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Wang F, Mu HF, Wang C, Tang Y, Si MY, Peng J. LncRNA PCAT6 promotes progression and metastasis of colonic neuroendocrine carcinoma via MAPK pathway. World J Gastrointest Oncol 2025; 17:96230. [PMID: 39958556 PMCID: PMC11755991 DOI: 10.4251/wjgo.v17.i2.96230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 09/18/2024] [Accepted: 12/02/2024] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND Colonic neuroendocrine carcinomas (NECs) are highly malignant and invasive with poor prognosis. Long noncoding RNAs (LncRNAs) participate in the tumorigenesis and metastasis of multiple cancers. AIM To detect the roles and mechanisms of lncRNA prostate cancer associated transcript 6 (PCAT6) in the progression of colonic NEC. METHODS Human NEC and adjacent normal samples were collected for immunohistochemistry staining of CgA and real-time quantitative polymerase chain reaction (RT-qPCR) of PCAT6 mRNA level. Subcutaneous xenograft tumor model and lung metastasis model were established in nude mice. The lung tissues were stained by hematoxylin and eosin to assess pulmonary metastasis. The expression of epithelial-mesenchymal transition (EMT)-related markers and pathway-related genes was measured by RT-qPCR and western blotting. CD56 expression was assessed by immunofluorescence staining. The biological functions of PCAT6 were examined by cell counting kit-8, colony formation assays, Transwell assays and wound healing assays. The interaction between PCAT6 and its potential downstream target was verified by luciferase reporter assays. RESULTS LncRNA PCAT6 was upregulated in human NEC samples and LCC-18 cells, and its high expression was positively correlated with poor prognosis in patients with colonic NEC. Additionally, the expression of PCAT6 was positively associated with the proliferation, migration, invasion, and EMT of LCC-18 cells. Moreover, PCAT6 facilitated tumor growth, lung metastasis and EMT in xenografts. Mechanistically, PCAT6 promoted the activation of MAPK to enhance the EMT in colonic NEC by targeting miR-326. CONCLUSION In conclusion, lncRNA PCAT6 accelerates the process of colonic NEC by activating ERK/p38 MAPK signaling through targeting miR-326. These results might provide useful information for exploring the potential therapeutic targets in colonic NEC.
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Affiliation(s)
- Fei Wang
- Department of General Surgery, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
| | - Hai-Feng Mu
- Department of General Surgery, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
| | - Chun Wang
- Department of General Surgery, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
| | - Yue Tang
- Department of General Surgery, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
| | - Ming-Yuan Si
- Department of Pathology, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
| | - Jing Peng
- Department of General Surgery, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
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Tan W, Xiao C, Ma M, Cao Y, Huang Z, Wang X, Kang R, Li Z, Li E. Role of non-coding RNA in lineage plasticity of prostate cancer. Cancer Gene Ther 2025; 32:1-10. [PMID: 39496938 DOI: 10.1038/s41417-024-00834-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 09/03/2024] [Accepted: 09/11/2024] [Indexed: 11/06/2024]
Abstract
The treatment of prostate cancer (PCa) has made great progress in recent years, but treatment resistance always develops and can even lead to fatal disease. Exploring the mechanism of drug resistance is of great significance for improving treatment outcomes and developing biomarkers with predictive value. It is increasingly recognized that mechanism of drug resistance in advanced PCa is related to lineage plasticity and tissue differentiation. Specifically, one of the mechanisms by which castration-resistant prostate cancer (CRPC) cells acquire drug resistance and transform into neuroendocrine prostate cancer (NEPC) cells is lineage plasticity. NEPC is a subtype of PCa that is highly aggressive and lethal, with a median survival of only 7 months. With the development of high-throughput RNA sequencing technology, more and more non-coding RNAs have been identified, which play important roles in different diseases through different mechanisms. Several ncRNAs have shown great potential in PCa lineage plasticity and as biomarkers. In the review, the role of ncRNA in PCa lineage plasticity and its use as biomarkers were reviewed.
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Affiliation(s)
- Wenhui Tan
- Institute of Translational Medicine, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, China
| | - Changkai Xiao
- Department of Urology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Min Ma
- Institute of Translational Medicine, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, China
| | - Youhan Cao
- Department of Urology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Zhenguo Huang
- Department of Urology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xiaolan Wang
- Department of Urology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Ran Kang
- Department of Urology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Zhenfa Li
- Affiliated Hengyang Hospital of Hunan Normal University & Hengyang Central Hospital, Hengyang, 421001, Hunan, China.
| | - Ermao Li
- Institute of Translational Medicine, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, China.
