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1
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Bayasgalan T, Kanda M, Sato Y, Zhu H, Hamrah MH, Martinez FEG, Shinozuka T, Ito Y, Sasahara M, Shimizu D, Umeda S, Inokawa Y, Hattori N, Hayashi M, Tanaka C, Kodera Y. SPOCD1 Enhances Cancer Cell Activities and Serves as a Prognosticator in Esophageal Squamous Cell Carcinoma. Cancer Genomics Proteomics 2025; 22:306-325. [PMID: 39993802 PMCID: PMC11880929 DOI: 10.21873/cgp.20503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/02/2025] [Accepted: 01/13/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND/AIM Comprehensive transcriptome analysis has revealed SPOC Domain Containing 1 (SPOCD1) as a potential biomarker for esophageal squamous cell carcinoma (ESCC). However, the expression and oncological roles of SPOCD1 in ESCC remains underexplored. We aimed to evaluate the role of SPOCD1 in oncogenesis and prognosis of ESCC in vitro and in vivoMaterials and Methods: The Cancer Cell Line Encyclopedia (CCLE) database was utilized to evaluate correlations between SPOCD1 expression and oncogenes in ESCC. mRNA and protein levels were measured by qRT-PCR and Simple Western assays, respectively. siRNA-mediated knockdown and overexpression experiments assessed the effects of SPOCD1 expression on proliferation, migration, and invasion of ESCC cell lines. In vivo, siRNA knockdown effects on tumor growth were tested in mouse xenograft models. SPOCD1 mRNA levels in 164 resected tissues were correlated with clinicopathological parameters and survival, while a cohort of 177 patients was analyzed for protein expression and survival. RESULTS SPOCD1 mRNA expression varied widely among ESCC cell lines and correlated with epithelial-mesenchymal transition-related genes. Knockdown significantly suppressed proliferation, migration, and invasion (p<0.001), while overexpression increased proliferation (p<0.001). In vivo, siRNA knockdown reduced tumor growth compared to both si-control (p=0.005) and untransfected groups (p<0.001). High SPOCD1 mRNA expression was linked to poor disease-specific survival (p=0.009, HR=1.965, 95% CI=1.187-3.252) and disease-free survival (p=0.047, HR=1.602, 95% CI=1.007-2.549). Similarly, elevated protein levels were associated with unfavorable disease-specific (p=0.013, HR=1.860, 95% CI=1.137-3.041) and disease-free survival (p=0.032, HR=1.618, 95% CI=1.042-2.513). CONCLUSION SPOCD1 expression correlates with the aggressiveness of ESCC cells, and its expression levels in tumor tissues may serve as a prognostic factor for ESCC patients.
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Affiliation(s)
- Tuvshin Bayasgalan
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan;
| | - Yusuke Sato
- Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Haote Zhu
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mohammad Hussain Hamrah
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | - Takahiro Shinozuka
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuki Ito
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiro Sasahara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Dai Shimizu
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinichi Umeda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshikuni Inokawa
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Norifumi Hattori
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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2
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Tucci FA, Pennisi R, Rigiracciolo DC, Filippone MG, Bonfanti R, Romeo F, Freddi S, Guerrera E, Soriani C, Rodighiero S, Gunby RH, Jodice G, Sanguedolce F, Renne G, Fusco N, Di Fiore PP, Pruneri G, Bertalot G, Musi G, Vago G, Tosoni D, Pece S. Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis. Nat Commun 2024; 15:10378. [PMID: 39627202 PMCID: PMC11615365 DOI: 10.1038/s41467-024-54246-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 11/05/2024] [Indexed: 12/06/2024] Open
Abstract
Advances in bladder cancer (BCa) treatment have been hampered by the lack of predictive biomarkers and targeted therapies. Here, we demonstrate that loss of the tumor suppressor NUMB promotes aggressive bladder tumorigenesis and worsens disease outcomes. Retrospective cohort studies show that NUMB-loss correlates with poor prognosis in post-cystectomy muscle-invasive BCa patients and increased risk of muscle invasion progression in non-muscle invasive BCa patients. In mouse models, targeted Numb ablation induces spontaneous tumorigenesis and sensitizes the urothelium to carcinogenic insults, accelerating tumor onset and progression. Integrative transcriptomic and functional analyses in mouse and human BCa models reveal that upregulation of YAP transcriptional activity via a RHOA/ROCK-dependent pathway is a hallmark of NUMB-deficient BCa. Pharmacological or genetic inhibition of this molecular pathway selectively inhibits proliferation and invasion of NUMB-deficient BCa cells in 3D-Matrigel organoids. Thus, NUMB-loss could serve as a biomarker for identifying high-risk patients who may benefit from targeted anti-RHOA/ROCK/YAP therapies.
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Grants
- IG 23049 Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
- IG 23060 Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
- MIUR-PRIN2017 Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
- MIUR/PRIN2020 Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
- 5x1000 funds Ministero della Salute (Ministry of Health, Italy)
- Ricerca Corrente Ministero della Salute (Ministry of Health, Italy)
- RF-2016-02361540 Ministero della Salute (Ministry of Health, Italy)
- RF-2021-12373957 Ministero della Salute (Ministry of Health, Italy)
- Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
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Affiliation(s)
- F A Tucci
- European Institute of Oncology IRCCS, Milan, Italy
- School of Pathology, University of Milan, Milan, Italy
| | - R Pennisi
- European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology, University of Turin, Turin, Italy
| | - D C Rigiracciolo
- European Institute of Oncology IRCCS, Milan, Italy
- IRCCS Scientific Institute San Raffaele, Milan, Italy
| | - M G Filippone
- European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - R Bonfanti
- European Institute of Oncology IRCCS, Milan, Italy
| | - F Romeo
- European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - S Freddi
- European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - E Guerrera
- European Institute of Oncology IRCCS, Milan, Italy
| | - C Soriani
- European Institute of Oncology IRCCS, Milan, Italy
| | - S Rodighiero
- European Institute of Oncology IRCCS, Milan, Italy
| | - R H Gunby
- European Institute of Oncology IRCCS, Milan, Italy
| | - G Jodice
- European Institute of Oncology IRCCS, Milan, Italy
| | - F Sanguedolce
- Department of Pathology, University of Foggia, Foggia, Italy
| | - G Renne
- European Institute of Oncology IRCCS, Milan, Italy
| | - N Fusco
- European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - P P Di Fiore
- European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - G Pruneri
- School of Pathology, University of Milan, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - G Bertalot
- Department of Anatomy and Pathological Histology, APSS, Trento, Italy
- Centre for Medical Sciences-CISMed, University of Trento, Trento, Italy
| | - G Musi
- European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - G Vago
- School of Pathology, University of Milan, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - D Tosoni
- European Institute of Oncology IRCCS, Milan, Italy.
| | - S Pece
- European Institute of Oncology IRCCS, Milan, Italy.
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
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3
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Kayama E, Uemura M, Onagi A, Meguro S, Ogawa S, Yaginuma K, Matsuoka K, Hoshi S, Koguchi T, Hata J, Sato Y, Akaihata H, Honma R, Watanabe S, Kojima Y. A Novel Gene Expression Scoring System Predicts Recurrence in Non-Muscle-Invasive Bladder Cancer Patients. Cancer Med 2024; 13:e70349. [PMID: 39540204 PMCID: PMC11561421 DOI: 10.1002/cam4.70349] [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: 04/15/2024] [Revised: 10/05/2024] [Accepted: 10/07/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Despite the high recurrence rate of non-muscle-invasive bladder cancer (NMIBC), there are limitations in accurately predicting recurrence after transurethral resection of bladder tumor (TURBT) based on clinicopathological factors alone. However, prediction of recurrence using biomolecular characteristics of bladder tumors has not been applied to clinical practice. The objective of this study was to establish a new gene expression scoring system for identifying patients at high risk of recurrence. METHODS NMIBC and normal bladder samples were subjected to microarray analysis to obtain gene expression profiles. We identified 6 genes that were specifically upregulated in bladder cancer and also in recurrent cases. All patients were randomly grouped into a discovery cohort (n = 59) and a validation cohort (n = 30). Gene expression score (GES) was defined as the mean Z-score of the 6 genes specific for recurrent bladder cancer. RESULTS The intravesical recurrence rate of the high GES group (n = 38) was higher than the low GES group (n = 21). GES was significantly associated with recurrence-free survival in the validation cohort as well. In prognostic analysis, the European Organization for Research and Treatment of Cancer (EORTC) risk classification was not related to recurrence after TURBT in either univariate or multivariate analysis. On the other hand, the GES we developed was an independent factor for recurrence in NMIBC. CONCLUSIONS A novel gene expression scoring system was shown to predict recurrence in NMIBC patients after TURBT and might be helpful in clinical decision-making for NMIBC patients.
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Affiliation(s)
- Emina Kayama
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Motohide Uemura
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
- Department of UrologyIwase General HospitalFukushimaJapan
| | - Akifumi Onagi
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Satoru Meguro
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Soichiro Ogawa
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Kei Yaginuma
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Kanako Matsuoka
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Seiji Hoshi
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Tomoyuki Koguchi
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Junya Hata
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Yuichi Sato
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | - Hidenori Akaihata
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
| | | | - Shinya Watanabe
- Translational Research CenterFukushima Medical UniversityFukushimaJapan
| | - Yoshiyuki Kojima
- Department of UrologyFukushima Medical University School of MedicineFukushimaJapan
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Wang D, Wei Z, Lin F, Wang Y, Liu X, Li Q, Sun L, Yang S. Protective effects of villi mesenchymal stem cells on human umbilical vein endothelial cells by inducing SPOCD1 expression in cases of gestational diabetes mellitus. Biochem Biophys Res Commun 2023; 686:149177. [PMID: 37953105 DOI: 10.1016/j.bbrc.2023.149177] [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: 08/03/2023] [Revised: 10/16/2023] [Accepted: 10/27/2023] [Indexed: 11/14/2023]
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is characterized by a lack of response to insulin in pregnancies, and often accompanied by severe complications. GDM is associated with structural and functional alterations, particularly endothelial dysfunction, in various tissues. This study is aimed to investigate the effect of placental mesenchymal stem cells (MSCs) on the endothelial biological function of human umbilical vein endothelial cells (HUVECs) and their molecular mechanisms. METHODS Villi mesenchymal stem cells (VMSCs) were co-cultured with HUVECs, and transcriptomic analysis of differential genes was performed in HUVECs under high-glucose induction. Lentiviral transfection was performed to construct HUVECs with stable knockdown or overexpression of SPOCD1. The immunohistochemical assays were used to detect the expression of SPOCD1 in GDM patients. TUNEL fluorescence staining was applied for detection of the HUVEC apoptosis. β galactosidase staining assay was performed to detect the cell senescence. Electron microscopy was used to detect the cell pyroptosis. qRT-PCR and western blot assays were conducted for identifying the mRNA & protein expressions of genes. RESULTS VMSCs, when co-cultured with HUVECs, could inhibit the apoptosis, pyroptosis and senescence induced by high-glucose condition in HUVECs. Transcriptomic results showed an upregulation of SPOCD1 expression induced by VMSCs in HUVECs. Overexpression of SPOCD1 inhibited high-level glucose-induced apoptosis, pyroptosis and senescence in HUVECs via the β-catenin pathway. CONCLUSION VMSCs induce β-catenin activation by upregulating the expression of SPOCD1 in HUVECs, which ultimately inhibits high-level glucose-induced apoptosis, pyroptosis and senescence in HUVECs. This observation provides potential therapeutic insight for future GDM treatment.
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Affiliation(s)
- Dawei Wang
- Department of Obstetrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhenying Wei
- Department of Obstetrics, The Qingdao Women and Children's Hospital, Qingdao, China
| | - Fangfei Lin
- Department of Obstetrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yiqian Wang
- Department of Obstetrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaogang Liu
- Department of Obstetrics, People's Hospital of Yuxi City, Yuxi, China
| | - Qiuyi Li
- Department of Obstetrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lin Sun
- Department of Obstetrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shengmei Yang
- Department of Obstetrics, The Affiliated Hospital of Qingdao University, Qingdao, China.
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Donelan W, Brisbane W, O'Malley P, Crispen P, Kusmartsev S. Hyaluronan Metabolism in Urologic Cancers. Adv Biol (Weinh) 2023; 7:e2300168. [PMID: 37615259 DOI: 10.1002/adbi.202300168] [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: 05/01/2023] [Revised: 07/06/2023] [Indexed: 08/25/2023]
Abstract
Hyaluronan (HA) is one of the major components of the extracellular matrix in tumor tissue. Recent reports have made it clear that the balance of HA synthesis and degradation is critical for tumor progression. HA is synthesized on the cytoplasmic surface of the plasma membrane by hyaluronan synthases (HAS) and extruded into the extracellular space. Excessive HA production in cancer is associated with enhanced HA degradation in the tumor microenvironment, leading to the accumulation of HA fragments with small molecular weight. These perturbations in both HA synthesis and degradation may play important roles in tumor progression. Recently, it has become increasingly clear that small HA fragments can induce a variety of biological events, such as angiogenesis, cancer-promoting inflammation, and tumor-associated immune suppression. Progression of urologic malignancies, particularly of prostate and bladder cancers, as well as of certain types of kidney cancer show markedly perturbed metabolism of tumor-associated HA. This review highlights the recent research findings regarding HA metabolism in tumor microenvironments with a special focus on urologic cancers. It also will discuss the potential implications of these findings for the development of novel therapeutic interventions for the treatment of prostate, bladder, and kidney cancers.
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Affiliation(s)
| | - Wayne Brisbane
- UCLA Medical Center, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | | | - Paul Crispen
- University of Florida, Gainesville, FL, 32611, USA
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Cheng H, Liu Y, Chen G. Identification of potential DNA methylation biomarkers related to diagnosis in patients with bladder cancer through integrated bioinformatic analysis. BMC Urol 2023; 23:135. [PMID: 37563710 PMCID: PMC10413619 DOI: 10.1186/s12894-023-01307-5] [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: 03/15/2023] [Accepted: 08/01/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUND Bladder cancer (BLCA) is one of the most common malignancies among tumors worldwide. There are no validated biomarkers to facilitate such treatment diagnosis. DNA methylation modification plays important roles in epigenetics. Identifying methylated differentially expressed genes is a common method for the discovery of biomarkers. METHODS Bladder cancer data were obtained from Gene Expression Omnibus (GEO), including the gene expression microarrays GSE37817( 18 patients and 3 normal ), GSE52519 (9 patients and 3 normal) and the gene methylation microarray GSE37816 (18 patients and 3 normal). Aberrantly expressed genes were obtained by GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed using the DAVID database and KOBAS. Protein-protein interactions (PPIs) and hub gene networks were constructed by STRING and Cytoscape software. The validation of the results which was confirmed through four online platforms, including Gene Expression Profiling Interactive Analysis (GEPIA), Gene Set Cancer Analysis (GSCA), cBioProtal and MEXPRESS. RESULTS In total, 253 and 298 upregulated genes and 674 and 454 downregulated genes were identified for GSE37817 and GSE52519, respectively. For the GSE37816 dataset, hypermethylated and hypomethylated genes involving 778 and 3420 genes, respectively, were observed. Seventeen hypermethylated and low expression genes were enriched in biological processes associated with different organ development and morphogenesis. For molecular function, these genes showed enrichment in extracellular matrix structural constituents. Pathway enrichment showed drug metabolic enzymes and several amino acids metabolism, PI3K-Akt, Hedgehog signaling pathway. The top 3 hub genes screened by Cytoscape software were EFEMP1, SPARCL1 and ABCA8. The research results were verified using the GEPIA, GSCA, cBioProtal and EXPRESS databases, and the hub hypermethylated low expression genes were validated. CONCLUSION This study screened possible aberrantly methylated expression hub genes in BLCA by integrated bioinformatics analysis. The results may provide possible methylation-based biomarkers for the precise diagnosis and treatment of BLCA in the future.
