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Newell ME, Babbrah A, Aravindan A, Rathnam R, Halden RU. DNA Methylation in Urine and Feces Indicative of Eight Major Human Cancer Types Globally. Life (Basel) 2025; 15:482. [PMID: 40141826 PMCID: PMC11943902 DOI: 10.3390/life15030482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
Toxic chemicals and epigenetic biomarkers associated with cancer have been used successfully in clinical diagnostic screening of feces and urine from individuals, but they have been underutilized in a global setting. We analyzed peer-reviewed literature to achieve the following: (i) compile epigenetic biomarkers of disease, (ii) explore whether research locations are geographically aligned with disease hotspots, and (iii) determine the potential for tracking disease-associated epigenetic biomarkers. Studies (n = 1145) of epigenetic biomarkers (n = 146) in urine and feces from individuals have established notable diagnostic potential for detecting and tracking primarily gastric and urinary cancers. Panels with the highest sensitivity and specificity reported more than once were SEPT9 (78% and 93%, respectively) and the binary biomarker combinations GDF15, TMEFF2, and VIM (93% and 95%), NDRG4 and BMP3 (98% and 90%), and TWIST1 and NID2 (76% and 79%). Screening for epigenetic biomarkers has focused on biospecimens from the U.S., Europe, and East Asia, whereas data are limited in regions with similar/higher disease incidence rates (i.e., data for New Zealand, Japan, and Australia for colorectal cancer). The epigenetic markers discussed here may aid in the future monitoring of multiple cancers from individual- to population-level scales by leveraging the emerging science of wastewater-based epidemiology (WBE).
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Affiliation(s)
- Melanie Engstrom Newell
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ 85281, USA
| | - Ayesha Babbrah
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Anumitha Aravindan
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Raj Rathnam
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Rolf U. Halden
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
- School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ 85281, USA
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Huang Z, Zhang T, Pan J, Zhang G, Jiang L, Jiang H, Wan P, Peng Y, Zou W, Liu Q, Chen N. Transcriptomic Profiles for Elucidating Response of Bladder Intracavitary Hyperthermic Perfusion Chemotherapy in High-Risk Nonmuscular Invasive Bladder Cancer. Cancer Med 2025; 14:e70672. [PMID: 39980308 PMCID: PMC11842869 DOI: 10.1002/cam4.70672] [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: 08/26/2023] [Revised: 01/25/2025] [Accepted: 01/29/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Bladder intracavitary hyperthermic perfusion chemotherapy (HIPEC) is a promising treatment for non-muscular invasive bladder cancer (NMIBC). However, the molecular mechanisms underlying the response to HIPEC remain poorly understood. This study aimed to elucidate the transcriptomic profiles associated with the response to HIPEC in NMIBC patients. METHODS RNA sequencing was performed on bladder tumor samples from NMIBC patients who underwent HIPEC treatment. Differentially expressed genes (DEGs) between responders and non-responders to HIPEC were identified. Gene ontology and pathway analysis were conducted to explore the biological functions and pathways enriched in the DEGs. Additionally, the expression of specific immune-related genes was evaluated for their association with HIPEC response. The diagnostic efficiency of selected genes in predicting relapse before and after HIPEC treatment was assessed in a validation cohort. RESULTS We assessed the expression status of differentially expressed genes (DEGs) between responders and non-responders to HIPEC. Gene ontology and pathway analysis revealed that DEGs were enriched in immune-related pathways, including cytokine-cytokine receptor interaction, chemokine signaling pathway, and antigen processing and presentation. Furthermore, the expression of several immune-related genes, including ZMAP4, UPP2, and GALR1, was significantly associated with the response to HIPEC. Therefore, the immune system's reaction plays a crucial role in the response to HIPEC in patients with NMIBC. At last, a considerable diagnostic efficiency that tissue TMEFF2, KRT222, and GTSF1 in predicting relapse in NMIBC patients after HIPEC treatment, and ZMAP4, UPP2, and GALR1 in predicting relapse in NMIBC patients before HIPEC treatment in the validation cohort. CONCLUSION Transcriptomic profiling revealed that immune-related pathways and genes play a crucial role in the response to HIPEC in NMIBC patients. These findings suggest that transcriptomic profiling could provide a valuable tool for predicting treatment outcomes and identifying therapeutic targets for NMIBC.