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Cao Y, Jia M, Duan C, Yang Z, Cheng B, Wang R. The m 6A regulators in prostate cancer: molecular basis and clinical perspective. Front Pharmacol 2024; 15:1448872. [PMID: 39268470 PMCID: PMC11391310 DOI: 10.3389/fphar.2024.1448872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 08/14/2024] [Indexed: 09/15/2024] Open
Abstract
Prostate cancer (PCa) is the second leading cause of cancer-related death among men in western countries. Evidence has indicated the significant role of the androgen receptor (AR) as the main driving factor in controlling the development of PCa, making androgen receptor inhibition (ARI) therapy a pivotal management approach. In addition, AR independent signaling pathways also contribute to PCa progression. One such signaling pathway that has garnered our attention is N6-Methyladenosine (m6A) signaling, which refers to a chemical modification on RNA with crucial roles in RNA metabolism and disease progression, including PCa. It is important to comprehensively summarize the role of each individual m6A regulator in PCa development and understand its interaction with AR signaling. This review aims to provide a thorough summary of the involvement of m6A regulators in PCa development, shedding light on their upstream and downstream signaling pathways. This summary sets the stage for a comprehensive review that would benefit the scientific community and clinical practice by enhancing our understanding of the biology of m6A regulators in the context of PCa.
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Affiliation(s)
- Yu Cao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Man Jia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Chunyan Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Zhihui Yang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Bo Cheng
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Ronghao Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
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Farc O, Budisan L, Zaharie F, Țăulean R, Vălean D, Talvan E, Neagoe IB, Zănoagă O, Braicu C, Cristea V. Expression and Functional Analysis of Immuno-Micro-RNAs mir-146a and mir-326 in Colorectal Cancer. Curr Issues Mol Biol 2024; 46:7065-7085. [PMID: 39057062 PMCID: PMC11276483 DOI: 10.3390/cimb46070421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
Micro-RNAs (miRNAs) are non-coding RNAs with importance in the development of cancer. They are involved in both tumor development and immune processes in tumors. The present study aims to characterize the behavior of two miRNAs, the proinflammatory miR-326-5p and the anti-inflammatory miR-146a-5p, in colorectal cancer (CRC), to decipher the mechanisms that regulate their expression, and to study potential applications. Tissue levels of miR-326-5p and miR-146a-5p were determined by qrt-PCR (real-time quantitative reverse transcription polymerase chain reaction) in 45 patients with colorectal cancer in tumoral and normal adjacent tissue. Subsequent bioinformatic analysis was performed to characterize the transcriptional networks that control the expression of the two miRNAs. The biomarker potential of miRNAs was assessed. The expression of miR-325-5p and miR-146a-5p was decreased in tumors compared to normal tissue. The two miRNAs are regulated through a transcriptional network, which originates in the inflammatory and proliferative pathways and regulates a set of cellular functions related to immunity, proliferation, and differentiation. The miRNAs coordinate distinct modules in the network. There is good biomarker potential of miR-326 with an AUC (Area under the curve) of 0.827, 0.911 sensitivity (Sn), and 0.689 specificity (Sp), and of the combination miR-326-miR-146a, with an AUC of 0.845, Sn of 0.75, and Sp of 0.89. The miRNAs are downregulated in the tumor tissue. They are regulated by a transcriptional network in which they coordinate distinct modules. The structure of the network highlights possible therapeutic approaches. MiR-326 and the combination of the two miRNAs may serve as biomarkers in CRC.
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Affiliation(s)
- Ovidiu Farc
- Research Center for Functional Genomics, Biomedicine and Translational Medicine “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (O.F.); (I.B.N.); (O.Z.); (C.B.)
| | - Liviuta Budisan
- Research Center for Functional Genomics, Biomedicine and Translational Medicine “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (O.F.); (I.B.N.); (O.Z.); (C.B.)
| | - Florin Zaharie
- Surgical Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (F.Z.); (R.Ț.); (D.V.)
| | - Roman Țăulean
- Surgical Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (F.Z.); (R.Ț.); (D.V.)
| | - Dan Vălean
- Surgical Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (F.Z.); (R.Ț.); (D.V.)
| | - Elena Talvan
- Faculty of Medicine Lucian Blaga, University of Sibiu, 550169 Sibiu, Romania;
| | - Ioana Berindan Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (O.F.); (I.B.N.); (O.Z.); (C.B.)
| | - Oana Zănoagă
- Research Center for Functional Genomics, Biomedicine and Translational Medicine “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (O.F.); (I.B.N.); (O.Z.); (C.B.)
| | - Cornelia Braicu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (O.F.); (I.B.N.); (O.Z.); (C.B.)