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Affiliation(s)
- Hongxia Cheng
- School of Biological and Pharmaceutical Engineering, Wuhan Huaxia Institute of Technology, Wuhan, 430223, Hubei, China.
| | - Yuhua Liu
- School of Biological and Pharmaceutical Engineering, Wuhan Huaxia Institute of Technology, Wuhan, 430223, Hubei, China
| | - Gang Chen
- School of Biological and Pharmaceutical Engineering, Wuhan Huaxia Institute of Technology, Wuhan, 430223, Hubei, China
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Blanca A, Lopez-Beltran A, Lopez-Porcheron K, Gomez-Gomez E, Cimadamore A, Bilé-Silva A, Gogna R, Montironi R, Cheng L. Risk Classification of Bladder Cancer by Gene Expression and Molecular Subtype. Cancers (Basel) 2023; 15:cancers15072149. [PMID: 37046810 PMCID: PMC10093178 DOI: 10.3390/cancers15072149] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/31/2023] [Accepted: 04/02/2023] [Indexed: 04/08/2023] Open
Abstract
This study evaluated a panel including the molecular taxonomy subtype and the expression of 27 genes as a diagnostic tool to stratify bladder cancer patients at risk of aggressive behavior, using a well-characterized series of non-muscle invasive bladder cancer (NMIBC) as well as muscle-invasive bladder cancer (MIBC). The study was conducted using the novel NanoString nCounter gene expression analysis. This technology allowed us to identify the molecular subtype and to analyze the gene expression of 27 bladder-cancer-related genes selected through a recent literature search. The differential gene expression was correlated with clinicopathological variables, such as the molecular subtypes (luminal, basal, null/double negative), histological subtype (conventional urothelial carcinoma, or carcinoma with variant histology), clinical subtype (NMIBC and MIBC), tumor stage category (Ta, T1, and T2–4), tumor grade, PD-L1 expression (high vs. low expression), and clinical risk categories (low, intermediate, high and very high). The multivariate analysis of the 19 genes significant for cancer-specific survival in our cohort study series identified TP53 (p = 0.0001), CCND1 (p = 0.0001), MKI67 (p < 0.0001), and molecular subtype (p = 0.005) as independent predictors. A scoring system based on the molecular subtype and the gene expression signature of TP53, CCND1, or MKI67 was used for risk assessment. A score ranging from 0 (best prognosis) to 7 (worst prognosis) was obtained and used to stratify our patients into two (low [score 0–2] vs. high [score 3–7], model A) or three (low [score 0–2] vs. intermediate [score 3–4] vs. high [score 5–7], model B) risk categories with different survival characteristics. Mean cancer-specific survival was longer (122 + 2.7 months) in low-risk than intermediate-risk (79.4 + 9.4 months) or high-risk (6.2 + 0.9 months) categories (p < 0.0001; model A); and was longer (122 + 2.7 months) in low-risk than high-risk (58 + 8.3 months) (p < 0.0001; model B). In conclusion, the molecular risk assessment model, as reported here, might be used better to select the appropriate management for patients with bladder cancer.
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Affiliation(s)
- Ana Blanca
- Department of Urology, Maimonides Biomedical Research Institute of Cordoba, University Hospital of Reina Sofia, UCO, 14004 Cordoba, Spain
| | - Antonio Lopez-Beltran
- Department of Morphological Sciences, University of Cordoba Medical School, 14004 Cordoba, Spain
| | - Kevin Lopez-Porcheron
- Department of Morphological Sciences, University of Cordoba Medical School, 14004 Cordoba, Spain
| | - Enrique Gomez-Gomez
- Department of Urology, Maimonides Biomedical Research Institute of Cordoba, University Hospital of Reina Sofia, UCO, 14004 Cordoba, Spain
| | - Alessia Cimadamore
- Department of Medical Area (DAME), Institute of Pathological Anatomy, University of Udine, 33100 Udine, Italy
| | - Andreia Bilé-Silva
- Urology Department, Egas Moniz Hospital, Centro Hospitalar de Lisboa Occidental, 1349-019 Lisbon, Portugal
| | - Rajan Gogna
- Department of Human & Molecular Genetics, VCU Institute of Molecular Medicine (VIMM), VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
- BRIC-Biotech Research & Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark
- Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal
| | - Rodolfo Montironi
- Molecular Medicine and Cell Therapy Foundation, Polytechnic University of Marche, 60121 Ancona, Italy
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Brown University Warren Alpert Medical School, Lifespan Academic Medical Center, and the Legorreta Cancer Center at Brown University, Providence, RI 02903, USA
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8
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Omar M, Dinalankara W, Mulder L, Coady T, Zanettini C, Imada EL, Younes L, Geman D, Marchionni L. Using biological constraints to improve prediction in precision oncology. iScience 2023; 26:106108. [PMID: 36852282 PMCID: PMC9958363 DOI: 10.1016/j.isci.2023.106108] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 12/20/2022] [Accepted: 01/28/2023] [Indexed: 02/05/2023] Open
Abstract
Many gene signatures have been developed by applying machine learning (ML) on omics profiles, however, their clinical utility is often hindered by limited interpretability and unstable performance. Here, we show the importance of embedding prior biological knowledge in the decision rules yielded by ML approaches to build robust classifiers. We tested this by applying different ML algorithms on gene expression data to predict three difficult cancer phenotypes: bladder cancer progression to muscle-invasive disease, response to neoadjuvant chemotherapy in triple-negative breast cancer, and prostate cancer metastatic progression. We developed two sets of classifiers: mechanistic, by restricting the training to features capturing specific biological mechanisms; and agnostic, in which the training did not use any a priori biological information. Mechanistic models had a similar or better testing performance than their agnostic counterparts, with enhanced interpretability. Our findings support the use of biological constraints to develop robust gene signatures with high translational potential.
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Affiliation(s)
- Mohamed Omar
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Wikum Dinalankara
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Lotte Mulder
- Technical University Delft, 2628 CD Delft, the Netherlands
| | - Tendai Coady
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Claudio Zanettini
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Eddie Luidy Imada
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Laurent Younes
- Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Donald Geman
- Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Luigi Marchionni
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
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Wang Z, Huang Z, Cao X, Zhang F, Cai J, Tang P, Yang C, Li S, Yu D, Yan Y, Shen B. A prognostic model based on necroptosis-related genes for prognosis and therapy in bladder cancer. BMC Urol 2023; 23:10. [PMID: 36709279 PMCID: PMC9883845 DOI: 10.1186/s12894-023-01175-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 01/09/2023] [Indexed: 01/30/2023] Open
Abstract
Bladder cancer, one of the most prevalent malignant cancers, has high rate of recurrence and metastasis. Owing to genomic instability and high-level heterogeneity of bladder cancer, chemotherapy and immunotherapy drugs sensitivity and lack of prognostic markers, the prognosis of bladder cancer is unclear. Necroptosis is a programmed modality of necrotic cell death in a caspase-independent form. Despite the fact that necroptosis plays a critical role in tumor growth, cancer metastasis, and cancer patient prognosis, necroptosis-related gene sets have rarely been studied in bladder cancer. As a result, the development of new necroptosis-related prognostic indicators for bladder cancer patients is critical. Herein, we assessed the necroptosis landscape of bladder cancer patients from The Cancer Genome Atlas database and classified them into two unique necroptosis-related patterns, using the consensus clustering. Then, using five prognosis-related genes, we constructed a prognostic model (risk score), which contained 5 genes (ANXA1, DOK7, FKBP10, MAP1B and SPOCD1). And a nomogram model was also developed to offer the clinic with a more useful prognostic indicator. We found that risk score was significantly associated with clinicopathological characteristics, TIME, and tumor mutation burden in patients with bladder cancer. Moreover, risk score was a valid guide for immunotherapy, chemotherapy, and targeted drugs. In our study, DOK7 was chosen to further verify our prognosis model, and functional assays indicated that knockdown the expression of DOK7 could prompt bladder cancer proliferation and migration. Our work demonstrated the potential role of prognostic model based on necroptosis genes in the prognosis, immune landscape and response efficacy of immunotherapy of bladder cancer.
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Affiliation(s)
- Zeyi Wang
- grid.412478.c0000 0004 1760 4628Department of Urology, Shanghai General Hospital of Nanjing Medical University, Shanghai, 200080 China
| | - Zhengnan Huang
- grid.24516.340000000123704535Department of Urology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065 China
| | - Xiangqian Cao
- grid.412478.c0000 0004 1760 4628Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080 China
| | - Fang Zhang
- grid.412478.c0000 0004 1760 4628Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080 China
| | - Jinming Cai
- grid.412478.c0000 0004 1760 4628Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080 China
| | - Pengfei Tang
- grid.412478.c0000 0004 1760 4628Department of Urology, Shanghai General Hospital of Nanjing Medical University, Shanghai, 200080 China
| | - Chenkai Yang
- grid.412478.c0000 0004 1760 4628Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080 China
| | - Shengzhou Li
- grid.412478.c0000 0004 1760 4628Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080 China
| | - Dong Yu
- grid.73113.370000 0004 0369 1660Department of Precision Medicine, Center of Translation Medicine, Naval Medical University, Shanghai, 200082 China
| | - Yilin Yan
- grid.412478.c0000 0004 1760 4628Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080 China
| | - Bing Shen
- grid.412478.c0000 0004 1760 4628Department of Urology, Shanghai General Hospital of Nanjing Medical University, Shanghai, 200080 China ,grid.412478.c0000 0004 1760 4628Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080 China
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10
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Gan L, Yang C, Zhao L, Wang S, Gao Z, Ye Y. Prognostic Biomarker SPOCD1 and Its Correlation with Immune Infiltrates in Colorectal Cancer. Biomolecules 2023; 13:biom13020209. [PMID: 36830578 PMCID: PMC9953389 DOI: 10.3390/biom13020209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/08/2023] [Accepted: 01/13/2023] [Indexed: 01/24/2023] Open
Abstract
The biological role of the spen paralogue and orthologue C-terminal domain containing 1 (SPOCD1) has been investigated in human malignancies, but its function in colorectal cancer (CRC) is unclear. This study investigated the association between SPOCD1 expression and clinicopathological features of CRC cases, as well as its prognostic value and biological function based on large-scale databases and clinical samples. The results showed that the expression level of SPOCD1 was elevated in CRC, which was generally associated with shortened survival time and poor clinical indexes, including advanced T, N, and pathologic stages. Multivariate Cox regression analysis showed that elevated SPOCD1 expression was an independent factor for poor prognosis in CRC patients. Functional enrichment analysis of SPOCD1 and its co-expressed genes revealed that SPOCD1 could act as an oncogene by regulating gene expression in essential functions and pathways of tumorigenesis, such as extracellular matrix organization, chemokine signaling pathways, and calcium signaling pathways. In addition, immune cell infiltration results showed that SPOCD1 expression was associated with various immune cells, especially macrophages. Furthermore, our findings suggested a possible function for SPOCD1 in the polarization of macrophages from M1 to M2 in CRC. In conclusion, SPOCD1 is a promising diagnostic and prognostic marker for CRC, opening new avenues for research and treatment.
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Affiliation(s)
- Lin Gan
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China
- Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
| | - Changjiang Yang
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China
- Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
| | - Long Zhao
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China
- Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
| | - Shan Wang
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China
- Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
| | - Zhidong Gao
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China
- Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
- Correspondence: (Z.G.); (Y.Y.)
| | - Yingjiang Ye
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China
- Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
- Correspondence: (Z.G.); (Y.Y.)
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11
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Price ZK, Lokman NA, Yoshihara M, Kajiyama H, Oehler MK, Ricciardelli C. Disabled-2 ( DAB2): A Key Regulator of Anti- and Pro-Tumorigenic Pathways. Int J Mol Sci 2022; 24:ijms24010696. [PMID: 36614139 PMCID: PMC9821069 DOI: 10.3390/ijms24010696] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 01/03/2023] Open
Abstract
Disabled-2 (DAB2), a key adaptor protein in clathrin mediated endocytosis, is implicated in the regulation of key signalling pathways involved in homeostasis, cell positioning and epithelial to mesenchymal transition (EMT). It was initially identified as a tumour suppressor implicated in the initiation of ovarian cancer, but was subsequently linked to many other cancer types. DAB2 contains key functional domains which allow it to negatively regulate key signalling pathways including the mitogen activated protein kinase (MAPK), wingless/integrated (Wnt) and transforming growth factor beta (TGFβ) pathways. Loss of DAB2 is primarily associated with activation of these pathways and tumour progression, however this review also explores studies which demonstrate the complex nature of DAB2 function with pro-tumorigenic effects. A recent strong interest in microRNAs (miRNA) in cancer has identified DAB2 as a common target. This has reignited an interest in DAB2 research in cancer. Transcriptomics of tumour associated macrophages (TAMs) has also identified a pro-metastatic role of DAB2 in the tumour microenvironment. This review will cover the broad depth literature on the tumour suppressor role of DAB2, highlighting its complex relationships with different pathways. Furthermore, it will explore recent findings which suggest DAB2 has a more complex role in cancer than initially thought.
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Affiliation(s)
- Zoe K. Price
- Discipline of Obstetrics and Gynaecology, Robinson Research Institute, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
| | - Noor A. Lokman
- Discipline of Obstetrics and Gynaecology, Robinson Research Institute, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
| | - Masato Yoshihara
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 464-0813, Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 464-0813, Japan
| | - Martin K. Oehler
- Discipline of Obstetrics and Gynaecology, Robinson Research Institute, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
- Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| | - Carmela Ricciardelli
- Discipline of Obstetrics and Gynaecology, Robinson Research Institute, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
- Correspondence: ; Tel.:+61-08-8313-8255
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12
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Zhou D, Zhu F, Huang ZH, Zhang H, Fan LQ, Fan JY. SPOC domain-containing protein 1 regulates the proliferation and apoptosis of human spermatogonial stem cells through adenylate kinase 4. World J Stem Cells 2022; 14:822-838. [PMID: 36619695 PMCID: PMC9813840 DOI: 10.4252/wjsc.v14.i12.822] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/07/2022] [Accepted: 11/30/2022] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Spermatogonial stem cells (SSCs) are the origin of male spermatogenesis, which can reconstruct germ cell lineage in mice. However, the application of SSCs for male fertility restoration is hindered due to the unclear mechanisms of proliferation and self-renewal in humans.