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Affiliation(s)
- Zhicheng Huang
- Shantou University Medical College Meizhou Clinical CollegeMeizhouGuangdong ProvinceChina
- Department of UrologyMeizhou People's HospitalMeizhouGuangdong ProvinceChina
| | - Tianhui Zhang
- Shantou University Medical College Meizhou Clinical CollegeMeizhouGuangdong ProvinceChina
- Department of Magnetic Resonance ImagingMeizhou People's HospitalMeizhouGuangdong ProvinceChina
| | - Jinghua Pan
- Department of General SurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhouChina
| | - Guihao Zhang
- Shantou University Medical College Meizhou Clinical CollegeMeizhouGuangdong ProvinceChina
- Department of UrologyMeizhou People's HospitalMeizhouGuangdong ProvinceChina
| | - Linjun Jiang
- Shantou University Medical College Meizhou Clinical CollegeMeizhouGuangdong ProvinceChina
- Department of UrologyMeizhou People's HospitalMeizhouGuangdong ProvinceChina
| | - Huiming Jiang
- Shantou University Medical College Meizhou Clinical CollegeMeizhouGuangdong ProvinceChina
- Department of UrologyMeizhou People's HospitalMeizhouGuangdong ProvinceChina
| | - Pei Wan
- Shantou University Medical College Meizhou Clinical CollegeMeizhouGuangdong ProvinceChina
- Department of UrologyMeizhou People's HospitalMeizhouGuangdong ProvinceChina
| | - Ying Peng
- Shantou University Medical College Meizhou Clinical CollegeMeizhouGuangdong ProvinceChina
- Department of UrologyMeizhou People's HospitalMeizhouGuangdong ProvinceChina
| | - Wenchao Zou
- Shantou University Medical College Meizhou Clinical CollegeMeizhouGuangdong ProvinceChina
- Department of UrologyMeizhou People's HospitalMeizhouGuangdong ProvinceChina
| | - Qinghua Liu
- Shantou University Medical College Meizhou Clinical CollegeMeizhouGuangdong ProvinceChina
- Department of PathologyMeizhou People's HospitalMeizhouGuangdong ProvinceChina
| | - Nanhui Chen
- Shantou University Medical College Meizhou Clinical CollegeMeizhouGuangdong ProvinceChina
- Department of UrologyMeizhou People's HospitalMeizhouGuangdong ProvinceChina
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Zou L, Zhang Z, Chen J, Guo R, Tong X, Ju Y, Lu H, Yang H, Wang J, Zong Y, Xu X, Jin X, Xiao L, Jia H, Zhang T, Liu X. Unraveling the impact of host genetics and factors on the urinary microbiome in a young population. mBio 2024; 15:e0277324. [PMID: 39513726 PMCID: PMC11633168 DOI: 10.1128/mbio.02773-24] [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: 09/10/2024] [Accepted: 10/16/2024] [Indexed: 11/15/2024] Open
Abstract
The significance of the urinary microbiome in maintaining health and contributing to disease development is increasingly recognized. However, a comprehensive understanding of this microbiome and its influencing factors remains elusive. Utilizing whole metagenomic and whole-genome sequencing, along with detailed metadata, we characterized the urinary microbiome and its influencing factors in a cohort of 1,579 Chinese individuals. Our findings unveil the distinctiveness of the urinary microbiome from other four body sites, delineating five unique urotypes dominated by Gardnerella vaginalis, Sphingobium fluviale, Lactobacillus iners, Variovorax sp. PDC80, and Acinetobacter junii, respectively. We identified 108 host factors significantly influencing the urinary microbiome, collectively explaining 12.92% of the variance in microbial composition. Notably, gender-related factors, including sex hormones, emerged as key determinants in defining urotype groups, microbial composition and pathways, with the urinary microbiome exhibiting strong predictive ability for gender (area under the curve [AUC] = 0.843). Furthermore, we discovered 43 genome-wide significant associations between host genetic loci and specific urinary bacteria, Acinetobacter in particular, linked to eight host loci (P < 5 × 10-8). These associations were also modulated by gender and sex hormone levels. In summary, our study provides novel insights into the impact of host genetics and other factors on the urinary microbiome, shedding light on its implications for host health and disease. IMPORTANCE The urinary microbiome, essential to human health, reveals its unique qualities in our study of 1,579 Chinese individuals. We identified distinctive microbial profiles, or "urotypes," and uncovered strong gender-related influences, particularly from sex hormones, on these microbial communities. Our research highlights significant genetic associations affecting specific urinary bacteria, indicating a deep interaction between our genetics and our microbiome. These insights not only enhance our understanding of the urinary microbiome's role in health and disease but also open new pathways for personalized medical strategies, making our findings crucial for future diagnostic and therapeutic innovations. This work underscores the intricate relationship between our body's biological processes and the microorganisms within, providing valuable knowledge for both scientific and medical communities.