| | - Victor Cristea
- Immunology Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania;
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Li P, Cui P, Yue Q, Xu Z, Liu Z. Exploring the potential biological significance of KDELR family genes in lung adenocarcinoma. Sci Rep 2024; 14:14820. [PMID: 38937522 PMCID: PMC11211404 DOI: 10.1038/s41598-024-65425-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 06/20/2024] [Indexed: 06/29/2024] Open
Abstract
The Lys-Asp-Glu-Leu receptor (KDELR) family genes play critical roles in a variety of biological processes in different tumors. Our study aimed to provide a comprehensive analysis of the potential roles of KDELRs in lung adenocarcinoma (LUAD). Utilizing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, as well as clinical samples, we conducted a series of analyses and validations using R software tools and various online resources. The results showed that KDELR family genes and proteins were highly expressed and associated with a poor prognosis of LUAD. Promoter hypomethylation and the competing endogenous RNA (ceRNA) network of PCAT6/hsa-miR-326/KDELR1 might be potential causes of aberrant KDELR1 overexpression in LUAD. Three key Transcription factors (TFs) (SPI1, EP300, and MAZ) and a TFs-miRNAs-KDELRs network (involving 11 TFs) might be involved in modulating KDELRs expression abnormalities. Gene Set Enrichment Analysis (GSEA) indicated enrichment of genes highly expressing KDELR1, KDELR2, and KDELR3 in MTORC1_SIGNALING, P53_PATHWAY, and ANGIOGENESIS. Negative correlations between KDELRs expression and CD8 + T cell infiltration, as well as CTLA-4 expression. Our multiple analyses suggested that the KDELRs are important signaling molecules in LUAD. These results provided novel insights for developing prognostic markers and novel therapies of LUAD.
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Affiliation(s)
- Peitong Li
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Pengfei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Qing Yue
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Zijun Xu
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Ziling Liu
- Cancer Center, The First Hospital of Jilin University, Changchun, China.
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Pan J, Tong F, Ren N, Ren L, Yang Y, Gao F, Xu Q. Role of N 6‑methyladenosine in the pathogenesis, diagnosis and treatment of prostate cancer (Review). Oncol Rep 2024; 51:88. [PMID: 38757383 PMCID: PMC11110010 DOI: 10.3892/or.2024.8747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 04/19/2024] [Indexed: 05/18/2024] Open
Abstract
Prostate cancer (PCa) affects males of all racial and ethnic groups, and leads to higher rates of mortality in those belonging to a lower socioeconomic status due to the late detection of the disease. PCa affects middle‑aged males between the ages of 45 and 60 years, and is the highest cause of cancer‑associated mortality in Western countries. As the most abundant and common mRNA modification in higher eukaryotes, N6‑methyladenosine (m6A) is widely distributed in mammalian cells and influences various aspects of mRNA metabolism. Recent studies have found that abnormal expression levels of various m6A regulators significantly affect the development and progression of various types of cancer, including PCa. The present review discusses the influence of m6A regulatory factors on the pathogenesis and progression of PCa through mRNA modification based on the current state of research on m6A methylation modification in PCa. It is considered that the treatment of PCa with micro‑molecular drugs that target the epigenetics of the m6A regulator to correct abnormal m6A modifications is a direction for future research into current diagnostic and therapeutic approaches for PCa.