AIM To investigate the role and mechanism of SPOC domain-containing protein 1 (SPOCD1) in human SSC proliferation.
METHODS We analyzed publicly available human testis single-cell RNA sequencing (RNA-seq) data and found that SPOCD1 is predominantly expressed in SSCs in the early developmental stages. Small interfering RNA was applied to suppress SPOCD1 expression to detect the impacts of SPOCD1 inhibition on SSC proliferation and apoptosis. Subsequently, we explored the target genes of SPOCD1 using RNA-seq and confirmed their role by restoring the expression of the target genes. In addition, we examined SPOCD1 expression in some non-obstructive azoospermia (NOA) patients to explore the correlation between SPOCD1 and NOA.
RESULTS The uniform manifold approximation and projection clustering and pseudotime analysis showed that SPOCD1 was highly expressed in the early stages of SSC, and immunohistological results showed that SPOCD1 was mainly localized in glial cell line-derived neurotrophic factor family receptor alpha-1 positive SSCs. SPOCD1 knockdown significantly inhibited cell proliferation and promoted apoptosis. RNA-seq results showed that SPOCD1 knockdown significantly downregulated genes such as adenylate kinase 4 (AK4). Overexpression of AK4 in SPOCD1 knockdown cells partially reversed the phenotypic changes, indicating that AK4 is a functional target gene of SPOCD1. In addition, we found a significant downregulation of SPOCD1 expression in some NOA patients, suggesting that the downregulation of SPOCD1 may be relevant for NOA.
CONCLUSION Our study broadens the understanding of human SSC fate determination and may offer new theories on the etiology of male infertility.
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Affiliation(s)
- Dai Zhou
- Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha 410000, Hunan Province, China
- Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, Hunan Province, China
- College of Life Sciences, Hunan Normal University, Changsha 410000, Hunan Province, China
- Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410000, Hunan Province, China
| | - Fang Zhu
- Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha 410000, Hunan Province, China
| | - Zeng-Hui Huang
- Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha 410000, Hunan Province, China
- Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, Hunan Province, China
- Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410000, Hunan Province, China
| | - Huan Zhang
- Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha 410000, Hunan Province, China
- Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, Hunan Province, China
- Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410000, Hunan Province, China
| | - Li-Qing Fan
- Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha 410000, Hunan Province, China
- Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, Hunan Province, China
- Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410000, Hunan Province, China
| | - Jing-Yu Fan
- Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha 410000, Hunan Province, China
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, United States
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13
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Zhao Z, Wang C, Chu P, Lu X. Key Genes Associated with Tumor-Infiltrating Non-regulatory CD4- and CD8-Positive T Cells in Microenvironment of Hepatocellular Carcinoma. Biochem Genet 2022; 60:1762-1780. [PMID: 35092558 PMCID: PMC9470630 DOI: 10.1007/s10528-021-10175-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 12/06/2021] [Indexed: 12/16/2022]
Abstract
The immune microenvironment in hepatocellular carcinoma (HCC), especially T-cell infiltration, plays a key role in the prognosis and drug sensitivity of HCC. Our study aimed to analyze genes related to non-regulatory CD4+ and CD8+ T cell in HCC. Data of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) database. According to stromal and immune score retrieved by Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm, differentiated expressed genes (DEGs) between high and low stromal/immune scoring groups were collected. Using Cibersort algorithm, abundance of immune cells was calculated and genes related with CD4+ and CD8+ T cells were selected. Protein-protein interaction (PPI) networks and networks of microRNA (miRNA)-target gene interactions were illustrated, in which CD4+ and CD8+ T cell-related core genes were selected. Finally, Cox regression test and Kaplan-Meier (K-M) survival analysis were conducted. Totally, 1579 DEGs were identified, where 103 genes and 407 genes related with CD4+ and CD8+ T cell were selected, respectively. Each of 30 core genes related to CD4+ T cells and CD8+ T cells were selected by PPI network. Four genes each related with the two types of T cells had a significant impact on prognosis of HCC patients. Amongst, KLRB1 and IL18RAP were final two genes related to both two kinds of T cells and associated with overall survival of the HCC patients.
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Affiliation(s)
- Zijun Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuaifuyuan, Wangfujing, Beijing, 100730, China
| | - Chaonan Wang
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Peishan Chu
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuaifuyuan, Wangfujing, Beijing, 100730, China.
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14
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Nishi K, Fu W, Kiyama R. Novel estrogen-responsive genes (ERGs) for the evaluation of estrogenic activity. PLoS One 2022; 17:e0273164. [PMID: 35976950 PMCID: PMC9385026 DOI: 10.1371/journal.pone.0273164] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/03/2022] [Indexed: 11/19/2022] Open
Abstract
Estrogen action is mediated by various genes, including estrogen-responsive genes (ERGs). ERGs have been used as reporter-genes and markers for gene expression. Gene expression profiling using a set of ERGs has been used to examine statistically reliable transcriptomic assays such as DNA microarray assays and RNA sequencing (RNA-seq). However, the quality of ERGs has not been extensively examined. Here, we obtained a set of 300 ERGs that were newly identified by six sets of RNA-seq data from estrogen-treated and control human breast cancer MCF-7 cells. The ERGs exhibited statistical stability, which was based on the coefficient of variation (CV) analysis, correlation analysis, and examination of the functional association with estrogen action using database searches. A set of the top 30 genes based on CV ranking were further evaluated quantitatively by RT-PCR and qualitatively by a functional analysis using the GO and KEGG databases and by a mechanistic analysis to classify ERα/β-dependent or ER-independent types of transcriptional regulation. The 30 ERGs were characterized according to (1) the enzymes, such as metabolic enzymes, proteases, and protein kinases, (2) the genes with specific cell functions, such as cell-signaling mediators, tumor-suppressors, and the roles in breast cancer, (3) the association with transcriptional regulation, and (4) estrogen-responsiveness. Therefore, the ERGs identified here represent various cell functions and cell signaling pathways, including estrogen signaling, and thus, may be useful to evaluate estrogenic activity.
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Affiliation(s)
- Kentaro Nishi
- Department of Life Science, Faculty of Life Science, Kyushu Sangyo University Matsukadai, Higashi-ku, Fukuoka, Japan
| | - Wenqiang Fu
- Department of Life Science, Faculty of Life Science, Kyushu Sangyo University Matsukadai, Higashi-ku, Fukuoka, Japan
| | - Ryoiti Kiyama
- Department of Life Science, Faculty of Life Science, Kyushu Sangyo University Matsukadai, Higashi-ku, Fukuoka, Japan
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15
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Zhao J, Chang L, Tu J, Sun B, Wei X. Evaluation of Annexins Family as Potential Biomarker for Predicting Progression and Prognosis in Clear Renal Cell Carcinoma. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:8748434. [PMID: 39290334 PMCID: PMC11407897 DOI: 10.1155/2022/8748434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 04/23/2022] [Accepted: 04/26/2022] [Indexed: 09/19/2024]
Abstract
Background Annexins family (ANXAs), as a Ca2+-dependent phospholipid-binding protein superfamily, participates in a wide variety of biological activities and has been reported to be dysregulated in numerous types of human cancers. Evidence from cell lines and human tissues indicates that ANAXs are involved in kidney clear renal cell carcinoma (KIRC) tumorigenesis. However, their prognostic value and expression pattern associated with KIRC remain to be elucidated. Methods We visited public databases, including ONCOMINE, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier plotter, cBioPortal, and GeneMANIA, to conduct comprehensive bioinformatics analysis and tried to detect basic relationships between each Annexins family member and KIRC. Results We found that the expression level of ANXA1/2/4/5/6/7/8/13 in clear renal cell carcinoma tissue was higher than that in the kidney tissue, while the expression level of ANXA3/9/11 in the former was lower than that in the latter. The expression level of ANXA7/8/13 is related to the stage of the tumour. Survival analysis using the Kaplan-Meier plotter database showed that a high transcription level of ANXA2/5/8/10 is related to a low overall survival rate (OS) in predicting KIRC patients. In contrast, high ANXA3/4/7/9/11/13 levels are associated with a high OS in these patients. Conclusions Our study implies that ANXA4/8/13 are potential targets of precision therapy for patients with KIRC and that ANXA2/5/8/10 are new biomarkers for the prognosis of KIRC.
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Affiliation(s)
- Jiyu Zhao
- Department of Urology, ChuiYangLiu Hospital Affiliated to Tsinghua University, 100021 Beijing, China
| | - Luchen Chang
- Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Jianping Tu
- Department of Urology, The Third Hospital of Xiamen, 361199 Xiamen, Fujian, China
| | - Bei Sun
- Department of Outpatient Office, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Xi Wei
- Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060 Tianjin, China
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16
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Lin Z, Chen L, Wu T, Zhang Y, Huang X, Chen Y, Chen J, Xu Y. Prognostic Value of SPOCD1 in Esophageal Squamous Cell Carcinoma: A Comprehensive Study Based on Bioinformatics and Validation. Front Genet 2022; 13:872026. [PMID: 35646092 PMCID: PMC9130929 DOI: 10.3389/fgene.2022.872026] [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: 02/09/2022] [Accepted: 04/20/2022] [Indexed: 12/24/2022] Open
Abstract
In the study, we aimed to explore and analyze the potential function of SPOC Domain Containing 1 (SPOCD1) in esophageal squamous cell carcinoma (ESCC). We performed a comprehensive analysis of gene expression of SPOCD1 and its corresponding clinicopathological features in ESCC. In particular, the correlation between SPOCD1 and ESCC was evaluated using a wide range of analysis tools and databases, including TCGA, GTEx, GenePattern, CellMiner, GDSC, and STRING datasets. Different bioinformatics analyses, including differential expression analysis, mutation analysis, drug sensitivity analysis, function analysis, pathway analysis, co-expression network analysis, immune cell infiltration analysis, and survival analysis, were carried out to comprehensively explore the potential molecular mechanisms and functional effects of SPOCD1 on the initiation and progression of ESCC. The expression of SPOCD1 was upregulated in ESCC tissues compared to those in normal tissues. In the high SPOCD1 expression group, we found apparent mutations in TP53, TTN, and MUC16 genes, which were 92, 36, and 18%, respectively. GO and KEGG enrichment analysis of SPOCD1 and its co-expressed genes demonstrated that it may serve as an ESCC oncogene by regulating the genes expression in the essential functions and pathways of tumorigenesis, such as glycosaminoglycan binding, Cytokine-cytokine receptor interaction, and Ras signaling pathway. Besides, the immune cell infiltration results revealed that SPOCD1 expression was positively correlated with Macrophages M0 and Mast cells activated cells, and negatively correlated with plasma cells and T cells follicular helper cell infiltration. Finally, ESCC patients with high expression of SPOCD1 indicated poor overall survival. qRT-PCR demonstrated that the SPOCD1 expression in ESCC tissues was significantly higher than adjacent tissues (p < 0.001). Our study indicated that SPOCD1 was increased in ESCC tissues. The current data support the oncogenic role of SPOCD1 in the occurrence and development of ESCC. Most importantly, SPOCD1 might be an independent prognostic factor for ESCC patients.
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Affiliation(s)
- Zhizhong Lin
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
| | - Lin Chen
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
| | - Tingting Wu
- The School of Nusing, Fujian Medical University, Fuzhou, China.,Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Yiping Zhang
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
| | - Xinyi Huang
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
| | - Yuanmei Chen
- Department of Thoracic Surgery, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
| | - Junqiang Chen
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
| | - Yuanji Xu
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
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17
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Zhu C, Wu Q, Yang N, Zheng Z, Zhou F, Zhou Y. Immune Infiltration Characteristics and a Gene Prognostic Signature Associated With the Immune Infiltration in Head and Neck Squamous Cell Carcinoma. Front Genet 2022; 13:848841. [PMID: 35586567 PMCID: PMC9108548 DOI: 10.3389/fgene.2022.848841] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 04/04/2022] [Indexed: 12/15/2022] Open
Abstract
Background: Immunotherapy has become the new standard of care for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC), and PD-L1 is a widely used biomarker for immunotherapeutic response. However, PD-L1 expression in most cancer patients is low, and alternative biomarkers used to screen the population benefiting from immunotherapy are still being explored. Tumor microenvironment (TME), especially tumor immune-infiltrating cells, regulates the body’s immunity, affects the tumor growth, and is expected to be a promising biomarker for immunotherapy. Purpose: This article mainly discussed how the immune-infiltrating cell patterns impacted immunity, thereby affecting HNSCC patients’ prognosis. Method: The immune-infiltrating cell profile was generated by the CIBERSORT algorithm based on the transcriptomic data of HNSCC. Consensus clustering was used to divide groups with different immune cell infiltration patterns. Differentially expressed genes (DEGs) obtained from the high and low immune cell infiltration (ICI) groups were subjected to Kaplan–Meier and univariate Cox analysis. Significant prognosis-related DEGs were involved in the construction of a prognostic signature using multivariate Cox analysis. Results: In our study, 408 DEGs were obtained from high- and low-ICI groups, and 59 of them were significantly associated with overall survival (OS). Stepwise multivariate Cox analysis developed a 16-gene prognostic signature, which could distinguish favorable and poor prognosis of HNSCC patients. An ROC curve and nomogram verified the sensitivity and accuracy of the prognostic signature. The AUC values for 1 year, 2 years, and 3 years were 0.712, 0.703, and 0.700, respectively. TCGA-HNSCC cohort, GSE65858 cohort, and an independent GSE41613 cohort proved a similar prognostic significance. Notably, the prognostic signature distinguished the expression of promising immune inhibitory receptors (IRs) well and could predict the response to immunotherapy. Conclusion: We established a tumor immune cell infiltration (TICI)-based 16-gene signature, which could distinguish patients with different prognosis and help predict the response to immunotherapy.