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Affiliation(s)
| | | | | | | | | | - Yanmei Ju
- BGI Research, Shenzhen, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Haorong Lu
- China National Genebank, BGI-Shenzhen, Shenzhen, China
| | - Huanming Yang
- BGI Research, Shenzhen, China
- James D. Watson Institute of Genome Sciences, Hangzhou, China
| | - Jian Wang
- BGI Research, Shenzhen, China
- James D. Watson Institute of Genome Sciences, Hangzhou, China
| | | | - Xun Xu
- BGI Research, Shenzhen, China
| | - Xin Jin
- BGI Research, Shenzhen, China
| | - Liang Xiao
- BGI Research, Shenzhen, China
- Shenzhen Engineering Laboratory of Detection and Intervention of Human Intestinal Microbiome, BGI-Shenzhen, Shenzhen, China
| | - Huijue Jia
- Institute of Precision Medicine–Greater Bay Area (Guangzhou), Fudan University, Guangzhou, China
| | - Tao Zhang
- BGI Research, Wuhan, China
- Shenzhen Key Laboratory of Human Commensal Microorganisms and Health Research, BGI Research, Shenzhen, China
| | - Xiaomin Liu
- BGI Research, Wuhan, China
- Shenzhen Key Laboratory of Human Commensal Microorganisms and Health Research, BGI Research, Shenzhen, China
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Salminen A. GDF15/MIC-1: a stress-induced immunosuppressive factor which promotes the aging process. Biogerontology 2024; 26:19. [PMID: 39643709 PMCID: PMC11624233 DOI: 10.1007/s10522-024-10164-0] [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: 09/06/2024] [Accepted: 11/28/2024] [Indexed: 12/09/2024]
Abstract
The GDF15 protein, a member of the TGF-β superfamily, is a stress-induced multifunctional protein with many of its functions associated with the regulation of the immune system. GDF15 signaling provides a defence against the excessive inflammation induced by diverse stresses and tissue injuries. Given that the aging process is associated with a low-grade inflammatory state, called inflammaging, it is not surprising that the expression of GDF15 gradually increases with aging. In fact, the GDF15 protein is a core factor secreted by senescent cells, a state called senescence-associated secretory phenotype (SASP). Many age-related stresses, e.g., mitochondrial and endoplasmic reticulum stresses as well as inflammatory, metabolic, and oxidative stresses, induce the expression of GDF15. Although GDF15 signaling is an effective anti-inflammatory modulator, there is robust evidence that it is a pro-aging factor promoting the aging process. GDF15 signaling is not only an anti-inflammatory modulator but it is also a potent immunosuppressive enhancer in chronic inflammatory states. The GDF15 protein can stimulate immune responses either non-specifically via receptors of the TGF-β superfamily or specifically through the GFRAL/HPA/glucocorticoid pathway. GDF15 signaling stimulates the immunosuppressive network activating the functions of MDSCs, Tregs, and M2 macrophages and triggering inhibitory immune checkpoint signaling in senescent cells. Immunosuppressive responses not only suppress chronic inflammatory processes but they evoke many detrimental effects in aged tissues, such as cellular senescence, fibrosis, and tissue atrophy/sarcopenia. It seems that the survival functions of GDF15 go awry in persistent inflammation thus promoting the aging process and age-related diseases.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