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Affiliation(s)
- Junjie Pan
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Affiliated Hangzhou First People's Hospital, Hangzhou, Zhejiang 310051, P.R. China
| | - Fei Tong
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Ning Ren
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Affiliated Hangzhou First People's Hospital, Hangzhou, Zhejiang 310051, P.R. China
| | - Lanqi Ren
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Affiliated Hangzhou First People's Hospital, Hangzhou, Zhejiang 310051, P.R. China
| | - Yibei Yang
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Affiliated Hangzhou First People's Hospital, Hangzhou, Zhejiang 310051, P.R. China
| | - Feng Gao
- Department of Urology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310007, P.R. China
| | - Qiaoping Xu
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
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7
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Dai Z, Lin L, Xu Y, Hu L, Gou S, Xu X. Extracellular vesicle dynamics in COPD: understanding the role of miR-422a, SPP1 and IL-17 A in smoking-related pathology. BMC Pulm Med 2024; 24:173. [PMID: 38609925 PMCID: PMC11010439 DOI: 10.1186/s12890-024-02978-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) induced by smoking poses a significant global health challenge. Recent findings highlight the crucial role of extracellular vesicles (EVs) in mediating miRNA regulatory networks across various diseases. This study utilizes the GEO database to uncover distinct expression patterns of miRNAs and mRNAs, offering a comprehensive understanding of the pathogenesis of smoking-induced COPD. This study aims to investigate the mechanisms by which extracellular vesicles (EVs) mediate the molecular network of miR-422a-SPP1 to delay the onset of COPD caused by smoking. METHODS The smoking-related miRNA chip GSE38974-GPL7723 was obtained from the GEO database, and candidate miRs were retrieved from the Vesiclepedia database. Downstream target genes of the candidate miRs were predicted using mRNA chip GSE38974-GPL4133, TargetScan, miRWalk, and RNA22 databases. This prediction was integrated with COPD-related genes from the GeneCards database, downstream target genes predicted by online databases, and key genes identified in the core module of WGCNA analysis to obtain candidate genes. The candidate genes were subjected to KEGG functional enrichment analysis using the "clusterProfiler" package in R language, and a protein interaction network was constructed. In vitro experiments involved overexpressing miRNA or extracting extracellular vesicles from bronchial epithelial cell-derived exosomes, co-culturing them with myofibroblasts to observe changes in the expression levels of the miR-422a-SPP1-IL-17 A regulatory network, and assessing protein levels of fibroblast differentiation-related factors α-SMA and collagen I using Western blot analysis. RESULTS The differential gene analysis of chip GSE38974-GPL7723 and the retrieval results from the Vesiclepedia database identified candidate miRs, specifically miR-422a. Subsequently, an intersection was taken among the prediction results from TargetScan, miRWalk, and RNA22 databases, the COPD-related gene retrieval results from GeneCards database, the WGCNA analysis results of chip GSE38974-GPL4133, and the differential gene analysis results. This intersection, combined with KEGG functional enrichment analysis, and protein-protein interaction analysis, led to the final screening of the target gene SPP1 and its upstream regulatory gene miR-422a. KEGG functional enrichment analysis of mRNAs correlated with SPP1 revealed the IL-17 signaling pathway involved. In vitro experiments demonstrated that miR-422a inhibition targets suppressed the expression of SPP1 in myofibroblasts, inhibiting differentiation phenotype. Bronchial epithelial cells, under cigarette smoke extract (CSE) stress, could compensate for myofibroblast differentiation phenotype by altering the content of miR-422a in their Extracellular Vesicles (EVs). CONCLUSION The differential gene analysis of Chip GSE38974-GPL7723 and the retrieval results from the Vesiclepedia database identified candidate miRs, specifically miR-422a. Further analysis involved the intersection of predictions from TargetScan, miRWalk, and RNA22 databases, gene search on COPD-related genes from the GeneCards database, WGCNA analysis from Chip GSE38974-GPL4133, and differential gene analysis, combined with KEGG functional enrichment analysis and protein interaction analysis. Ultimately, the target gene SPP1 and its upstream regulatory gene miR-422a were selected. KEGG functional enrichment analysis on mRNAs correlated with SPP1 revealed the involvement of the IL-17 signaling pathway. In vitro experiments showed that miR-422a targeted inhibition suppressed the expression of SPP1 in myofibroblast cells, inhibiting differentiation phenotype. Furthermore, bronchial epithelial cells could compensate for myofibroblast differentiation phenotype under cigarette smoke extract (CSE) stress by altering the miR-422a content in their extracellular vesicles (EVs).
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Affiliation(s)
- Zhihui Dai
- Department of Respiratory and Critical Care Medicine, Yongkang First People's Hospital, Hangzhou Medical College, No. 599 Jinshan West Road, 321300, Yongkang, Zhejiang Province, P. R. China
| | - Li Lin
- Department of Respiratory and Critical Care Medicine, Yongkang First People's Hospital, Hangzhou Medical College, No. 599 Jinshan West Road, 321300, Yongkang, Zhejiang Province, P. R. China
| | - Yanan Xu
- Department of Respiratory and Critical Care Medicine, Yongkang First People's Hospital, Hangzhou Medical College, No. 599 Jinshan West Road, 321300, Yongkang, Zhejiang Province, P. R. China
| | - Lifang Hu
- Department of Respiratory and Critical Care Medicine, Yongkang First People's Hospital, Hangzhou Medical College, No. 599 Jinshan West Road, 321300, Yongkang, Zhejiang Province, P. R. China
| | - Shiping Gou
- Department of Respiratory and Critical Care Medicine, Yongkang First People's Hospital, Hangzhou Medical College, No. 599 Jinshan West Road, 321300, Yongkang, Zhejiang Province, P. R. China
| | - Xinkai Xu
- Department of Respiratory and Critical Care Medicine, Yongkang First People's Hospital, Hangzhou Medical College, No. 599 Jinshan West Road, 321300, Yongkang, Zhejiang Province, P. R. China.