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Affiliation(s)
- Chunmei Zhu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qiuji Wu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ningning Yang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhewen Zheng
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Fuxiang Zhou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
- *Correspondence: Fuxiang Zhou, ; Yunfeng Zhou,
| | - Yunfeng Zhou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
- *Correspondence: Fuxiang Zhou, ; Yunfeng Zhou,
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Tonyali S. Combining Clinical Parameters and Immunohistochemical Markers Might Strengthen Prediction of Recurrence of Non-Muscle Invasive Bladder Cancer. J INVEST SURG 2022; 35:1195. [DOI: 10.1080/08941939.2022.2047244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Senol Tonyali
- Department of Urology, Istanbul University Istanbul School of Medicine, Istanbul, Turkey
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19
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[Detection of DNA methylation of HYAL2 gene for differentiating malignant from benign thyroid tumors]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:123-129. [PMID: 35249879 PMCID: PMC8901399 DOI: 10.12122/j.issn.1673-4254.2022.01.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE To assess the value of DNA methylation level of HYAL2 gene as a molecular marker for differential diagnosis of malignant and benign thyroid tumors. METHODS DNA methylation of HYAL2 gene in tissue specimens of 190 patients with papillary thyroid cancer (PTC) and 190 age- and gender-matched patients with benign thyroid tumors was examined by mass spectrometry, and the protein expression of HYAL2 was detected immunohistochemically for another 55 pairs of patients. Logistic regression analysis was performed to calculate the odds ratio (OR) and evaluate the correlation of per 10% reduction in DNA methylation with PTC. Receiver operating characteristic (ROC) curve analysis was performed and the area under curve (AUC) was calculated to assess the predictive value of alterations in HYAL2 methylation. RESULTS Hypomethylation of HYAL2_CpG_3 was significantly correlated with early-stage PTC (OR=1.51, P=0.001), even in stage I cancer (OR=1.42, P=0.007). Age-stratified analysis revealed a significantly stronger correlation between increased HYAL2_CpG_ 3 methylation and early-stage PTC in patients below 50 years than in those older than 50 years (OR: 1.89 vs 1.37, P < 0.05); ROC analysis also showed a larger AUC of 0.787 in younger patients. The results of immunohistochemistry showed that patients with PTC had significantly higher protein expressions of HYAL2 than patients with benign tumors. CONCLUSION The alterations of DNA methylation level of HYAL2 gene is significantly correlated with early-stage PTC, suggesting the value of DNA methylation level as a potential biomarker for differentiation of malignant from benign thyroid tumors.
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20
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Park S, Rong L, Owczarek TB, Bernardo MD, Shoulson RL, Chua CW, Kim JY, Lankarani A, Chakrapani P, Syed T, McKiernan JM, Solit DB, Shen MM, Al-Ahmadie HA, Abate-Shen C. Novel Mouse Models of Bladder Cancer Identify a Prognostic Signature Associated with Risk of Disease Progression. Cancer Res 2021; 81:5161-5175. [PMID: 34470779 PMCID: PMC8609963 DOI: 10.1158/0008-5472.can-21-1254] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/11/2021] [Accepted: 08/31/2021] [Indexed: 11/16/2022]
Abstract
To study the progression of bladder cancer from non-muscle-invasive to muscle-invasive disease, we have developed a novel toolkit that uses complementary approaches to achieve gene recombination in specific cell populations in the bladder urothelium in vivo, thereby allowing us to generate a new series of genetically engineered mouse models (GEMM) of bladder cancer. One method is based on the delivery of adenoviruses that express Cre recombinase in selected cell types in the urothelium, and a second uses transgenic drivers in which activation of inducible Cre alleles can be limited to the bladder urothelium by intravesicular delivery of tamoxifen. Using both approaches, targeted deletion of the Pten and p53 tumor suppressor genes specifically in basal urothelial cells gave rise to muscle-invasive bladder tumors. Furthermore, preinvasive lesions arising in basal cells displayed upregulation of molecular pathways related to bladder tumorigenesis, including proinflammatory pathways. Cross-species analyses comparing a mouse gene signature of early bladder cancer with a human signature of bladder cancer progression identified a conserved 28-gene signature of early bladder cancer that is associated with poor prognosis for human bladder cancer and that outperforms comparable gene signatures. These findings demonstrate the relevance of these GEMMs for studying the biology of human bladder cancer and introduce a prognostic gene signature that may help to stratify patients at risk for progression to potentially lethal muscle-invasive disease. SIGNIFICANCE: Analyses of bladder cancer progression in a new series of genetically engineered mouse models has identified a gene signature of poor prognosis in human bladder cancer.
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Affiliation(s)
- Soonbum Park
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, New York
| | - Lijie Rong
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, New York
| | - Tomasz B Owczarek
- Department of Urology, Columbia University Irving Medical Center, New York, New York
| | - Matteo Di Bernardo
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, New York
| | - Rivka L Shoulson
- Institute of Comparative Medicine, Columbia University, New York, New York
| | - Chee-Wai Chua
- Department of Urology, Columbia University Irving Medical Center, New York, New York
- Department of Medicine, Columbia University Irving Medical Center, New York, New York
- Department of Genetics & Development, Columbia University Irving Medical Center, New York, New York
- Department of Systems Biology, Columbia University Irving Medical Center, New York, New York
| | - Jaime Y Kim
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, New York
| | - Amir Lankarani
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, New York
| | - Prithi Chakrapani
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, New York
| | - Talal Syed
- Department of Urology, Columbia University Irving Medical Center, New York, New York
- Department of Medicine, Columbia University Irving Medical Center, New York, New York
- Department of Genetics & Development, Columbia University Irving Medical Center, New York, New York
- Department of Systems Biology, Columbia University Irving Medical Center, New York, New York
- Department of Biological Sciences, Columbia University, New York, New York
| | - James M McKiernan
- Department of Urology, Columbia University Irving Medical Center, New York, New York
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - David B Solit
- Departments of Human Oncology and Pathogenesis and Medicine, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York
- Weill Medical College, Cornell University, New York, New York
| | - Michael M Shen
- Department of Urology, Columbia University Irving Medical Center, New York, New York
- Department of Medicine, Columbia University Irving Medical Center, New York, New York
- Department of Genetics & Development, Columbia University Irving Medical Center, New York, New York
- Department of Systems Biology, Columbia University Irving Medical Center, New York, New York
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Hikmat A Al-Ahmadie
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Cory Abate-Shen
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, New York.
- Department of Urology, Columbia University Irving Medical Center, New York, New York
- Department of Systems Biology, Columbia University Irving Medical Center, New York, New York
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
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Martinez-Morales P, Morán Cruz I, Roa-de la Cruz L, Maycotte P, Reyes Salinas JS, Vazquez Zamora VJ, Gutierrez Quiroz CT, Montiel-Jarquin AJ, Vallejo-Ruiz V. Hallmarks of glycogene expression and glycosylation pathways in squamous and adenocarcinoma cervical cancer. PeerJ 2021; 9:e12081. [PMID: 34540372 PMCID: PMC8415283 DOI: 10.7717/peerj.12081] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/06/2021] [Indexed: 12/18/2022] Open
Abstract
Background Dysregulation of glycogene expression in cancer can lead to aberrant glycan expression, which can promote tumorigenesis. Cervical cancer (CC) displays an increased expression of glycogenes involved in sialylation and sialylated glycans. Here, we show a comprehensive analysis of glycogene expression in CC to identify glycogene expression signatures and the possible glycosylation pathways altered. Methods First, we performed a microarray expression assay to compare glycogene expression changes between normal and cervical cancer tissues. Second, we used 401 glycogenes to analyze glycogene expression in adenocarcinoma and squamous carcinoma from RNA-seq data at the cBioPortal for Cancer Genomics. Results The analysis of the microarray expression assay indicated that CC displayed an increase in glycogenes related to GPI-anchored biosynthesis and a decrease in genes associated with chondroitin and dermatan sulfate with respect to normal tissue. Also, the glycogene analysis of CC samples by the RNA-seq showed that the glycogenes involved in the chondroitin and dermatan sulfate pathway were downregulated. Interestingly the adenocarcinoma tumors displayed a unique glycogene expression signature compared to squamous cancer that shows heterogeneous glycogene expression divided into six types. Squamous carcinoma type 5 (SCC-5) showed increased expression of genes implicated in keratan and heparan sulfate synthesis, glycosaminoglycan degradation, ganglio, and globo glycosphingolipid synthesis was related to poorly differentiated tumors and poor survival. Squamous carcinoma type 6 (SCC-6) displayed an increased expression of genes involved in chondroitin/dermatan sulfate synthesis and lacto and neolacto glycosphingolipid synthesis and was associated with nonkeratinizing squamous cancer and good survival. In summary, our study showed that CC tumors are not a uniform entity, and their glycome signatures could be related to different clinicopathological characteristics.
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Affiliation(s)
- Patricia Martinez-Morales
- CONACYT-Centro de Investigación Biomédica de Oriente, Mexican Institute of Social Security, Metepec, Puebla, México
| | - Irene Morán Cruz
- Centro de Investigación Biomédica de Oriente, Laboratory of Molecular Biology, Instituto Mexicano del Seguro Social, Metepec, Puebla, México
| | - Lorena Roa-de la Cruz
- Department of Biological Chemical Sciences, Universidad de las Américas-Puebla, San Andrés Cholula, Puebla, Mexico
| | - Paola Maycotte
- Centro de Investigación Biomédica de Oriente, Laboratory of Cell Biology, Instituto Mexicano del Seguro Social, Metepec, Puebla, México
| | - Juan Salvador Reyes Salinas
- Hospital de especialidades, General Manuel Ávila Camacho, Instituto Mexicano del Seguro Social, Puebla, Puebla, México
| | - Victor Javier Vazquez Zamora
- Hospital de especialidades, General Manuel Ávila Camacho, Instituto Mexicano del Seguro Social, Puebla, Puebla, México
| | | | - Alvaro Jose Montiel-Jarquin
- Hospital de especialidades, General Manuel Ávila Camacho, Instituto Mexicano del Seguro Social, Puebla, Puebla, México
| | - Verónica Vallejo-Ruiz
- Centro de Investigación Biomédica de Oriente, Laboratory of Molecular Biology, Instituto Mexicano del Seguro Social, Metepec, Puebla, México
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22
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Yahyazadeh R, Bashash D, Ghaffari P, Kord S, Safaroghli-Azar A, Ghaffari SH. Evaluation of hTERT, KRT7, and survivin in urine for noninvasive detection of bladder cancer using real-time PCR. BMC Urol 2021; 21:64. [PMID: 33874920 PMCID: PMC8054358 DOI: 10.1186/s12894-021-00838-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 04/15/2021] [Indexed: 12/30/2022] Open
Abstract
Background Transitional cell carcinoma (TCC) of the bladder is the second most common genitourinary malignancy. Because of the low sensitivity of urinary cytology and the invasiveness and expense of frequent cystoscopies for the detection of low-grade superficial lesions, we aim to establish a sensitive molecular approach to detect bladder cancer noninvasively. Methods Voided urine samples were collected from 80 patients with bladder cancer at the time of diagnosis, in addition to 30 patients with non-bladder cancer urological diseases and 20 healthy volunteers. The level of hTERT, KRT7, and survivin (SVV) mRNAs were analyzed using a qRT-PCR assay. Results The optimal threshold values for hTERT, KRT7, and SVV in urine were calculated by ROC curves analysis. The overall sensitivity was 81.3%, 91.3%, and 68.8% for hTERT, KRT7, and SVV, respectively, which were significantly higher than urine cytology (22.2%, p < 0.001). A higher positive ratio was obtained using multi-marker detection in comparison to single marker detection. The combined use of markers increased the sensitivity of cytology from 22.2 to 100%. In contrast with the urine cytology method, the sensitivity of these biomarkers was not correlated with the grades and stages of the bladder tumors. Conclusions Our data indicate that urinary hTERT, KRT7, and SVV have superior sensitivities over cytology. The combined use of these markers offers a powerful potential assay and promising tool for a sensitive, noninvasive, and highly specific diagnostic method and follow-up of low-grade TCC of the bladder.
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Affiliation(s)
- Reza Yahyazadeh
- Department of Urology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, School of Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeid Kord
- Hematology, Oncology and Stem Cell Transplantation Research Center, School of Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, School of Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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Can repeat biopsy be skipped after initial complete resection of T1 bladder cancer? The role of a novel urinary mRNA biomarker. Urol Oncol 2021; 39:437.e11-437.e19. [PMID: 33785220 DOI: 10.1016/j.urolonc.2021.02.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/05/2021] [Accepted: 02/07/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVES To prospectively investigate the role of a urinary mRNA biomarker (Xpert Test) after initial complete resection of T1 bladder cancer (BC) for the prediction of positive repeat biopsy for malignancy. METHODS Patients who underwent TURBT for NMIBC between September 2018 and April 2020 were included. Patients with benign pathology, incomplete resection, concomitant CIS/upper tract urothelial tumor or muscle invasive BC, were excluded. 2 to 6 weeks after primary TURBT, voided urine sample was retrieved for Xpert analysis and patients were scheduled for repeat biopsy. The primary outcome was to determine the role of positive Xpert test to predict positive repeat biopsy for malignancy. RESULTS During the study period, 254 patients met the study inclusion criteria of which 61 (24%) patients had recurrent NMIBC. Complete resection was censured by the presence of detrusor muscle in the specimen with documented T1 disease in all study participants. Xpert test was positive in 128 patients; of whom 85 (66.4%) showed positive repeat biopsy (HR=6.2, 95%CI=3.46-9.4, P = 0.002). The sensitivity, specificity, positive and negative predictive values of Xpert test for repeat biopsy were 85.9% (95%CI: 82-89), 72.3% (95%CI: 68-76), 66.4% (95%CI: 62-71) and 88.9% (95%CI: 85-94), respectively. On median (range) follow up of 12(3-25) months, tumor recurrence was encountered in 84 (35%) patients. On multivariate Cox regression analysis, Xpert test was significantly associated with tumor recurrence (HR= 9.7, 95%CI=5-18, P <0.001). CONCLUSIONS Positive Xpert test after primary complete resection of T1 BC is significantly associated with positive repeat biopsy for malignancy. In addition, Xpert test is an independent predictor of early tumor recurrence. Xpert test might be applied after initial complete resection of NMIBC to minimize unnecessary repeat biopsy with potential saving of healthcare costs and reduction in patient morbidity.
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24
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Differential gene expression profile between progressive and de novo muscle invasive bladder cancer and its prognostic implication. Sci Rep 2021; 11:6132. [PMID: 33731721 PMCID: PMC7969618 DOI: 10.1038/s41598-021-85137-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 02/19/2021] [Indexed: 12/13/2022] Open
Abstract
This study aimed to ascertain gene expression profile differences between progressive muscle-invasive bladder cancer (MIBC) and de novo MIBC, and to identify prognostic biomarkers to improve patients’ treatment. Retrospective multicenter study in which 212 MIBC patients who underwent radical cystectomy between 2000 and 2019 were included. Gene expression profiles were determined in 26 samples using Illumina microarrays. The expression levels of 94 genes were studied by quantitative PCR in an independent set of 186 MIBC patients. In a median follow-up of 16 months, 46.7% patients developed tumor progression after cystectomy. In our series, progressive MIBC patients show a worse tumor progression (p = 0.024) and cancer-specific survival (CSS) (p = 0.049) than the de novo group. A total of 480 genes were found to be differently expressed between both groups. Differential expression of 24 out of the 94 selected genes was found in an independent cohort. RBPMC2 and DSC3 were found as independent prognostic biomarkers of tumor progression and CALD1 and LCOR were identified as prognostic biomarkers of CSS between both groups. In conclusion, progressive and de novo MIBC patients show different clinical outcome and gene expression profiles. Gene expression patterns may contribute to predict high-risk of progression to distant metastasis or CSS.