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Silva-Ferreira M, Carvalho JA, Salta S, Henriques TS, Pereira Rodrigues P, Monteiro-Reis S, Henrique R, Jerónimo C. Diagnostic Test Accuracy of Urinary DNA Methylation-based Biomarkers for the Detection of Primary and Recurrent Bladder Cancer: A Systematic Review and Meta-analysis. Eur Urol Focus 2024; 10:922-934. [PMID: 38897871 DOI: 10.1016/j.euf.2024.05.024] [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: 03/21/2024] [Revised: 05/13/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND AND OBJECTIVE Diagnosis of primary and relapsed bladder carcinomas is accomplished by urethrocystoscopy, an invasive procedure, combined with urinary cytology, with limited sensitivity, resulting in a substantial burden. Thus, noninvasive biomarkers have been investigated, among which DNA methylation has shown promise. This systematic review and meta-analysis sought to assess the diagnostic accuracy of DNA methylation biomarkers reported in the literature for bladder cancer detection, pinpointing the most informative one. METHODS The search for this systematic review and meta-analysis was conducted on PubMed, Scopus, and Cochrane Library for relevant studies published until December 31, 2022. A meta-analysis was performed using a random-effect model, to compute the pooled sensitivity and specificity of the markers. PROSPERO's registration ID for the study is CRD42023397703. KEY FINDINGS AND LIMITATIONS Out of the 2297 studies retrieved, 68 were included in the final analysis, despite considerable heterogeneity. These involved 12 696 participants, of whom 5557 were diagnosed with bladder cancer. Using diagnostic odds ratio (DOR) as a comparative measure, the five most promising markers (pooled sensitivity, specificity, and DOR) were SALL3 (61%, 97%, and 55.67, respectively), PENK (77%, 93%, and 47.90, respectively), ZNF154 (87%, 90%, and 45.07, respectively), VIM (82%, 90%, and 44.81, respectively), and POU4F2 (81%, 89%, and 34.89, respectively). Urinary cytology identified bladder cancer with 55% sensitivity, 92% specificity, and 14.37 DOR. CONCLUSIONS AND CLINICAL IMPLICATIONS DNA methylation biomarkers disclose high accuracy for bladder cancer detection in urine. Nonetheless, validation studies in different clinical settings are scarce, hampering clinical use. The identified biomarkers should be prioritized in future validation studies. PATIENT SUMMARY In this meta-analysis, we include previously published studies that used urine samples of bladder cancer patients' from all around the globe. We were able to compare the diagnostic accuracy of noninvasive markers across different populations. We were able to conclude on the most promising DNA methylation markers to detect bladder cancer using urine.
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Affiliation(s)
- Mariana Silva-Ferreira
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Master Program in Oncology, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
| | - João A Carvalho
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Doctoral Program in Medical Science, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal; Department of Urology & Urology Clinics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Sofia Salta
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Doctoral Program in Pathology and Molecular Genetics, ICBAS - School of Medicine and Biomedical Sciences - University of Porto, Porto, Portugal
| | - Teresa S Henriques
- CINTESIS@RISE - Health Research Network & MEDCIDS, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Pedro Pereira Rodrigues
- CINTESIS@RISE - Health Research Network & MEDCIDS, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Sara Monteiro-Reis
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Institute of Science and Innovation in Mechanical and Industrial Engineering (INEGI), Porto, Portugal
| | - Rui Henrique
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; Department of Pathology and Molecular Immunology, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.
| | - Carmen Jerónimo
- Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center - Raquel Seruca (Porto.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal; Department of Pathology and Molecular Immunology, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.
