Smoothened loss is a characteristic of neuroendocrine prostate cancer

Abstract

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.

A New Risk Score Based on Eight Hepatocellular Carcinoma- Immune Gene Expression Can Predict the Prognosis of the Patients

“…Expression of CHGA has been reported to be associated with prognosis in colorectal cancer (22)(23)(24), and is generally recognized as the main biomarker for neuroendocrine neoplasms (25,26). Recently, CHGA has been proposed as an early diagnosis biomarker for gastric cancer (27), prostate cancer (28), and pancreatic neuroendocrine tumors (29).…”

A importância da atividade física na prevenção do câncer de próstata

“…Aspectos moleculares e genéticos também estão envolvidos na relação entre atividade física e prevenção do câncer de próstata. Pesquisas, como a de Wang et al (2021), têm explorado os efeitos da atividade física na regulação de genes relacionados ao crescimento tumoral e à apoptose celular na próstata. Evidências sugerem que a atividade física pode influenciar positivamente a expressão gênica, contribuindo para a supressão do desenvolvimento de células cancerígenas.…”

Highly expressed FAM189B predicts poor prognosis in hepatocellular carcinoma

“…This study was approved by the Medical Ethics Committee of Shandong Provincial Qianfoshan Hospital according to the Declaration of Helsinki, and the number of the approval was S092. Immunohistochemical assay was performed according to a routine protocol as previously reported (27). The primary antibody of FAM189B (Invitrogen, PA5-52318) was diluted with the ratio of 1:50.…”