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Champion M, Chiquet J, Neuvial P, Elati M, Radvanyi F, Birmelé E. Identification of deregulation mechanisms specific to cancer subtypes. J Bioinform Comput Biol 2021; 19:2140003. [PMID: 33653235 DOI: 10.1142/s0219720021400035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
In many cancers, mechanisms of gene regulation can be severely altered. Identification of deregulated genes, which do not follow the regulation processes that exist between transcription factors and their target genes, is of importance to better understand the development of the disease. We propose a methodology to detect deregulation mechanisms with a particular focus on cancer subtypes. This strategy is based on the comparison between tumoral and healthy cells. First, we use gene expression data from healthy cells to infer a reference gene regulatory network. Then, we compare it with gene expression levels in tumor samples to detect deregulated target genes. We finally measure the ability of each transcription factor to explain these deregulations. We apply our method on a public bladder cancer data set derived from The Cancer Genome Atlas project and confirm that it captures hallmarks of cancer subtypes. We also show that it enables the discovery of new potential biomarkers.
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Affiliation(s)
| | - Julien Chiquet
- Université Paris Saclay, AgroParisTech, INRAE, UMR MIA-Paris, Paris, France
| | - Pierre Neuvial
- Institut de Mathématiques de Toulouse, UMR 5219, Université de Toulouse, CNRS, France
| | - Mohamed Elati
- CANTHER, University of Lille, CNRS UMR 1277, Inserm U9020, 59045 Lille cedex, France
| | - François Radvanyi
- Institut Curie, PSL Research University, CNRS, UMR144, Paris, France
| | - Etienne Birmelé
- Université de Paris, CNRS, MAP5 UMR8145, Paris, France.,Institut de Recherche Mathématique Avancée, UMR 7501 Université de Strasbourg, CNRS, Strasbourg, France
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Kulasekaran G, Chaineau M, Piscopo VEC, Verginelli F, Fotouhi M, Girard M, Tang Y, Dali R, Lo R, Stifani S, McPherson PS. An Arf/Rab cascade controls the growth and invasiveness of glioblastoma. J Cell Biol 2021; 220:e202004229. [PMID: 33443570 PMCID: PMC7812876 DOI: 10.1083/jcb.202004229] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 10/27/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma is the most common and deadly malignant brain cancer. We now demonstrate that loss of function of the endosomal GTPase Rab35 in human brain tumor initiating cells (BTICs) increases glioblastoma growth and decreases animal survival following BTIC implantation in mouse brains. Mechanistically, we identify that the GTPase Arf5 interacts with the guanine nucleotide exchange factor (GEF) for Rab35, DENND1/connecdenn, and allosterically enhances its GEF activity toward Rab35. Knockdown of either Rab35 or Arf5 increases cell migration, invasiveness, and self-renewal in culture and enhances the growth and invasiveness of BTIC-initiated brain tumors in mice. RNAseq of the tumors reveals up-regulation of the tumor-promoting transcription factor SPOCD1, and disruption of the Arf5/Rab35 axis in glioblastoma cells leads to strong activation of the epidermal growth factor receptor, with resulting enhancement of SPOCD1 levels. These discoveries reveal an unexpected cascade between an Arf and a Rab and indicate a role for the cascade, and thus endosomal trafficking, in brain tumors.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Peter S. McPherson
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
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Liu Z, Sun T, Zhang Z, Bi J, Kong C. An 18-gene signature based on glucose metabolism and DNA methylation improves prognostic prediction for urinary bladder cancer. Genomics 2021; 113:896-907. [PMID: 33096258 DOI: 10.1016/j.ygeno.2020.10.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/23/2020] [Accepted: 10/16/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Glucose metabolism and DNA methylation play important roles in cancers. We aimed to identify glucose metabolism-related genes that were DNA methylation associated to establish a prognostic signature of bladder cancer (BLCA). METHODS With BLCA sample transcriptome data from The Cancer Genome Atlas (TCGA) and methylation data from TCGA 450 K microarray, glucose metabolism-related genes associated to prognosis and DNA methylation were identified and a prognostic signature was established. GSEA and WGCNA analysis were performed and two genes, UCHL1 and PYCR1, were selected for functional validations. RESULTS 18 target genes were identified and the signature based on them was considered an effective and independent prognostic factor. Several pathways were enriched in the high-risk group by GSEA and three modules of genes were identified by WGCNA. UCHL1 and PYCR1 proliferated proliferation, migration and invasion ability of bladder cancer cells. CONCLUSIONS The 18-gene signature is an independent prognostic factor for bladder cancer patients.
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Affiliation(s)
- Zhuonan Liu
- Department of Urology, Fist Hospital of China Medical University, School of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province 110004, PR China
| | - Tianshui Sun
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, PR China
| | - Zhe Zhang
- Department of Urology, Fist Hospital of China Medical University, School of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province 110004, PR China
| | - Jianbin Bi
- Department of Urology, Fist Hospital of China Medical University, School of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province 110004, PR China.
| | - Chuize Kong
- Department of Urology, Fist Hospital of China Medical University, School of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province 110004, PR China.
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Dominguez-Gutierrez PR, Kwenda EP, Donelan W, O'Malley P, Crispen PL, Kusmartsev S. Hyal2 Expression in Tumor-Associated Myeloid Cells Mediates Cancer-Related Inflammation in Bladder Cancer. Cancer Res 2020; 81:648-657. [PMID: 33239427 DOI: 10.1158/0008-5472.can-20-1144] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 11/17/2020] [Accepted: 11/20/2020] [Indexed: 11/16/2022]
Abstract
The increased presence of myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in tumor tissue has been extensively reported. However, their role in the regulation of hyaluronan (HA) metabolism in the tumor microenvironment has not been established. Here we describe a novel function of tumor-associated myeloid cells related to the enhanced breakdown of extracellular HA in human bladder cancer tissue, leading to the accumulation of small HA fragments with molecular weight (MW) <20 kDa. Increased fragmentation of extracellular HA and accumulation of low molecular weight HA (LMW-HA) in tumor tissue was associated with elevated production of multiple inflammatory cytokines, chemokines, and angiogenic factors. The fragmentation of HA by myeloid cells was mediated by the membrane-bound enzyme hyaluronidase 2 (Hyal2). Increased numbers of Hyal2+CD11b+ myeloid cells were detected in the tumor tissue as well as in the peripheral blood of patients with bladder cancer. Coexpression of CD33 suggested that these cells belong to monocytic myeloid-derived suppressor cells. The HA-degrading function of Hyal2-expressing MDSCs could be enhanced by exposure to tumor-conditioned medium, and IL1β was identified as one of the factors involved in the stimulation of Hyal2 activity. CD44-mediated signaling played an important role in the regulation of HA-degrading activity of Hyal2-expressing myeloid cells, as the engagement of CD44 receptor with specific mAb triggered translocation of Hyal2 enzyme to the cellular surface and stimulated secretion of IL1β. Taken together, this work identifies Hyal2-expressing tumor-associated myeloid cells as key players in the accumulation of LMW-HA in the tumor microenvironment and cancer-related inflammation and angiogenesis. SIGNIFICANCE: This study identifies Hyal2-expressing tumor-associated myeloid cells of monocyte-macrophage lineage as contributors to hyaluronan degradation in bladder cancer tissue, leading to accumulation of inflammatory and proangiogenic low molecular weight hyaluronan fragments.
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Affiliation(s)
| | | | - William Donelan
- Department of Urology, University of Florida, Gainesville, Florida
| | - Padraic O'Malley
- Department of Urology, University of Florida, Gainesville, Florida
| | - Paul L Crispen
- Department of Urology, University of Florida, Gainesville, Florida
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Chen Z, Zhou L, Liu L, Hou Y, Xiong M, Yang Y, Hu J, Chen K. Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat Commun 2020; 11:5077. [PMID: 33033240 PMCID: PMC7545162 DOI: 10.1038/s41467-020-18916-5] [Citation(s) in RCA: 362] [Impact Index Per Article: 72.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 09/18/2020] [Indexed: 12/23/2022] Open
Abstract
Although substantial progress has been made in cancer biology and treatment, clinical outcomes of bladder carcinoma (BC) patients are still not satisfactory. The tumor microenvironment (TME) is a potential target. Here, by single-cell RNA sequencing on 8 BC tumor samples and 3 para tumor samples, we identify 19 different cell types in the BC microenvironment, indicating high intra-tumoral heterogeneity. We find that tumor cells down regulated MHC-II molecules, suggesting that the downregulated immunogenicity of cancer cells may contribute to the formation of an immunosuppressive microenvironment. We also find that monocytes undergo M2 polarization in the tumor region and differentiate. Furthermore, the LAMP3 + DC subgroup may be able to recruit regulatory T cells, potentially taking part in the formation of an immunosuppressive TME. Through correlation analysis using public datasets containing over 3000 BC samples, we identify a role for inflammatory cancer-associated fibroblasts (iCAFs) in tumor progression, which is significantly related to poor prognosis. Additionally, we characterize a regulatory network depending on iCAFs. These results could help elucidate the protumor mechanisms of iCAFs. Our results provide deep insight into cancer immunology and provide an essential resource for drug discovery in the future.
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Affiliation(s)
- Zhaohui Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lijie Zhou
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China
| | - Lilong Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China
| | - Yaxin Hou
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China
| | - Ming Xiong
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yu Yang
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Junyi Hu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
- Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China.
| | - Ke Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
- Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China.
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30
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Kang HW, Kim WJ, Yun SJ. The therapeutic and prognostic implications of molecular biomarkers in urothelial carcinoma. Transl Cancer Res 2020; 9:6609-6623. [PMID: 35117271 PMCID: PMC8798786 DOI: 10.21037/tcr-20-1243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 04/20/2020] [Indexed: 12/27/2022]
Abstract
Urothelial cell carcinoma (UCC) of the bladder and upper urinary tract is a heterogeneous disease with distinct biologic features resulting in different clinical behaviors. Bladder cancer (BC) is classified into non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). NMIBC is associated with high recurrence rates and risk of progression to invasive disease, whereas MIBC is complicated by systemic recurrence after radical cystectomy because of the limited efficacy of available therapies. UCC of the upper urinary tract (UUT-UCC) is a rare but aggressive urologic cancer characterized by multifocality, local recurrence, and metastasis. Conventional histopathologic evaluation of UCC, including tumor stage and grade, cannot accurately predict the behavior of BC and UUT-UCC. Recent clinical and preclinical studies aimed at understanding the molecular landscape of UCC have provided insight into molecular subtyping, inter- or intratumoral heterogeneity, and potential therapeutic targets. Combined analysis of molecular markers and standard pathological features may improve risk stratification and help monitor tumor progression and treatment response, ultimately improving patient outcomes. This review discusses prognostic and therapeutic biomarkers for BC and UUT-UCC, and describes recent advances in molecular stratification that may guide prognosis, patient stratification, and treatment selection.
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Affiliation(s)
- Ho Won Kang
- Department of Urology, School of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, South Korea.,Department of Urology, Chungbuk National University Hospital, Cheongju, South Korea
| | - Wun-Jae Kim
- Department of Urology, School of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, South Korea.,Department of Urology, Chungbuk National University Hospital, Cheongju, South Korea
| | - Seok Joong Yun
- Department of Urology, School of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, South Korea.,Department of Urology, Chungbuk National University Hospital, Cheongju, South Korea
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31
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Bellmunt J, Kim J, Reardon B, Perera-Bel J, Orsola A, Rodriguez-Vida A, Wankowicz SA, Bowden M, Barletta JA, Morote J, de Torres I, Juanpere N, Lloreta-Trull J, Hernandez S, Mouw KW, Taplin ME, Cejas P, Long HW, Van Allen EM, Getz G, Kwiatkowski DJ. Genomic Predictors of Good Outcome, Recurrence, or Progression in High-Grade T1 Non-Muscle-Invasive Bladder Cancer. Cancer Res 2020; 80:4476-4486. [PMID: 32868381 DOI: 10.1158/0008-5472.can-20-0977] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/27/2020] [Accepted: 08/20/2020] [Indexed: 11/16/2022]
Abstract
High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non-muscle-invasive bladder cancer with unpredictable outcome and poorly understood risk factors. Here, we examined the association of somatic mutation profiles with nonrecurrent disease (GO, good outcome), recurrence (R), or progression (PD) in a cohort of HGT1 patients. Exome sequencing was performed on 62 HGT1 and 15 matched normal tissue samples. Both tumor only (TO) and paired analyses were performed, focusing on 95 genes known to be mutated in bladder cancer. Somatic mutations, copy-number alterations, mutation load, and mutation signatures were studied. Thirty-three GO, 10 R, 18 PD, and 1 unknown outcome patients were analyzed. Tumor mutational burden (TMB) was similar to muscle-invasive disease and was highest in GO, intermediate in PD, and lowest in R patients (P = 0.017). DNA damage response gene mutations were associated with higher TMB (P < 0.0001) and GO (P = 0.003). ERCC2 and BRCA2 mutations were associated with GO. TP53, ATM, ARID1A, AHR, and SMARCB1 mutations were more frequent in PD. Focal copy-number gain in CCNE1 and CDKN2A deletion was enriched in PD or R (P = 0.047; P = 0.06). APOBEC (46%) and COSMIC5 (34%) signatures were most frequent. APOBEC-A and ERCC2 mutant tumors (COSMIC5) were associated with GO (P = 0.047; P = 0.0002). pT1b microstaging was associated with a genomic cluster (P = 0.05) with focal amplifications of E2F3/SOX4, PVRL4, CCNE1, and TP53 mutations. Findings were validated using external public datasets. These findings require confirmation but suggest that management of HGT1 bladder cancer may be improved via molecular characterization to predict outcome. SIGNIFICANCE: Detailed genetic analyses of HGT1 bladder tumors identify features that correlate with outcome, e.g., high mutational burden, ERCC2 mutations, and high APOBEC-A/ERCC2 mutation signatures were associated with good outcome.