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Gavrikova T, Nakamura N, Davydova J, Antonarakis ES, Yamamoto M. Infectivity-Enhanced, Conditionally Replicative Adenovirus for COX-2-Expressing Castration-Resistant Prostate Cancer. Viruses 2023; 15:901. [PMID: 37112881 PMCID: PMC10144787 DOI: 10.3390/v15040901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
BACKGROUND The development of conditionally replicative adenoviruses (CRAds) for castration-resistant prostate cancer (CRPC), particularly neuroendocrine prostate cancer (NEPC), has two major obstacles: choice of control element and poor infectivity. We applied fiber-modification-based infectivity enhancement and an androgen-independent promoter (cyclooxynegase-2, COX-2) to overcome these issues. METHODS The properties of the COX-2 promoter and the effect of fiber modification were tested in two CRPC cell lines (Du-145 and PC3). Fiber-modified COX-2 CRAds were tested in vitro for cytocidal effect as well as in vivo for antitumor effect with subcutaneous CRPC xenografts. RESULTS In both CRPC cell lines, the COX-2 promoter showed high activity, and Ad5/Ad3 fiber modification significantly enhanced adenoviral infectivity. COX-2 CRAds showed a potent cytocidal effect in CRPC cells with remarkable augmentation by fiber modification. In vivo, COX-2 CRAds showed an antitumor effect in Du-145 while only Ad5/Ad3 CRAd showed the strongest antitumor effect in PC3. CONCLUSION COX-2 promoter-based, infectivity-enhanced CRAds showed a potent antitumor effect in CRPC/NEPC cells.
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Affiliation(s)
- Tatyana Gavrikova
- Division of Human Gene Therapy, Department of Surgery, Medicine and Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Naohiko Nakamura
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Julia Davydova
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Emmanuel S. Antonarakis
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Masato Yamamoto
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
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Kufe D. Dependence on MUC1-C in Progression of Neuroendocrine Prostate Cancer. Int J Mol Sci 2023; 24:3719. [PMID: 36835130 PMCID: PMC9967814 DOI: 10.3390/ijms24043719] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/11/2023] [Accepted: 02/11/2023] [Indexed: 02/16/2023] Open
Abstract
Castration resistant prostate cancer (CRPC) is responsive to androgen receptor (AR) axis targeted agents; however, patients invariably relapse with resistant disease that often progresses to neuroendocrine prostate cancer (NEPC). Treatment-related NEPC (t-NEPC) is highly aggressive with limited therapeutic options and poor survival outcomes. The molecular basis for NEPC progression remains incompletely understood. The MUC1 gene evolved in mammals to protect barrier tissues from loss of homeostasis. MUC1 encodes the transmembrane MUC1-C subunit, which is activated by inflammation and contributes to wound repair. However, chronic activation of MUC1-C contributes to lineage plasticity and carcinogenesis. Studies in human NEPC cell models have demonstrated that MUC1-C suppresses the AR axis and induces the Yamanaka OSKM pluripotency factors. MUC1-C interacts directly with MYC and activates the expression of the BRN2 neural transcription factor (TF) and other effectors, such as ASCL1, of the NE phenotype. MUC1-C also induces the NOTCH1 stemness TF in promoting the NEPC cancer stem cell (CSC) state. These MUC1-C-driven pathways are coupled with activation of the SWI/SNF embryonic stem BAF (esBAF) and polybromo-BAF (PBAF) chromatin remodeling complexes and global changes in chromatin architecture. The effects of MUC1-C on chromatin accessibility integrate the CSC state with the control of redox balance and induction of self-renewal capacity. Importantly, targeting MUC1-C inhibits NEPC self-renewal, tumorigenicity and therapeutic resistance. This dependence on MUC1-C extends to other NE carcinomas, such as SCLC and MCC, and identify MUC1-C as a target for the treatment of these aggressive malignancies with the anti-MUC1 agents now under clinical and preclinical development.