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Huang FF, Di XF, Bai MH. Analysis of urine cell-free DNA in bladder cancer diagnosis by emerging bioactive technologies and materials. Front Bioeng Biotechnol 2024; 12:1458362. [PMID: 39295845 PMCID: PMC11408225 DOI: 10.3389/fbioe.2024.1458362] [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: 07/02/2024] [Accepted: 08/23/2024] [Indexed: 09/21/2024] Open
Abstract
Urinary cell-free DNA (UcfDNA) is gaining recognition as an important biomarker for diagnosing bladder cancer. UcfDNA contains tumor derived DNA sequences, making it a viable candidate for non-invasive early detection, diagnosis, and surveillance of bladder cancer. The quantification and qualification of UcfDNA have demonstrated high sensitivity and specificity in the molecular characterization of bladder cancer. However, precise analysis of UcfDNA for clinical bladder cancer diagnosis remains challenging. This review summarizes the history of UcfDNA discovery, its biological properties, and the quantitative and qualitative evaluations of UcfDNA for its clinical significance and utility in bladder cancer patients, emphasizing the critical role of UcfDNA in bladder cancer diagnosis. Emerging bioactive technologies and materials currently offer promising tools for multiple UcfDNA analysis, aiming to achieve more precise and efficient capture of UcfDNA, thereby significantly enhancing diagnostic accuracy. This review also highlights breakthroughs in detection technologies and substrates with the potential to revolutionize bladder cancer diagnosis in clinic.
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Affiliation(s)
- Fei-Fei Huang
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Xiao-Fei Di
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Mo-Han Bai
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
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Suda K, Arii R, Ma H, Suzuki T, Shibuya S, Koga H, Lane GJ, Yamataka A. Mitochondrial viability in neurogenic bladder urothelium after sigmoidocolocystoplasty. Implications for persistent vesicoureteral reflux. Pediatr Surg Int 2024; 40:222. [PMID: 39136794 DOI: 10.1007/s00383-024-05803-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/02/2024] [Indexed: 12/14/2024]
Abstract
PURPOSE We investigated whether inflammatory cell infiltration (ICI), fibrosis, and mitochondrial viability of the neurogenic bladder urothelium are involved in the mechanism of persistent vesicoureteral reflux (VUR) after sigmoidocolocystoplasty (SCP). METHODS Bladder biopsies obtained 1994-2023 from 62 neurogenic bladder patients were examined by hematoxylin and eosin for ICI, Masson's trichrome for fibrosis, and immunofluorescence for urothelial growth differentiation factor 15 (GDF15; a mitochondrial stress-responsive cytokine) (positive/negative) and heat shock protein 60 (HSP60; a mitochondrial matrix marker) (strong ≥ 50%/weak≤ 50%) expression. GDF15 + /weak HSP60 indicated compromised mitochondrial viability. Cystometry measured neobladder compliance/capacity. RESULTS Mean ages (years) at SCP and bladder biopsies were 9.4 ± 4.6 and 14.2 ± 7.1, respectively. VUR was present in 38/62 patients (51 ureters) at SCP and resolved with SCP alone in 4/38 patients, with SCP and ureteroneocystostomy in 17/38, and persisted in 17/38. Fibrosis was significantly denser in GDF15 + (n = 24)/weak HSP60 (n = 31) compared with GDF15- (n = 38)/strong HSP60 (n = 31) (p < 0.001 and p < 0.01, respectively). Differences in ICI were significant for GDF15 + vs. GDF15- (p < 0.05) but not for HSP60. Patients with VUR after SCP had higher incidence of GDF15 + /weak HSP60 compared with cases without VUR (p < 0.05 and p < 0.001, respectively). CONCLUSION Viability of mitochondria appears to be compromised with possible etiologic implications for VUR persisting after SCP.