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Affiliation(s)
- Joaquim Bellmunt
- Beth Israel Deaconess Medical Center, Boston, Massachusetts. .,Harvard Medical School University, Boston, Massachusetts.,The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.,IMIM-Hospital del Mar Medical Research Institute; Hospital del Mar, Barcelona, Spain
| | - Jaegil Kim
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Brendan Reardon
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Júlia Perera-Bel
- IMIM-Hospital del Mar Medical Research Institute; Hospital del Mar, Barcelona, Spain
| | - Anna Orsola
- IMIM-Hospital del Mar Medical Research Institute; Hospital del Mar, Barcelona, Spain
| | - Alejo Rodriguez-Vida
- IMIM-Hospital del Mar Medical Research Institute; Hospital del Mar, Barcelona, Spain
| | - Stephanie A Wankowicz
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Michaela Bowden
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Justine A Barletta
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Juan Morote
- Department of Urology, University Hospital Valle de Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Inés de Torres
- Department of Pathology, University Hospital Valle de Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Nuria Juanpere
- Department of Pathology, University Hospital del Mar, Pompeu Fabra University, Barcelona, Spain
| | - Josep Lloreta-Trull
- Department of Pathology, University Hospital del Mar, Pompeu Fabra University, Barcelona, Spain
| | - Silvia Hernandez
- Department of Pathology, University Hospital del Mar, Pompeu Fabra University, Barcelona, Spain
| | - Kent W Mouw
- Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts
| | - Mary-Ellen Taplin
- Harvard Medical School University, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Paloma Cejas
- Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, Massachusetts
| | - Henry W Long
- Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, Massachusetts
| | - Eliezer M Van Allen
- Harvard Medical School University, Boston, Massachusetts.,The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Gad Getz
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.,Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.,Department of Pathology, Harvard Medical School, Boston, Massachusetts
| | - David J Kwiatkowski
- Harvard Medical School University, Boston, Massachusetts. .,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
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32
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Liu X, Yang M, Guo Y, Lu X. Annexin A10 is a novel prognostic biomarker of papillary thyroid cancer. Ir J Med Sci 2020; 190:59-65. [PMID: 32451762 DOI: 10.1007/s11845-020-02263-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 05/16/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND The incidence of thyroid cancer (TC) is increasing rapidly worldwide. The target therapy for papillary TC (PTC) is limited, and the studies of PTC prognostic biomarkers are not common. As a new member of annexin A (ANXA) family, the function and clinical significance of ANXA10 in PTC have not been well investigated. METHODS Expressions of all the 12 ANXA members were detected with qPCR in 12 PTC tissues, and the ANXA10 mRNAs in PTCs and their adjacent normal thyroid tissues were compared. The subcellular location and expression of ANXA10 in 121 PTC patients were investigated with immunohistochemistry, which further classified the patients into subgroups with low or high ANXA10. The clinical significance and prognostic value of ANXA10 were estimated by analyzing its correlation with clinical factors and overall survival rates by the chi-squared test, univariate analyses, and multivariate analyses. RESULTS ANXA10 had the highest expression in PTCs among all the ANXA members. Moreover, ANXA10 was significantly upregulated in PTC compared with normal thyroid tissues. The PTC patients with low and high expression of ANXA10 took up 70.25% (85/121) and 29.75% (36/121), respectively. ANXA10 expression was associated with tumor size, differentiation, and overall survival rates of PTC. ANXA10 was an independent prognostic biomarker predicting the poor outcome of PTC. CONCLUSIONS ANXA10 expression was upregulated in PTC, and it was an independent prognostic biomarker of PTC, suggesting that ANXA10 may be a promising target for individual treatment of ANXA10.
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Affiliation(s)
- Xiaoyun Liu
- Department of Cardiology, YIDU Central Hospital, Weifang, China
| | - Meijing Yang
- Department of Cardiology, YIDU Central Hospital, Weifang, China
| | - Yang Guo
- Department of Cardiology, YIDU Central Hospital, Weifang, China
| | - Xiaofei Lu
- Department of Thyroid and Breast Surgery, Central Hospital affiliated to Shandong First Medical University, # 105 Jiefang Road, Jinan, 250013, China.
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33
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Shi R, Bao X, Rogowski P, Schäfer C, Schmidt-Hegemann NS, Unger K, Lu S, Sun J, Buchner A, Stief C, Belka C, Li M. Establishment and Validation of an Individualized Cell Cycle Process-Related Gene Signature to Predict Cancer-Specific Survival in Patients with Bladder Cancer. Cancers (Basel) 2020; 12:cancers12051146. [PMID: 32370292 PMCID: PMC7281226 DOI: 10.3390/cancers12051146] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/24/2020] [Accepted: 04/24/2020] [Indexed: 12/20/2022] Open
Abstract
More accurate models are essential to identify high-risk bladder cancer (BCa) patients who will benefit from adjuvant therapies and thus helpful to facilitate personalized management of BCa. Among various cancer-related hallmarks and pathways, cell cycle process (CCP) was identified as a dominant risk factor for cancer-specific survival (CSS) in BCa. Using a series of bioinformatic and statistical approaches, a CCP-related gene signature was established, and the prognostic value was validated in other independent BCa cohorts. In addition, the risk score derived from the gene signature serves as a promising marker for therapeutic resistance. In combination with clinicopathological features, a nomogram was constructed to provide more accurate prediction for CSS, and a decision tree was built to identify high-risk subgroup of muscle invasive BCa patients. Overall, the gene signature could be a useful tool to predict CSS and help to identify high-risk subgroup of BCa patients, which may benefit from intensified adjuvant therapy.
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Affiliation(s)
- Run Shi
- Department of Radiation Oncology, University Hospital, LMU Munich, D-81377 Munich, Germany; (R.S.); (P.R.); (C.S.); (N.-S.S.-H.); (K.U.); (J.S.); (C.B.)
| | - Xuanwen Bao
- Technical University of Munich, D-80333 Munich, Germany;
| | - Paul Rogowski
- Department of Radiation Oncology, University Hospital, LMU Munich, D-81377 Munich, Germany; (R.S.); (P.R.); (C.S.); (N.-S.S.-H.); (K.U.); (J.S.); (C.B.)
| | - Christian Schäfer
- Department of Radiation Oncology, University Hospital, LMU Munich, D-81377 Munich, Germany; (R.S.); (P.R.); (C.S.); (N.-S.S.-H.); (K.U.); (J.S.); (C.B.)
| | - Nina-Sophie Schmidt-Hegemann
- Department of Radiation Oncology, University Hospital, LMU Munich, D-81377 Munich, Germany; (R.S.); (P.R.); (C.S.); (N.-S.S.-H.); (K.U.); (J.S.); (C.B.)
| | - Kristian Unger
- Department of Radiation Oncology, University Hospital, LMU Munich, D-81377 Munich, Germany; (R.S.); (P.R.); (C.S.); (N.-S.S.-H.); (K.U.); (J.S.); (C.B.)
- Research Unit Radiation Cytogenetics, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, D-85764 Neuherberg, Germany
| | - Shun Lu
- Department of Radiotherapy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China;
| | - Jing Sun
- Department of Radiation Oncology, University Hospital, LMU Munich, D-81377 Munich, Germany; (R.S.); (P.R.); (C.S.); (N.-S.S.-H.); (K.U.); (J.S.); (C.B.)
| | - Alexander Buchner
- Department of Urology, University Hospital, LMU Munich, D-81377 Munich, Germany; (A.B.); (C.S.)
| | - Christian Stief
- Department of Urology, University Hospital, LMU Munich, D-81377 Munich, Germany; (A.B.); (C.S.)
| | - Claus Belka
- Department of Radiation Oncology, University Hospital, LMU Munich, D-81377 Munich, Germany; (R.S.); (P.R.); (C.S.); (N.-S.S.-H.); (K.U.); (J.S.); (C.B.)
| | - Minglun Li
- Department of Radiation Oncology, University Hospital, LMU Munich, D-81377 Munich, Germany; (R.S.); (P.R.); (C.S.); (N.-S.S.-H.); (K.U.); (J.S.); (C.B.)
- Correspondence:
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34
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Ma Q, Shao Y, Chen W, Quan C, Zhu Y, Xu X, Zhou Z, Wang S. Discovery of candidate gene expression signatures in peripheral blood for the screening of cervical cancer. Biomark Med 2020; 14:109-118. [PMID: 32064895 DOI: 10.2217/bmm-2019-0247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Aim: To investigate whether cervical cancer (CC) and cervical intraepithelial neoplasia (CIN) can be screened by analyzing gene expression profiling of peripheral blood. Methods: RNA-sequencing analysis of blood was performed on 11 CC patients, 21 CIN patients and 19 healthy controls (H). Fifty-nine genes were validated by quantitative real-time PCR using blood samples from 46 H, 83 CC and 32 CIN patients. Results: There were significant differences in the expression levels of six genes between CC and H, five genes between CIN and H and four genes between CC and CIN (p < 0.05). Four genes discriminated cervical lesions from H with a sensitivity of 82.61%, a specificity of 87.83% and an area under the curve of 0.8981. Three genes discriminated CC from CIN with a sensitivity of 53.13%, a specificity of 96.39% and an area under the curve of 0.7786. Conclusion: Our findings provided a promising noninvasive quantitative real-time PCR diagnostic assay of CC and CIN.
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Affiliation(s)
- Qiuling Ma
- Department of Biotechnology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, China.,Department of Hematology, The Second Affiliated Hospital of Henan University of Chinese Medicine (The Henan Province Hospital of Traditional Chinese Medicine), 6 Dongfeng Road, Zhengzhou 450002, China
| | - Yong Shao
- Department of Biotechnology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, China
| | - Wei Chen
- Department of Gynecology, The Second Affiliated Hospital of Guangzhou Medical University, 250 East Changgang Road, Guangzhou 510260, China
| | - Cheng Quan
- Department of Biotechnology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, China
| | - Yanhui Zhu
- Department of Biotechnology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, China
| | - Xiaohong Xu
- Department of Clinical Lab, Zhejiang Cancer Hospital, 1 East Banshan Road, Gongshu District, Hangzhou 310022, China
| | - Zhe Zhou
- Department of Biotechnology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, China
| | - Shengqi Wang
- Department of Biotechnology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, China
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35
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Yin H, Zhang C, Gou X, He W, Gan D. Identification of a 13‑mRNA signature for predicting disease progression and prognosis in patients with bladder cancer. Oncol Rep 2020; 43:379-394. [PMID: 31894276 PMCID: PMC6967157 DOI: 10.3892/or.2019.7429] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 11/08/2019] [Indexed: 12/24/2022] Open
Abstract
There are no reliable criteria to assess risk of progression of non‑muscle invasive bladder cancer to muscle invasive bladder cancer. The aim of the present study was to identify potential markers based on gene expression profiling to improve predictive power of disease progression and prognosis in patients with bladder cancer. In the present study, we screened seventy‑three differentially expressed genes by analyzing bladder cancer samples with or without progression. Forty‑seven prognosis‑related genes were screened, 13 of which were identified to build a progression‑associated gene signature using the LASSO regression method. Based on this 13‑mRNA signature, patients were divided into high‑ and low‑risk groups, with different prognostic outcomes. The gene signature was an independent prognostic factor for overall survival. Receiver operating characteristic analysis suggested that the signature performed well in the validation cohort and its predictive power outperformed other several published signatures. CTHRC1, MMP11, AEBP1, SNCAIP, COL1A1 and S100A8 were identified as hub genes and their expression levels were detected using reverse transcriptase‑quantitative polymerase chain reaction. The expression of CTHRC1 was elevated in aggressive bladder cancer compared with non‑invasive type, which suggests CTHRC1 may be a valuable biomarker for prediction of prognosis and progression of bladder cancer. Collectively, this 13‑mRNA signature may be useful in predicting disease progression and prognosis, thereby contributing to individualized management of patients with bladder cancer.
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Affiliation(s)
- Hubin Yin
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Chen Zhang
- Department of Obstetrics and 4The Central Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xin Gou
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Weiyang He
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Daoju Gan
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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36
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Itami Y, Miyake M, Ohnishi S, Tatsumi Y, Gotoh D, Hori S, Morizawa Y, Iida K, Ohnishi K, Nakai Y, Inoue T, Anai S, Tanaka N, Fujii T, Shimada K, Furuya H, Khadka VS, Deng Y, Fujimoto K. Disabled Homolog 2 (DAB2) Protein in Tumor Microenvironment Correlates with Aggressive Phenotype in Human Urothelial Carcinoma of the Bladder. Diagnostics (Basel) 2020; 10:E54. [PMID: 31968685 PMCID: PMC7168324 DOI: 10.3390/diagnostics10010054] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 01/14/2020] [Accepted: 01/17/2020] [Indexed: 12/14/2022] Open
Abstract
Disabled homolog-2 (DAB2) has been reported to be a tumor suppressor gene. However, a number of contrary studies suggested that DAB2 promotes tumor invasion in urothelial carcinoma of the bladder (UCB). Here, we investigated the clinical role and biological function of DAB2 in human UCB. Immunohistochemical staining analysis for DAB2 was carried out on UCB tissue specimens. DAB2 expression levels were compared with clinicopathological factors. DAB2 was knocked-down by small interfering RNA (siRNA) transfection, and then its effects on cell proliferation, invasion, and migration, and changes to epithelial-mesenchymal transition (EMT)-related proteins were evaluated. In our in vivo assays, tumor-bearing athymic nude mice subcutaneously inoculated with human UCB cells (MGH-U-3 or UM-UC-3) were treated by DAB2-targeting siRNA. Higher expression of DAB2 was associated with higher clinical T category, high tumor grade, and poor oncological outcome. The knock-down of DAB2 decreased both invasion and migration ability and expression of EMT-related proteins. Significant inhibitory effects on tumor growth and invasion were observed in xenograft tumors of UM-UC-3 treated by DAB2-targeting siRNA. Our findings suggested that DAB2 expression was associated with poor prognosis through increased oncogenic properties including tumor proliferation, migration, invasion, and enhancement of EMT in human UCB.
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Affiliation(s)
- Yoshitaka Itami
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Makito Miyake
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Sayuri Ohnishi
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Yoshihiro Tatsumi
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Daisuke Gotoh
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Shunta Hori
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Yousuke Morizawa
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Kota Iida
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Kenta Ohnishi
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Yasushi Nakai
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Takeshi Inoue
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Satoshi Anai
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Nobumichi Tanaka
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
| | - Tomomi Fujii
- Department of Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan;
| | - Keiji Shimada
- Department of Pathology, Nara City Hospital, 1-50-1 Higashi kidera-cho, Nara 630-8305, Japan;
| | - Hideki Furuya
- Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Vedbar S. Khadka
- Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA; (V.S.K.); (Y.D.)
| | - Youping Deng
- Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA; (V.S.K.); (Y.D.)
| | - Kiyohide Fujimoto
- Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
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Liu D, Yang Y, Yan A, Yang Y. SPOCD1 accelerates ovarian cancer progression and inhibits cell apoptosis via the PI3K/AKT pathway. Onco Targets Ther 2020; 13:351-359. [PMID: 32021280 PMCID: PMC6974139 DOI: 10.2147/ott.s200317] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 05/29/2019] [Indexed: 12/21/2022] Open
Abstract
Background Ovarian cancer (OC) is the most common type of gynecological malignant tumors with poor prognosis. The spen paralogue and orthologue C-terminal domain containing 1 (SPOCD1) is a newly identified molecule that has been indicated to discriminate progressive in human solid tumors. However, the role of SPOCD1 in OC remains unknown. Methods The expression of SPOCD1 in OC and non-cancerous tissue was detected by Realtime polymerase chain reaction and immunohistochemical staining. The expression of SPOCD1 in OC cells (SKOV3 and CAOV3) was also detected by immunohistochemical staining. The effect of SPOCD1 on cell proliferation was analyzed by Cell Counting Kit 8 and colony formation assay, and cell migration was analyzed by transwell assay. Apoptosis was analyzed by flow cytometry. The protein expression of SPOCD1, PTEN, PI3K, p-AKT, and mTOR in OC cells was measured by Western blot. Results SPOCD1 expression was significantly upregulated in OC tissues compared with non-cancerous tissues (P<0.01), and was positively correlated to FIGO stage and tumor grade of OC. Also, SPOCD1 was significantly expressed in nucleus and cytoplasm of SKOV3 and CAOV3 cells. Kaplan–Meier analysis indicated that patients with high SPOCD1 expression had shorter overall survival (HR =1.512, 95%CI: 1.321–2.793, P=0.031) and progression-free survival (HR =1.875, 95%CI: 1.435–3.157, P=0.028). SPOCD1 was upregulated in OC SKOV3 and CAOV3 cells. Further investigation revealed that downregulation of SPOCD1 inhibited the SKOV3 and CAOV3 cells proliferation and migration. In addition, the deficit of SPOCD1 increased the apoptosis in SKOV3 and CAOV3 cells. PI3K/AKT pathway was inhibited by knockdown of SPOCD1 in SKOV3 and CAOV3 cells. Conclusions Our data suggest that SPOCD1 may act as a carcinogenesis factor by activating the PI3K/AKT pathway to restrained cell apoptosis in OC.