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Affiliation(s)
- Donald Kufe
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
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10
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Song S, Zhu Y, Zhang X, Chen S, Liu S. Prognostic values of long noncoding RNA in bone metastasis of prostate cancer: A systematic review and meta-analysis. Front Oncol 2023; 13:1085464. [PMID: 36890836 PMCID: PMC9986415 DOI: 10.3389/fonc.2023.1085464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/24/2023] [Indexed: 02/22/2023] Open
Abstract
Introduction Recent studies have shown that long non-coding RNAs are closely related to the occurrence and development of prostate cancer bone metastasis, and can be used as biomarkers to predict the prognosis of patients. Therefore, this study aimed to systematically evaluate the relationship between the expression levels of long non-coding RNAs and the prognosis of patients. Methods The studies of lncRNA in prostate cancer bone metastasis from Pubmed, Cochrane library, Embase, Ebsco, Web of science, Scopus, Ovid databases were analyzed, and Stata 15 was used for meta-analysis. Associations between lncRNA expression and patients' overall survival (OS) and bone metastasis-free survival (BMFS) were assessed by correlation analysis with pooled hazard ratios (HR) and 95% confidence intervals (CI). Furthermore, the results were validated using GEPIA2 and UALCAN, online database based on TCGA. Subsequently, the molecular mechanisms of the included lncRNAs were predicted based on the LncACTdb 3.0 database and the lnCAR database. Finally, we used clinical samples to validate lncRNAs that were significantly different in both databases. Results A total of 5 published studies involving 474 patients were included in this meta-analysis. The results showed that lncRNA overexpression was significantly associated with lower OS (HR = 2.55, 95% CI: 1.69 - 3.99, p < 0.05) and lower BMFS (OR = 3.16, 95% CI: 1.90 - 5.27, p < 0.05) in patients with prostate cancer bone metastasis. Based on validation from the GEPIA2 and UALCAN online databases, SNHG3 and NEAT1 were significantly up-regulated in prostate cancer. Further functional prediction showed that the lncRNAs included in the study were involved in regulating the occurrence and development of prostate cancer through the ceRNA axis. The result of clinical samples showed that SNHG3 and NEAT1 were expressed in prostate cancer bone metastasis at higher levels than in primary tumors. Conclusions LncRNA can be used as a novel predictive biomarker for predicting poor prognosis in patients with prostate cancer bone metastasis, which is worthy of clinical validation.
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Affiliation(s)
- Silu Song
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Department of Basic Medical, Jiamusi University, Jiamusi, China
| | - Yanli Zhu
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Department of Basic Medical, Jiamusi University, Jiamusi, China
| | - Xue Zhang
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Department of Basic Medical, Jiamusi University, Jiamusi, China
| | - Siyu Chen
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Department of Basic Medical, Jiamusi University, Jiamusi, China
| | - Shuang Liu
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Department of Basic Medical, Jiamusi University, Jiamusi, China
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Identification of the Regulatory Targets of miR-3687 and miR-4417 in Prostate Cancer Cells Using a Proteomics Approach. Int J Mol Sci 2022; 23:ijms231810565. [PMID: 36142477 PMCID: PMC9501364 DOI: 10.3390/ijms231810565] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/08/2022] [Accepted: 09/08/2022] [Indexed: 12/20/2022] Open
Abstract
MicroRNAs (miRNA) are ubiquitous non-coding RNAs that have a prominent role in cellular regulation. The expression of many miRNAs is often found deregulated in prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). Although their expression can be associated with PCa and CRPC, their functions and regulatory activity in cancer development are poorly understood. In this study, we used different proteomics tools to analyze the activity of hsa-miR-3687-3p (miR-3687) and hsa-miR-4417-3p (miR-4417), two miRNAs upregulated in CRPC. PCa and CRPC cell lines were transfected with miR-3687 or miR-4417 to overexpress the miRNAs. Cell lysates were analyzed using 2D gel electrophoresis and proteins were subsequently identified using mass spectrometry (Maldi-MS/MS). A whole cell lysate, without 2D-gel separation, was analyzed by ESI-MS/MS. The expression of deregulated proteins found across both methods was further investigated using Western blotting. Gene ontology and cellular process network analysis determined that miR-3687 and miR-4417 are involved in diverse regulatory mechanisms that support the CRPC phenotype, including metabolism and inflammation. Moreover, both miRNAs are associated with extracellular vesicles, which point toward a secretory mechanism. The tumor protein D52 isoform 1 (TD52-IF1), which regulates neuroendocrine trans-differentiation, was found to be substantially deregulated in androgen-insensitive cells by both miR-3687 and miR-4417. These findings show that these miRNAs potentially support the CRPC by truncating the TD52-IF1 expression after the onset of androgen resistance.