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Affiliation(s)
- Kazuto Suda
- Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
| | - Rumi Arii
- Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Hongzhao Ma
- Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Takamasa Suzuki
- Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Soichi Shibuya
- Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Hiroyuki Koga
- Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Geoffrey J Lane
- Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Atsuyuki Yamataka
- Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
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Rakshit I, Mandal S, Pal S, Bhattacharjee P. Advancements in bladder cancer detection: a comprehensive review on liquid biopsy and cell-free DNA analysis. THE NUCLEUS 2024. [DOI: 10.1007/s13237-024-00494-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 05/04/2024] [Indexed: 01/06/2025] Open
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Ocaña-Paredes B, Rivera-Orellana S, Ramírez-Sánchez D, Montalvo-Guerrero J, Freire MP, Espinoza-Ferrao S, Altamirano-Colina A, Echeverría-Espinoza P, Ramos-Medina MJ, Echeverría-Garcés G, Granda-Moncayo D, Jácome-Alvarado A, Andrade MG, López-Cortés A. The pharmacoepigenetic paradigm in cancer treatment. Front Pharmacol 2024; 15:1381168. [PMID: 38720770 PMCID: PMC11076712 DOI: 10.3389/fphar.2024.1381168] [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: 02/02/2024] [Accepted: 04/11/2024] [Indexed: 05/12/2024] Open
Abstract
Epigenetic modifications, characterized by changes in gene expression without altering the DNA sequence, play a crucial role in the development and progression of cancer by significantly influencing gene activity and cellular function. This insight has led to the development of a novel class of therapeutic agents, known as epigenetic drugs. These drugs, including histone deacetylase inhibitors, histone acetyltransferase inhibitors, histone methyltransferase inhibitors, and DNA methyltransferase inhibitors, aim to modulate gene expression to curb cancer growth by uniquely altering the epigenetic landscape of cancer cells. Ongoing research and clinical trials are rigorously evaluating the efficacy of these drugs, particularly their ability to improve therapeutic outcomes when used in combination with other treatments. Such combination therapies may more effectively target cancer and potentially overcome the challenge of drug resistance, a significant hurdle in cancer therapy. Additionally, the importance of nutrition, inflammation control, and circadian rhythm regulation in modulating drug responses has been increasingly recognized, highlighting their role as critical modifiers of the epigenetic landscape and thereby influencing the effectiveness of pharmacological interventions and patient outcomes. Epigenetic drugs represent a paradigm shift in cancer treatment, offering targeted therapies that promise a more precise approach to treating a wide spectrum of tumors, potentially with fewer side effects compared to traditional chemotherapy. This progress marks a step towards more personalized and precise interventions, leveraging the unique epigenetic profiles of individual tumors to optimize treatment strategies.
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Affiliation(s)
- Belén Ocaña-Paredes
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | | | - David Ramírez-Sánchez
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | | | - María Paula Freire
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | | | | | | | - María José Ramos-Medina
- German Cancer Research Center (DKFZ), Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Gabriela Echeverría-Garcés
- Centro de Referencia Nacional de Genómica, Secuenciación y Bioinformática, Instituto Nacional de Investigación en Salud Pública “Leopoldo Izquieta Pérez”, Quito, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
| | | | - Andrea Jácome-Alvarado
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - María Gabriela Andrade
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - Andrés López-Cortés
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
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Xi Y, Zhang XL, Luo QX, Gan HN, Liu YS, Shao SH, Mao XH. Helicobacter pylori regulates stomach diseases by activating cell pathways and DNA methylation of host cells. Front Cell Dev Biol 2023; 11:1187638. [PMID: 37215092 PMCID: PMC10192871 DOI: 10.3389/fcell.2023.1187638] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 04/25/2023] [Indexed: 05/24/2023] Open
Abstract
One of the most prevalent malignant tumors of the digestive tract is gastric cancer (GC). Age, high salt intake, Helicobacter pylori (H. pylori) infection, and a diet deficient in fruits and vegetables are risk factors for the illness. A significant risk factor for gastric cancer is infection with H. pylori. Infecting gastric epithelial cells with virulence agents secreted by H. pylori can cause methylation of tumor genes or carcinogenic signaling pathways to be activated. Regulate downstream genes' aberrant expression, albeit the precise mechanism by which this happens is unclear. Oncogene, oncosuppressor, and other gene modifications, as well as a number of different gene change types, are all directly associated to the carcinogenesis of gastric cancer. In this review, we describe comprehensive H. pylori and its virulence factors, as well as the activation of the NF-κB, MAPK, JAK/STAT signaling pathways, and DNA methylation following infection with host cells via virulence factors, resulting in abnormal gene expression. As a result, host-related proteins are regulated, and gastric cancer progression is influenced. This review provides insight into the H. pylori infection, summarizes a series of relevant papers, discusses the complex signaling pathways underlying molecular mechanisms, and proposes new approach to immunotherapy of this important disease.