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Affiliation(s)
- Dajiang Liu
- Department of Obstetrics and Gynecology, The First Hospital of Lan Zhou University, Lanzhou, China
| | - Yuan Yang
- The Reproductive Medicine Special Hospital, The First Hospital of Lanzhou University, Lanzhou, China
| | - Aiqin Yan
- Department of Obstetrics and Gynecology, Zhang ye People's Hospital Affiliated to Hexi University, Zhangye, China
| | - Yongxiu Yang
- Department of Obstetrics and Gynecology, The First Hospital of Lan Zhou University, Lanzhou, China
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Chen Y, Jiang S, Lu Z, Xue D, Xia L, Lu J, Wang H, Xu L, Li L, Li G. Development and verification of a nomogram for prediction of recurrence-free survival in clear cell renal cell carcinoma. J Cell Mol Med 2019; 24:1245-1255. [PMID: 31782902 PMCID: PMC6991630 DOI: 10.1111/jcmm.14748] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 06/20/2019] [Accepted: 07/02/2019] [Indexed: 12/25/2022] Open
Abstract
Nowadays, gene expression profiling has been widely used in screening out prognostic biomarkers in numerous kinds of carcinoma. Our studies attempt to construct a clinical nomogram which combines risk gene signature and clinical features for individual recurrent risk assessment and offer personalized managements for clear cell renal cell carcinoma. A total of 580 differentially expressed genes (DEGs) were identified via microarray. Functional analysis revealed that DEGs are of fundamental importance in ccRCC progression and metastasis. In our study, 338 ccRCC patients were retrospectively analysed and a risk gene signature which composed of 5 genes was obtained from a LASSO Cox regression model. Further analysis revealed that identified risk gene signature could usefully distinguish the patients with poor prognosis in training cohort (hazard ratio [HR] = 3.554, 95% confidence interval [CI] 2.261‐7.472, P < .0001, n = 107). Moreover, the prognostic value of this gene‐signature was independent of clinical features (P = .002). The efficacy of risk gene signature was verified in both internal and external cohorts. The area under receiver operating characteristic curve of this signature was 0.770, 0.765 and 0.774 in the training, testing and external validation cohorts, respectively. Finally, a nomogram was developed for clinicians and did well in the calibration plots. This nomogram based on risk gene signature and clinical features might provide a practical way for recurrence prediction and facilitating personalized managements of ccRCC patients after surgery.
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Affiliation(s)
- Yuanlei Chen
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shangjun Jiang
- Department of Urology, The First People's Hospital of Fuyang, Hangzhou, China
| | - Zeyi Lu
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dingwei Xue
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liqun Xia
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jieyang Lu
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Huan Wang
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liwei Xu
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liyang Li
- Department of Mathematics and Statistics Science, University College of London, London, UK
| | - Gonghui Li
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Zhuang C, Wang P, Sun T, Zheng L, Ming L. Expression levels and prognostic values of annexins in liver cancer. Oncol Lett 2019; 18:6657-6669. [PMID: 31807177 PMCID: PMC6876331 DOI: 10.3892/ol.2019.11025] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 09/10/2019] [Indexed: 02/07/2023] Open
Abstract
Annexins are a superfamily of calcium-dependent phospholipid-binding proteins that are implicated in a wide range of biological processes. The annexin superfamily comprises 13 members in humans (ANXAs), the majority of which are frequently dysregulated in cancer. However, the expression patterns and prognostic values of ANXAs in liver cancer are currently largely unknown. The present study aimed to analyze the expression levels of ANXAs and survival data in patients with liver cancer from the Oncomine, GEPIA, Kaplan-Meier plotter and cBioPortal for Cancer Genomics databases. The results demonstrated that ANXA1, A2, A3, A4 and A5 were upregulated, whereas ANXA10 was downregulated in liver cancer compared with normal liver tissues. The expression of ANXA10 was associated with pathological stage. High expression levels of ANXA2 and A5 were significantly associated with poor overall survival (OS) rate whereas ANXA7 and A10 were associated with increased OS. The prognostic values of ANXAs in liver cancer were determined based on sex and clinical stage, which revealed that ANXA2, A5, A7 and A10 were associated with OS in male, but not in female patients. In addition, the potential biological functions of ANXAs were identified by Gene Ontology functional annotation and Kyoto Encyclopedia of Genes Genomes pathway analysis; the results demonstrated that ANXAs may serve a role in liver cancer through the neuroactive ligand-receptor interaction pathway. In conclusion, the results of the present study suggested that ANXA1, A2, A3, A4, A5 and A10 may be potential therapeutic targets for liver cancer treatment, and that ANXA2, A5, A7 and A10 may be potential prognostic biomarkers of liver cancer.
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Affiliation(s)
- Chunbo Zhuang
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Pei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Ting Sun
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Lei Zheng
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Liang Ming
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Cao R, Yuan L, Ma B, Wang G, Qiu W, Tian Y. An EMT-related gene signature for the prognosis of human bladder cancer. J Cell Mol Med 2019; 24:605-617. [PMID: 31657881 PMCID: PMC6933372 DOI: 10.1111/jcmm.14767] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 09/06/2019] [Accepted: 09/23/2019] [Indexed: 12/24/2022] Open
Abstract
The transition from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is detrimental to bladder cancer (BLCA) patients. Here, we aimed to study the underlying mechanism of the subtype transition. Gene set variation analysis (GSVA) revealed the epithelial-mesenchymal transition (EMT) signalling pathway with the most positive correlation in this transition. Then, we built a LASSO Cox regression model of an EMT-related gene signature in BLCA. The patients with high risk scores had significantly worse overall survival (OS) and disease-free survival (DFS) than those with low risk scores. The EMT-related gene signature also performed favourably in the accuracy of prognosis and in the subtype survival analysis. Univariate and multivariate Cox regression analyses demonstrated that the EMT-related gene signature, pathological N stage and age were independent prognostic factors for predicting survival in BLCA patients. Furthermore, the predictive nomogram model was able to effectively predict the outcome of BLCA patients by appropriately stratifying the risk score. In conclusion, we developed a novel EMT-related gene signature that has tumour-promoting effects, acts as a negative independent prognostic factor and might facilitate personalized counselling and treatment in BLCA.
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Affiliation(s)
- Rui Cao
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lushun Yuan
- Division of Nephrology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Bo Ma
- Department of Stomatology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Gang Wang
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wei Qiu
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ye Tian
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Chen S, Zhang N, Shao J, Wang T, Wang X. A novel gene signature combination improves the prediction of overall survival in urinary bladder cancer. J Cancer 2019; 10:5744-5753. [PMID: 31737111 PMCID: PMC6843883 DOI: 10.7150/jca.30307] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 04/23/2019] [Indexed: 12/21/2022] Open
Abstract
Objectives: Bladder carcinoma is a clinical heterogeneous disease, which is with significant variability of the prognosis and high risk of death. This revealed prominently the need to identify high-efficiency cancer characteristics to predict clinical prognosis. Methods: Gene expression profiles of 93 bladder tumor patients from Gene Expression Omnibus data sets was performed in this study, along with 408 bladder tumor patients retrieved from The Cancer Genome Atlas database. The relationship of gene signature and overall survival was analyzed in the training cohort (n = 46). The validation for that was performed in an internal validation cohort (n = 47) and an external validation cohort (n = 408). Results: Four genes (TMPRSS11E, SCEL, KRT78, TMEM185A) were identified by univariable and multivariable Cox regression analysis. According to a risk score on the bases on the four-gene signature, we grouped these patients in high-risk group and low-risk group with significantly different overall survival in the training series and successfully validated it in both the internal and external validation cohorts. Subsequent studies demonstrated that the four-gene expression risk score was independent of radical cystectomy stage, chemotherapy and lymph node status. Higher rates of FAT4 mutation and MACF1 mutation in bladder tumors with high risk score were found compared with tumors with low risk score. Gene set enrichment analysis revealed high-risk score was associated with some tumor progression and recurrence associated pathways. Conclusions: This four-gene risk score might have potential clinical implications in the selection of high-risk urinary bladder cancer patients for aggressive therapy. The selected four genes might become potential therapeutic targets and diagnostic markers for urinary bladder cancer.
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Affiliation(s)
- Siteng Chen
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ning Zhang
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jialiang Shao
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tao Wang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiang Wang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Stenzl A, McConkey D, Bellmunt J. Does it matter whether a T1 high-grade tumor is molecularly classified? Eur Urol Oncol 2019; 4:837-842. [PMID: 31383572 DOI: 10.1016/j.euo.2019.07.009] [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: 03/18/2019] [Revised: 07/08/2019] [Accepted: 07/16/2019] [Indexed: 10/26/2022]
Abstract
A 58-yr-old male, 20 pack-year smoker, with hypertension was diagnosed with a single left-side high-grade papillary tumor with peritumoral carcinoma in situ, but no tumor was visible outside the bladder. En bloc resection was performed, and repeat transurethral resection of the bladder at 4 wk found no residual tumor. He was prescribed bacillus Calmette-Guérin (BCG) plus maintenance therapy, and cystoscopy at 9 mo found a T1b high-grade tumor, this time right sided. Is it important that the tumor should be molecularly characterized before a treatment decision is made, or is clinicopathologic characterization still the only viable option at this time? PATIENT SUMMARY: We discussed how new methods in pathology may help us find molecular structures that would help clinicians decide safely between cystectomy and conservative bladder-sparing strategies. The primary superficially infiltrative tumor and its similar recurrence 9 mo later were categorized based on standard clinical criteria, but here we discuss whether recently discovered methods for defining the molecular structure of tumors could mean that more bladder-preserving treatments might be an option.
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Affiliation(s)
- Arnulf Stenzl
- Department of Urology, University of Tübingen Medical School, Tübingen, Germany.
| | - David McConkey
- Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins Medical School, Baltimore, MD, USA
| | - Joaquim Bellmunt
- Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA
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Gao X, Zhang S, Chen Y, Wen X, Chen M, Wang S, Zhang Y. Development of a novel six-long noncoding RNA signature predicting survival of patients with bladder urothelial carcinoma. J Cell Biochem 2019; 120:19796-19809. [PMID: 31338862 DOI: 10.1002/jcb.29285] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Accepted: 06/18/2019] [Indexed: 12/18/2022]
Abstract
Bladder urothelial carcinoma is a malignant tumor with a high incidence in the uropoietic system. Considerable studies have shown that long noncoding RNA (lncRNA) plays an important role in the development and progression of bladder urothelial carcinoma. In this study, the lncRNA expression and clinical data of 377 bladder urothelial carcinoma patients were obtained from The Cancer Genome Atlas database and differentially expressed lncRNAs in cancer and normal groups were evaluated. Univariate COX and multivariate COX regression analyses of prognosis were performed on differentially expressed lncRNAs in the training data sets, six prognosis-related lncRNAs (LINC02195, LINC01484, LINC01468, SMC2-AS1, AC011298.1, and PTPRD-AS1) were assessed, and a six-lncRNA signature was constructed. The predictive capability of this six-lncRNA signature was validated in the testing data sets and entire data sets. The prognostic ability of the six-lncRNA signature was independent of other clinical elements after multivariate COX regression and stratified analyses of with other clinical elements. We performed functional enrichment analysis with the six prognosis-related lncRNAs. Results of functional enrichment revealed that these prognosis-related lncRNAs might promote the development and metastasis of bladder urothelial carcinoma. In summary, the six-lncRNA signature that we developed could effectively predict the prognosis of bladder urothelial carcinoma patients. This six-lncRNA signature might be a novel independent prognostic marker of bladder urothelial carcinoma. Moreover, it also provides novel insights into the mechanism of bladder urothelial carcinoma.
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Affiliation(s)
- Xin Gao
- Clinical Laboratory, The First People's Hospital of Huaihua of University of South China, Huaihua, Hunan, China.,Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan, China
| | - Shufang Zhang
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan, China
| | - Yinyi Chen
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan, China
| | - Xiaohong Wen
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan, China
| | - Mei Chen
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan, China
| | - Shunlan Wang
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan, China
| | - Yingai Zhang
- Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan, China
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Singh R, Bassett E, Chakravarti A, Parthun MR. Replication-dependent histone isoforms: a new source of complexity in chromatin structure and function. Nucleic Acids Res 2019; 46:8665-8678. [PMID: 30165676 PMCID: PMC6158624 DOI: 10.1093/nar/gky768] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 08/24/2018] [Indexed: 12/11/2022] Open
Abstract
Replication-dependent histones are expressed in a cell cycle regulated manner and supply the histones necessary to support DNA replication. In mammals, the replication-dependent histones are encoded by a family of genes that are located in several clusters. In humans, these include 16 genes for histone H2A, 22 genes for histone H2B, 14 genes for histone H3, 14 genes for histone H4 and 6 genes for histone H1. While the proteins encoded by these genes are highly similar, they are not identical. For many years, these genes were thought to encode functionally equivalent histone proteins. However, several lines of evidence have emerged that suggest that the replication-dependent histone genes can have specific functions and may constitute a novel layer of chromatin regulation. This Survey and Summary reviews the literature on replication-dependent histone isoforms and discusses potential mechanisms by which the small variations in primary sequence between the isoforms can alter chromatin function. In addition, we summarize the wealth of data implicating altered regulation of histone isoform expression in cancer.
