming
Smoothened loss is a characteristic of neuroendocrine prostate cancer
title Smoothened loss is a characteristic of neuroendocrine prostate cancer
title_full Smoothened loss is a characteristic of neuroendocrine prostate cancer
title_fullStr Smoothened loss is a characteristic of neuroendocrine prostate cancer
title_full_unstemmed Smoothened loss is a characteristic of neuroendocrine prostate cancer
title_short Smoothened loss is a characteristic of neuroendocrine prostate cancer
title_sort smoothened loss is a characteristic of neuroendocrine prostate cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251989/
https://www.ncbi.nlm.nih.gov/pubmed/33955576
http://dx.doi.org/10.1002/pros.24122
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