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Affiliation(s)
- Yue Xi
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xiao-Li Zhang
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, China
| | - Qing-Xin Luo
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hai-Ning Gan
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yu-Shi Liu
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Shi-He Shao
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xu-Hua Mao
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, China
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11
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Zhang S, Shen T, Zeng Y. Epigenetic Modifications in Prostate Cancer Metastasis and Microenvironment. Cancers (Basel) 2023; 15:cancers15082243. [PMID: 37190171 DOI: 10.3390/cancers15082243] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/30/2023] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
The gradual evolution of prostate tissue from benign tumor to malignant lesion or distant metastasis is driven by intracellular epigenetic changes and the tumor microenvironment remodeling. With the continuous study of epigenetic modifications, these tumor-driving forces are being discovered and are providing new treatments for cancer. Here we introduce the classification of epigenetic modification and highlight the role of epigenetic modification in tumor remodeling and communication of the tumor microenvironment.
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Affiliation(s)
- Shouyi Zhang
- Department of Urology, the Cancer Hospital of Dalian University of Technology & Liaoning Cancer Hospital, Shenyang 110042, China
| | - Tao Shen
- Department of Urology, Second Affiliated Hospital of Shenyang Medical College, No. 20 Beijiu Road, Heping District, Shenyang 110001, China
| | - Yu Zeng
- Department of Urology, the Cancer Hospital of Dalian University of Technology & Liaoning Cancer Hospital, Shenyang 110042, China
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12
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Baghel VS, Shinde S, Sinha V, Dixit V, Tiwari AK, Saxena S, Vishvakarma NK, Shukla D, Bhatt P. Inhibitors targeting epigenetic modifications in cancer. TRANSCRIPTION AND TRANSLATION IN HEALTH AND DISEASE 2023:287-324. [DOI: 10.1016/b978-0-323-99521-4.00007-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Pharo HD, Jeanmougin M, Ager-Wick E, Vedeld HM, Sørbø AK, Dahl C, Larsen LK, Honne H, Brandt-Winge S, Five MB, Monteiro-Reis S, Henrique R, Jeronimo C, Steven K, Wahlqvist R, Guldberg P, Lind GE. BladMetrix: a novel urine DNA methylation test with high accuracy for detection of bladder cancer in hematuria patients. Clin Epigenetics 2022; 14:115. [PMID: 36115961 PMCID: PMC9482155 DOI: 10.1186/s13148-022-01335-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 09/11/2022] [Indexed: 11/10/2022] Open
Abstract
Background Cystoscopy is the gold standard for bladder cancer detection, but is costly, invasive and has imperfect diagnostic accuracy. We aimed to identify novel and accurate DNA methylation biomarkers for non-invasive detection of bladder cancer in urine, with the potential to reduce the number of cystoscopies among hematuria patients. Results Biomarker candidates (n = 32) were identified from methylome sequencing of urological cancer cell lines (n = 16) and subjected to targeted methylation analysis in tissue samples (n = 60). The most promising biomarkers (n = 8) were combined into a panel named BladMetrix. The performance of BladMetrix in urine was assessed in a discovery series (n = 112), consisting of bladder cancer patients, patients with other urological cancers and healthy individuals, resulting in 95.7% sensitivity and 94.7% specificity. BladMetrix was furthermore evaluated in an independent prospective and blinded series of urine from patients with gross hematuria (n = 273), achieving 92.1% sensitivity, 93.3% specificity and a negative predictive value of 98.1%, with the potential to reduce the number of cystoscopies by 56.4%. Conclusions We here present BladMetrix, a novel DNA methylation urine test for non-invasive detection of bladder cancer, with high accuracy across tumor grades and stages, and the ability to spare a significant number of cystoscopies among patients with gross hematuria. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-022-01335-2.