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Role of MicroRNAs in Neuroendocrine Prostate Cancer. Noncoding RNA 2022; 8:ncrna8020025. [PMID: 35447888 PMCID: PMC9029336 DOI: 10.3390/ncrna8020025] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 03/24/2022] [Accepted: 03/24/2022] [Indexed: 11/25/2022] Open
Abstract
Therapy-induced neuroendocrine prostate cancer (t-NEPC/NEPC) is an aggressive variant of prostate cancer (PCa) that frequently emerges in castration-resistant prostate cancer (CRPC) under the selective pressure of androgen receptor (AR)-targeted therapies. This variant is extremely aggressive, metastasizes to visceral organs, tissues, and bones despite low serum PSA, and is associated with poor survival rates. It arises via a reversible trans-differentiation process, referred to as ‘neuroendocrine differentiation’ (NED), wherein PCa cells undergo a lineage switch and exhibit neuroendocrine features, characterized by the expression of neuronal markers such as enolase 2 (ENO2), chromogranin A (CHGA), and synaptophysin (SYP). The molecular and cellular mechanisms underlying NED in PCa are complex and not clearly understood, which contributes to a lack of effective molecular biomarkers for diagnosis and therapy of this variant. NEPC is thought to derive from prostate adenocarcinomas by clonal evolution. A characteristic set of genetic alterations, such as dual loss of retinoblastoma (RB1) and tumor protein (TP53) tumor suppressor genes and amplifications of Aurora kinase A (AURKA), NMYC, and EZH2, has been reported to drive NEPC. Recent evidence suggests that microRNAs (miRNAs) are important epigenetic players in driving NED in advanced PCa. In this review, we highlight the role of miRNAs in NEPC. These studies emphasize the diverse role that miRNAs play as oncogenes and tumor suppressors in driving NEPC. These studies have unveiled the important role of cellular processes such as the EMT and cancer stemness in determining NED in PCa. Furthermore, miRNAs are involved in intercellular communication between tumor cells and stromal cells via extracellular vesicles/exosomes that contribute to lineage switching. Recent studies support the promising potential of miRNAs as novel diagnostic biomarkers and therapeutic targets for NEPC.
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Liang X, Wang Y, Pei L, Tan X, Dong C. Identification of Prostate Cancer Risk Genetics Biomarkers Based on Intergraded Bioinformatics Analysis. Front Surg 2022; 9:856446. [PMID: 35372462 PMCID: PMC8967941 DOI: 10.3389/fsurg.2022.856446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/09/2022] [Indexed: 12/04/2022] Open
Abstract
Background Prostate cancer (PCa) is one of the most popular cancer types in men. Nevertheless, the pathogenic mechanisms of PCa are poorly understood. Hence, we aimed to identify the potential genetic biomarker of PCa in the present study. Methods High-throughput data set GSE46602 was obtained from the comprehensive gene expression database (GEO) for screening differentially expressed genes (DEGs). The common DEGs were further screened out using The Cancer Genome Atlas (TCGA) dataset. Functional enrichment analysis includes Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to study related mechanisms. The Cox and Lasso regression analyses were carried out to compress the target genes and construct the high-risk and low-risk gene model. Survival analyses were performed based on the gene risk signature model. The CIBERSORT algorithm was performed to clarify the correlation of the high- and low-risk gene model in risk and infiltration of immune cells in PCa. Results A total of 385 common DEGs were obtained. The results of functional enrichment analysis show that common DEGs play an important role in PCa. A three-gene signature model (KCNK3, AK5, and ARHGEF38) was established, and the model was significantly associated with cancer-related pathways, overall survival (OS), and tumor microenvironment (TME)-related immune cells in PCa. Conclusion This new risk model may contribute to further investigation in the immune-related pathogenesis in progression of PCa.
