ArticleThe Prostate2021
Smoothened loss is a characteristic of neuroendocrine prostate cancer.
Article in The Prostate, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Prognostic biomarkers and Hedgehog pathway activation in early prostate cancer neuroendocrine differentiation via spatial profiling.NPJ precision oncology · 2026Article
- Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review).Oncology reports · 2025Review
- PlexinD1 is a driver and a therapeutic target in advanced prostate cancer.EMBO molecular medicine · 2025Article
- Emerging proteins involved in castration‑resistant prostate cancer via the AR‑dependent and AR‑independent pathways (Review).International journal of oncology · 2023Review
- Advances in neuroendocrine prostate cancer research: From model construction to molecular network analyses.Laboratory investigation; a journal of technical methods and pathology · 2022Review
- Highly expressed FAM189B predicts poor prognosis in hepatocellular carcinoma.Pathology oncology research : POR · 2022Article
- Smoothened loss is a characteristic of neuroendocrine prostate cancer.The Prostate · 2021Article
- A New Risk Score Based on Eight Hepatocellular Carcinoma- Immune Gene Expression Can Predict the Prognosis of the Patients.Frontiers in oncology · 2021Article
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Authors and funding
7 authors.
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Abstract
purposeHedgehog (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.
methodsSix 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.
resultsThe 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.
conclusionThese 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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