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UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.

ABSTRACT: Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.

SUBMITTER: Liu S

PROVIDER: S-EPMC10897521 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.

Liu Shiqin S Chai Timothy T Garcia-Marques Fernando F Yin Qingqing Q Hsu En-Chi EC Shen Michelle M Shaw Toland Angus Martin AM Bermudez Abel A Hartono Alifiani B AB Massey Christopher F CF Lee Chung S CS Zheng Liwei L Baron Maya M Denning Caden J CJ Aslan Merve M Nguyen Holly M HM Nolley Rosalie R Zoubeidi Amina A Das Millie M Kunder Christian A CA Howitt Brooke E BE Soh H Tom HT Weissman Irving L IL Liss Michael A MA Chin Arnold I AI Brooks James D JD Corey Eva E Pitteri Sharon J SJ Huang Jiaoti J Stoyanova Tanya T

Cell reports. Medicine 20240119 2

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regul ...[more]

PMID: 38244540

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Project description:Introduction: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer, exhibiting rapid progression and is unresponsive to hormone therapy. Reliable prognostic assays and more effective treatments are critically required. However, the research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we successfully developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation from prostate adenocarcinoma. By comparing gene expression profiles of the parental adenocarcinoma line (LTL331) and the NEPC subline (LTL331R), we identified DEK, a gene not previously reported in prostate cancer, as a potential biomarker and target for NEPC. Methods: DEK protein expression in patient tissue-derived xenograft models and clinical samples was assessed by immunohistochemistry. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis. Results: Elevated DEK protein expression was observed in all clinical NEPC cases, which is distinct from their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration resistant prostate cancer (29.55%). Increased DEK expression is an independent clinical risk factor and is associated with shorter disease free survival in hormonal naïve prostate cancer patients. Reduction of DEK expression in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. Conclusions: The results suggest that DEK may play an important role in the progression of prostate cancer, especially NEPC and provide a potential biomarker to aid risk stratification of prostate cancer and a novel therapeutic target for treating NEPC. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis.

Project description:Abstract Glioma is the most common primary malignant tumor in the brain with extremely poor prognosis. Firstly, in order to find the important genes and mechanisms involved in the initiation and progression of glioma, we selected four groups of gene expression profiles from GEO dataset include GSE29796, GSE4290, GSE50161 and GSE7696 for comprehensive data analysis. We identified 360 differentially expressed genes (DEGs), then we screened out core gene which is CDK1 by protein-protein interaction (PPI) network analysis. So as to clarify whether CDK1 is an independent prognostic factor for glioma, we performed expression analysis and prognostic analysis. Meanwhile, in order to verify the expression and survival of CDK1, we used Western blot to detect CDK1 expression of 15 glioma specimens and corresponding adjacent tissues. Moreover, we divided the expression values of CDK1 gene in the CGGA database into high and low groups based on the median for differential expression analysis. Finally, to explore the molecular mechanism of action of CDK1 in gliomas, we conducted gene ontology (GO) enrichment analysis and gene collection enrichment analysis (GSEA),and performed gene co-expression analysis. The results revealed that the expression level of CDK1 in glioma was significantly higher than normal tissues, its high expression was closely associated with poor survival of glioma. And the prognostic analysis showed that CDK1 was an independent prognostic index of glioma. Through the mechanism analysis of GO and GSEA, it is demonstrated that CDK1 plays an important role in the mitosis cell cycle of glioma, and inhibiting the expression of CDK1 can affect the proliferation of glioma cells. Coexpression analysis displayed that the high expression of PCNA, MCM2, MCM3, MCM4, MCM6, PLK1, TTK and MAD2L1 are also correlated to the poor survival and prognosis of glioma. Hence CDK1 is an independent prognostic factor and potential therapeutic target of glioma. Furthermore ,we can affect the proliferation of glioma cells through inhibiting the expression of CDK1.

Project description:BackgroundThe vast majority of ovarian mucinous carcinomas are metastatic tumours derived from nonovarian primary cancers, typically gastrointestinal neoplasms. Therapy targeting claudin18.2 might be used in gastric, gastroesophageal junction and pancreatic cancers with high expression of claudin18.2. In this study, we aimed to profile the expression of claudin18.2 in primary ovarian mucinous carcinoma (POMC) and metastatic gastrointestinal mucinous carcinoma (MGMC).MethodsImmunohistochemistry was used to detect claudin 18.2 expression in whole tissue sections of ovarian mucinous carcinomas, including 32 POMCs and 44 MGMCs, 23 of which were derived from upper gastrointestinal primary tumours and 21 of which were derived from lower gastrointestinal primary tumours. Immunohistochemical studies for claudin18.2, SATB2, PAX8, CK7 and CK20 were performed in all 76 cases.ResultsAmong 76 primary and metastatic mucinous carcinomas, claudin18.2 was expressed in 56.6% (43/76) of cases. MGMCs from the upper gastrointestinal tract, including 22 derived from primary stomach tumours and one derived from a pancreas tumour, were positive for claudin 18.2 in 69.5% (16/23) of cases. MGMCs from the lower gastrointestinal tract, including 10 derived from primary appendiceal cancer and 11 derived from colorectal cancers, showed no claudin18.2 expression (0/21). The expression rate of claudin18.2 in primary ovarian mucinous neoplasms, including 22 primary ovarian mucinous carcinomas and 10 primary ovarian borderline mucinous tumours, was 84.4% (27/32). The common immunophenotypic characteristics of POMCs, upper gastrointestinal tract-derived MGMCs, and lower gastrointestinal tract-derived MGMCs were claudin18.2 + /PAX8 + /SATB2- (17/32), claudin18.2 + /PAX8-/SATB2- (16/23) and claudin18.2-/PAX8-/SATB2 + (19/21), respectively.ConclusionClaudin18.2 is highly expressed in POMCs and MGMCs derived from upper gastrointestinal tract primary tumours; therefore, claudin18.2-targeted therapy might serve as a potential therapeutic strategy for POMCs and MGMCs from the upper gastrointestinal tract.

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UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.

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UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.

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