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Affiliation(s)
| | | | | | | | - Chunhui Dong
- Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiahzuang, China
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Quan Y, Zhang X, Ping H. Construction of a risk prediction model using m6A RNA methylation regulators in prostate cancer: comprehensive bioinformatic analysis and histological validation. Cancer Cell Int 2022; 22:33. [PMID: 35045837 PMCID: PMC8772220 DOI: 10.1186/s12935-021-02438-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/30/2021] [Indexed: 02/06/2023] Open
Abstract
Background Epigenetic reprogramming reportedly has a crucial role in prostate cancer (PCa) progression. RNA modification is a hot topic in epigenetics, and N6-methyladenosine (m6A) accounts for approximately 60% of RNA chemical modifications. The aim of this study was to evaluate the m6A modification patterns in PCa patients and construct a risk prediction model using m6A RNA regulators. Materials and methods Analyses were based on the levels of 25 m6A regulators in The Cancer Genome Atlas (TCGA). Differentially expressed gene (DEG) and survival analyses were performed according to TCGA-PRAD clinicopathologic and follow-up information. To detect the influences of m6A regulators and their DEGs, consensus clustering analysis was performed, and tumor mutational burden (TMB) estimation and tumor microenvironment (TME) cell infiltration were assessed. mRNA levels of representative genes were verified using clinical PCa data. Results Diverse expression patterns of m6A regulators between tumor and normal (TN) tissues were detected regarding Gleason score (GS), pathological T stage (pT), TP53 mutation, and survival comparisons, with HNRNPA2B1 and IGFBP3 being intersecting genes. HNRNPA2B1 was upregulated in advanced stages (GS > 7, pT3, HR > 1, and TP53 mutation), as verified using clinical PCa tissue. Three distinct m6A modification patterns were identified through consensus clustering analysis, but no significant difference was found among these groups in recurrence-free survival (RFS) analysis. Six DEGs of m6A clusters (m6Aclusters) were screened through univariate Cox regression analysis. MMAB and PAIAP2 were intersecting genes for the five clinical factors. MMAB, which was upregulated in PCa compared with TN, was verified using clinical PCa samples. Three distinct subgroups were established according to the 6 DEGs. Cluster A involved the most advanced stages and had the poorest RFS. The m6A score (m6Ascore) was calculated based on the 6 genes, and the low m6Ascore group showed poor RFS with a negative association with infiltration for 16 of 23 immune-related cells. Conclusion We screened DEGs of m6Aclusters and identified 6 genes (BAIAP2, TEX264, MMAB, JAGN1, TIMM8AP1, and IMP3), with which we constructed a highly predictive model with prognostic value by dividing TCGA-PRAD into three distinct subgroups and performing m6Ascore analysis. This study helps to elucidate the integral effects of m6A modification patterns on PCa progression. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02438-1.
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PCAT6 May Be a Whistler and Checkpoint Target for Precision Therapy in Human Cancers. Cancers (Basel) 2021; 13:cancers13236101. [PMID: 34885209 PMCID: PMC8656686 DOI: 10.3390/cancers13236101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/21/2021] [Accepted: 11/29/2021] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Prostate cancer-associated transcript 6 (PCAT6), as a newly discovered carcinogenic long non-coding RNA (lncRNA), is abnormally expressed in multiple diseases. With the accumulation of studies on PCAT6, we have a deeper understanding of its biological functions and mechanisms. Therefore, in this review, the various molecular mechanisms by which PCAT6 promotes multiple tumorigenesis and progression are summarized and discussed. Furthermore, its potential diagnostic, prognostic, and immunotherapeutic values are also clarified. Abstract LncRNAs are involved in the occurrence and progressions of multiple cancers. Emerging evidence has shown that PCAT6, a newly discovered carcinogenic lncRNA, is abnormally elevated in various human malignant tumors. Until now, PCAT6 has been found to sponge various miRNAs to activate the signaling pathways, which further affects tumor cell proliferation, migration, invasion, cycle, apoptosis, radioresistance, and chemoresistance. Moreover, PCAT6 has been shown to exert biological functions beyond ceRNAs. In this review, we summarize the biological characteristics of PCAT6 in a variety of human malignancies and describe the biological mechanisms by which PCAT6 can facilitate tumor progression. Finally, we discuss its diagnostic and prognostic values and clinical applications in various human malignancies.
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Slabáková E, Kahounová Z, Procházková J, Souček K. Regulation of Neuroendocrine-like Differentiation in Prostate Cancer by Non-Coding RNAs. Noncoding RNA 2021; 7:ncrna7040075. [PMID: 34940756 PMCID: PMC8704250 DOI: 10.3390/ncrna7040075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/18/2021] [Accepted: 11/29/2021] [Indexed: 12/21/2022] Open
Abstract
Neuroendocrine prostate cancer (NEPC) represents a variant of prostate cancer that occurs in response to treatment resistance or, to a much lesser extent, de novo. Unravelling the molecular mechanisms behind transdifferentiation of cancer cells to neuroendocrine-like cancer cells is essential for development of new treatment opportunities. This review focuses on summarizing the role of small molecules, predominantly microRNAs, in this phenomenon. A published literature search was performed to identify microRNAs, which are reported and experimentally validated to modulate neuroendocrine markers and/or regulators and to affect the complex neuroendocrine phenotype. Next, available patients’ expression datasets were surveyed to identify deregulated microRNAs, and their effect on NEPC and prostate cancer progression is summarized. Finally, possibilities of miRNA detection and quantification in body fluids of prostate cancer patients and their possible use as liquid biopsy in prostate cancer monitoring are discussed. All the addressed clinical and experimental contexts point to an association of NEPC with upregulation of miR-375 and downregulation of miR-34a and miR-19b-3p. Together, this review provides an overview of different roles of non-coding RNAs in the emergence of neuroendocrine prostate cancer.
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