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Affiliation(s)
- Rajbir Singh
- Department of Radiation Oncology, The Ohio State University, Columbus, OH 43210, USA
| | - Emily Bassett
- Department of Radiation Oncology, The Ohio State University, Columbus, OH 43210, USA
| | - Arnab Chakravarti
- Department of Radiation Oncology, The Ohio State University, Columbus, OH 43210, USA
| | - Mark R Parthun
- Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, USA
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Su H, Jiang H, Tao T, Kang X, Zhang X, Kang D, Li S, Li C, Wang H, Yang Z, Zhang J, Li C. Hope and challenge: Precision medicine in bladder cancer. Cancer Med 2019; 8:1806-1816. [PMID: 30907072 PMCID: PMC6488142 DOI: 10.1002/cam4.1979] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/20/2018] [Accepted: 01/01/2019] [Indexed: 12/21/2022] Open
Abstract
Bladder cancer (BC) is a complex disease and could be classified into nonmuscle‐invasive BC (NMIBC) or muscle‐invasive BC (MIBC) subtypes according to the distinct genetic background and clinical prognosis. Until now, the golden standard and confirmed diagnosis of BC is cystoscopy and the major problems of BC are the high rate of recurrence and high costs in the clinic. Recent molecular and genetic studies have provided perspectives on the novel biomarkers and potential therapeutic targets of BC. In this article, we provided an overview of the traditional diagnostic approaches of BC, and introduced some new imaging, endoscopic, and immunological diagnostic technology in the accurate diagnosis of BC. Meanwhile, the minimally invasive precision treatment technique, immunotherapy, chemotherapy, gene therapy, and targeted therapy of BC were also included. Here, we will overview the diagnosis and therapy methods of BC used in clinical practice, focusing on their specificity, efficiency, and safety. On the basis of the discussion of the benefits of precision medicine in BC, we will also discuss the challenges and limitations facing the non‐invasive methods of diagnosis and precision therapy of BC. The molecularly targeted and immunotherapeutic approaches, and gene therapy methods to BC treatment improved the prognosis and overall survival of BC patients.
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Affiliation(s)
- Hongwei Su
- Department of Urology, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Haitao Jiang
- Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, China
| | - Tao Tao
- Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,Department of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen, China
| | - Xing Kang
- Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xu Zhang
- Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Danyue Kang
- Michigan State University, East Lansing, Michigan
| | - Shucheng Li
- Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Chengxi Li
- Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Haifeng Wang
- Department of Urology, The Second Affliated Hospital of Kunming Medical University, Kunming, China
| | - Zhao Yang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Jinku Zhang
- Department of pathology, First Central Hospital of Baoding, Baoding, Hebei, China
| | - Chong Li
- Department of Urology, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.,Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,Department of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen, China.,Beijing Jianlan Institute of Medicine, Beijing, China
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Mao Z, Ji A, Yang K, He W, Hu Y, Zhang Q, Zhang D, Xie L. Diagnostic performance of PCA3 and hK2 in combination with serum PSA for prostate cancer. Medicine (Baltimore) 2018; 97:e12806. [PMID: 30334974 PMCID: PMC6211911 DOI: 10.1097/md.0000000000012806] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVES The prostate cancer gene 3 (PCA3), human kallikrein 2, and miRNA-141 are promising prostate cancer (Pca) specific biomarkers. Our aim was to evaluate the detection of PCA3, human glandular kallikrein 2 (hk2), and miRNA-141 mRNA in peripheral blood of patients received prostate biopsy. What's more, we want to detect the value of combination of PSA (prostate specific antigen) in the early diagnosis of PCa. MATERIALS AND METHODS Hundred patients were divided into 2 groups according to the results of pathologic diagnosis. Quantitative real-time PCR (qRT-PCR) was used to evaluate the mRNA of PCA3, hk2, and miRNA-141 in peripheral blood. At the same time, analyze those clinical outcomes used in the patients. We compared these different outcomes to evaluate the value of new molecular markers. RESULTS The level of mRNA of PCA3, hK2, and miR-141 in Pca group were significantly higher than that in BPH. PSA had the highest sensitivity in predicting Pca diagnosis (76.7%); PCA3 had the highest specificity (82.5%). And the combination of PCA3, PSA, and hK2 improved area under the curve (AUC)-receiver operating characteristic (ROC) curve largely, especially those with PSA 4-10ng/mL. CONCLUSIONS PCA3, hK2, and miRNA-141 were biomarkers of Pca with potential clinical application value, especially in patients with PSA gray area. Combining PCA3, PSA, and hK2 performed better than individual biomarkers alone in predicting Pca.
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Affiliation(s)
- Zujie Mao
- Department of Urology, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road
| | - Alin Ji
- Department of Urology, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road
| | - Kebing Yang
- Department of Urology, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road
| | - Wei He
- Department of Urology, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road
| | - Yingfang Hu
- Department of Urology, Changxing People's Hospital, 66 Middle Taihu Road, Huzhou Zhejiang Province, People's Republic of China
| | - Qi Zhang
- Department of Urology, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road
| | - Dahong Zhang
- Department of Urology, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, 158 Shangtang Road
| | - Liping Xie
- Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road
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Dangi AD, Kumar RM, Kodiatte TA, Gowri M, Kumar S, Devasia A, Kekre N. Is there a role for second transurethral resection in pTa high-grade urothelial bladder cancer? Cent European J Urol 2018; 71:287-294. [PMID: 30386649 PMCID: PMC6202620 DOI: 10.5173/ceju.2018.1683] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 04/04/2018] [Accepted: 05/13/2018] [Indexed: 01/26/2023] Open
Abstract
Introduction Evidence for second transurethral resection of bladder tumour (TURBT) for pTa high-grade lesions is limited. This study aims to examine the role of a second TURBT in the pTa high-grade group and to generate recurrence and progression data for this group. Material and methods We retrospectively studied the clinical profiles and outcomes of all patients diagnosed with high-grade pTa lesions at first TURBT, between the years 2006–2015. Firstly, in patients who underwent a complete first TURBT, we calculated the proportion of patients with positive findings on second TURBT. Secondly, we assessed whether those who underwent a second TURBT had a longer recurrence-free survival compared to those who underwent a single TURBT. Results One hundred and twelve patients had a pTa high-grade urothelial bladder tumor (WHO 2004 classification) at first TURBT, out of whom 43 (38.3%) had a second TURBT. Indications for second TURBT were high-grade lesions (n = 36), absence of detrusor muscle (n = 2), and incomplete resection (n = 5). Out of the 36 patients who had a complete first TURBT and underwent a second look TURBT, 7 patients had positive findings (3 carcinoma in situ, 2 pTa low-grade lesions and 2 pTa high-grade lesions) and there was no upstaging. Of the 5 patients with an incomplete first TURBT, one upstaged to pT1 on second TURBT. Of the 81 patients who followed up with us, 25.9% had a recurrence and 8.6% progressed. The estimated median recurrence free survival was 60 months (95% CI 29.2–90.7) for the whole group and 76 months vs. 45 months for the second and single TURBT group respectively – a difference that was clinically, though not statistically, significant. Multiple (≥2) tumours had a lower recurrence free survival (HR of 4.60, CI 1.67-12.63, p = 0.003). Conclusions Of the patients with pTa high-grade tumours who had a second TURBT after a complete first TURBT, 19.4% had a positive finding. Multiple tumours are four times as likely to recur as solitary tumours. The role of a second TURBT in this group needs to be studied in larger patient cohorts before a recommendation regarding its lack of clinical utility can be made conclusively.
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Affiliation(s)
- Anuj Deep Dangi
- Department of Urology, Christian Medical College and Hospital, Vellore, India
| | - Ramani Manoj Kumar
- Department of Pathology, Christian Medical College and Hospital, Vellore, India
| | | | - Mahasampth Gowri
- Department of Bio-Statistics, Christian Medical College and Hospital, Vellore, India
| | - Santosh Kumar
- Department of Urology, Christian Medical College and Hospital, Vellore, India
| | - Antony Devasia
- Department of Urology, Christian Medical College and Hospital, Vellore, India
| | - Nitin Kekre
- Department of Urology, Christian Medical College and Hospital, Vellore, India
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Sakaguchi T, Yoshino H, Sugita S, Miyamoto K, Yonemori M, Osako Y, Meguro-Horike M, Horike SI, Nakagawa M, Enokida H. Bromodomain protein BRD4 inhibitor JQ1 regulates potential prognostic molecules in advanced renal cell carcinoma. Oncotarget 2018; 9:23003-23017. [PMID: 29796168 PMCID: PMC5955408 DOI: 10.18632/oncotarget.25190] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 04/05/2018] [Indexed: 12/14/2022] Open
Abstract
Sunitinib is a standard molecular-targeted drug used as a first-line treatment for metastatic clear cell renal cell carcinoma (ccRCC); however, resistance to sunitinib has become a major problem in medical practice. Recently, bromodomain containing 4 (BRD4), a member of the bromodomain family proteins, was identified as a promising therapeutic target, and its inhibitor JQ1 has been shown to have inhibitory effects in various human cancers. However, the anti-cancer effects of JQ1 in ccRCC, particularly sunitinib-resistant ccRCC, are still unclear. Here, we aimed to elucidate the anti-cancer effects of JQ1 and the mechanisms underlying BRD4 inhibition in sunitinib-sensitive and -resistant ccRCCs. Analysis of The Cancer Genome Atlas (TCGA) ccRCC cohort showed that patients with high BRD4 expression had shorter overall survival than those with low expression. JQ1 treatment significantly inhibited tumor growth of sunitinib-sensitive and -resistant ccRCC cells in part through MYC regulation. Based on RNA sequencing analyses of ccRCC cells treated with JQ1 to elucidate the mechanisms other than MYC regulation, we identified several oncogenes that may be potential therapeutic targets or prognostic markers; patients with high expression of SCG5, SPOCD1, RGS19, and ARHGAP22 had poorer overall survival than those with low expression in TCGA ccRCC cohort. Chromatin immunoprecipitation assays revealed that these oncogenes may be promising BRD4 targets, particularly in sunitinib-resistant ccRCC cells. These results identified SCG5, SPOCD1, RGS19, and ARHGAP22 as potential prognostic markers and showed that BRD4 inhibition may have applications as a potential therapeutic approach in sunitinib-sensitive and -resistant ccRCC.
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Affiliation(s)
- Takashi Sakaguchi
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Hirofumi Yoshino
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Satoshi Sugita
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Kazutaka Miyamoto
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Masaya Yonemori
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yoichi Osako
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Makiko Meguro-Horike
- Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan
| | - Shin-Ichi Horike
- Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan
| | - Masayuki Nakagawa
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Hideki Enokida
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Miyake M, Hori S, Morizawa Y, Tatsumi Y, Toritsuka M, Ohnishi S, Shimada K, Furuya H, Khadka VS, Deng Y, Ohnishi K, Iida K, Gotoh D, Nakai Y, Inoue T, Anai S, Torimoto K, Aoki K, Tanaka N, Konishi N, Fujimoto K. Collagen type IV alpha 1 (COL4A1) and collagen type XIII alpha 1 (COL13A1) produced in cancer cells promote tumor budding at the invasion front in human urothelial carcinoma of the bladder. Oncotarget 2018; 8:36099-36114. [PMID: 28415608 PMCID: PMC5482641 DOI: 10.18632/oncotarget.16432] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 03/15/2017] [Indexed: 12/12/2022] Open
Abstract
Current knowledge of the molecular mechanism driving tumor budding is limited. Here, we focused on elucidating the detailed mechanism underlying tumor budding in urothelial cancer of the bladder. Invasive urothelial cancer was pathologically classified into three groups as follows: nodular, trabecular, and infiltrative (tumor budding). Pathohistological analysis of the orthotopic tumor model revealed that human urothelial cancer cell lines MGH-U3, UM-UC-14, and UM-UC-3 displayed typical nodular, trabecular, and infiltrative patterns, respectively. Based on the results of comprehensive gene expression analysis using microarray (25 K Human Oligo chip), we identified two collagens, COL4A1 and COL13A1, which may contribute to the formation of the infiltrative pattern. Visualization of protein interaction networks revealed that proteins associated with connective tissue disorders, epithelial-mesenchymal transition, growth hormone, and estrogen were pivotal factors in tumor cells. To evaluate the invasion pattern of tumor cells in vitro, 3-D collective cell invasion assay using Matrigel was performed. Invadopodial formation was evaluated using Gelatin Invadopodia Assay. Knockdown of collagens with siRNA led to dramatic changes in invasion patterns and a decrease in invasion capability through decreased invadopodia. The in vivo orthotopic experimental model of bladder tumors showed that intravesical treatment with siRNA targeting COL4A1 and COL13A1 inhibited the formation of the infiltrative pattern. COL4A1 and COL13A1 production by cancer cells plays a pivotal role in tumor invasion through the induction of tumor budding. Blocking of these collagens may be an attractive therapeutic approach for treatment of human urothelial cancer of the bladder.
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Affiliation(s)
- Makito Miyake
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Shunta Hori
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Yosuke Morizawa
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Yoshihiro Tatsumi
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan.,Department of Pathology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Michihiro Toritsuka
- Department of Psychiatry, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Sayuri Ohnishi
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Keiji Shimada
- Department of Pathology, Nara City Hospital, Nara-shi, Nara, 630-8305, Japan
| | - Hideki Furuya
- Clinical and Translational Research Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Vedbar S Khadka
- Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA
| | - Youping Deng
- Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA
| | - Kenta Ohnishi
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Kota Iida
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Daisuke Gotoh
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Yasushi Nakai
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Takeshi Inoue
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Satoshi Anai
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Kazumasa Torimoto
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Katsuya Aoki
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Nobumichi Tanaka
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Noboru Konishi
- Department of Pathology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
| | - Kiyohide Fujimoto
- Department of Urology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan
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Molecular Progression Risk Score for Prediction of Muscle Invasion in Primary T1 High-Grade Bladder Cancer. Clin Genitourin Cancer 2018; 16:274-280. [PMID: 29571585 DOI: 10.1016/j.clgc.2018.02.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 02/05/2018] [Accepted: 02/16/2018] [Indexed: 11/24/2022]
Abstract
BACKGROUND Pathologic T1 high-grade (pT1HG) bladder cancer (BC) is characterized by a high progression rate and constitutes an important clinical challenge; however, there is no consensus on the prediction of progression in pT1HG BC. The purpose of this study was to validate previously published molecular progression risk score (MoPRS) for predicting muscle-invasive disease in pT1HG BC. MATERIALS AND METHODS The expression of an 8-gene progression-related classifier identified from microarray data was analyzed by real-time PCR, and the MoPRS was calculated in 121 newly recruited patients with pT1HG BC. Progression was defined as muscle invasion or metastasis. RESULTS Overall, the disease of 28 patients (23.1%) progressed to muscle-invasive BC during the median follow-up of 63.7 (interquartile range, 17.6-96.4) months. The MoPRS was significantly higher in 1973 World Health Organization grade 3 than grade 2 tumors (P = .004). Early development of invasive BC was more prevalent in the highest quartile MoPRS group than in the lowest to 75th percentile MoPRS groups according to Kaplan-Meier analysis. Multivariate Cox regression analysis revealed that the MoPRS was an independent predictor of invasive BC, either as a continuous variable (hazard ratio, 1.624; 95% confidence interval, 1.266-2.082; P < .001) or as a categorical variable (hazard ratio, 3.089; 95% confidence interval, 1.335-7.150; P = .008). CONCLUSION The MoPRS was an independent prognostic factor for identifying patients at high risk of invasive BC in patients with pT1HG BC. This scale may help identify patients who could benefit from more aggressive therapeutic intervention such as early cystectomy.
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