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14
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El azzouzi M, El ahanidi H, Hafidi Alaoui C, Chaoui I, Benbacer L, Tetou M, Hassan I, Bensaid M, Oukabli M, Ameur A, Al bouzidi A, El mzibri M, Attaleb M. Exploring urine sediments as a non-invasive method for DNA methylation detection in bladder cancer. AFRICAN JOURNAL OF UROLOGY 2022. [DOI: 10.1186/s12301-022-00298-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The main epigenetic event occurring during the bladder carcinogenesis process is DNA methylation, affecting genes involved in various metabolic pathways and cell regulation. The use of biological fluids such as urine sediments could be used as a non-invasive approach to enhance bladder cancer management. In this study, we aim to determine the promoter methylation status of a panel of genes in bladder cancer on tumor biopsies and urine sediments to evaluate the usefulness of urine samples as a non-invasive approach for methylation status assessment.
Methods
Using the methylation-specific PCR technique, we explored the promoter methylation status of hTERT, TWIST1, VIM and NID2 genes in 40 tumor biopsies and their paired urine samples from Moroccan bladder cancer patients.
Results
In this study, bladder tumors showed promoter hypermethylation frequency of individual genes as 90%, 85%, 62.5% and 72.5% in TWIST1, hTERT, NID2 and VIM genes, respectively.
Interestingly, the specificity of methylation detection in urine samples was 100% and the sensitivity to detect hypermethylation of TWIST1, hTERT, NID2 and VIM genes reached 91.7%; 97.1%; 84% and 82.8%, respectively.
Conclusions
Our results clearly show that the assessment of promoter hypermethylation in urine samples is highly specific and has high sensitivity. Furthermore, urine sediments would be a useful approach to detect the DNA methylation status of genes and its potential association with bladder cancer development.
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15
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DeLouize AM, Eick G, Karam SD, Snodgrass JJ. Current and future applications of biomarkers in samples collected through minimally invasive methods for cancer medicine and population-based research. Am J Hum Biol 2022; 34:e23665. [PMID: 34374148 PMCID: PMC9894104 DOI: 10.1002/ajhb.23665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 07/27/2021] [Accepted: 07/28/2021] [Indexed: 02/04/2023] Open
Abstract
Despite advances in cancer medicine and research, invasive and potentially risky procedures such as biopsies, venous blood tests, imaging, colonoscopy, and pap smear tests are still primarily used for screening, staging, and assessing response to therapy. The development and interdisciplinary use of biomarkers from urine, feces, saliva, scent, and capillary blood collected with minimally invasive methods represents a potential opportunity for integration with biomarker analysis for cancers, both in clinical practice (e.g., in screening, treatment, and disease monitoring, and improved quality of life for patients) and population-based research (e.g., in epidemiology/public health, studies of social and environmental determinants, and evolutionary medicine). In this article, we review the scientific rationale, benefits, challenges, and potential opportunities for measuring cancer-related biomarkers in samples collected through minimally invasive methods.
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Affiliation(s)
| | - Geeta Eick
- Department of Anthropology, University of Oregon, Eugene, Oregon, USA
| | - Sana D. Karam
- Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - J. Josh Snodgrass
- Department of Anthropology, University of Oregon, Eugene, Oregon, USA
- Center for Global Health, University of Oregon, Eugene, Oregon, USA
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16
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Harsanyi S, Novakova ZV, Bevizova K, Danisovic L, Ziaran S. Biomarkers of Bladder Cancer: Cell-Free DNA, Epigenetic Modifications and Non-Coding RNAs. Int J Mol Sci 2022; 23:13206. [PMID: 36361996 PMCID: PMC9653602 DOI: 10.3390/ijms232113206] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/17/2022] [Accepted: 10/27/2022] [Indexed: 11/29/2022] Open
Abstract
Bladder cancer (BC) is the 10th most frequent cancer in the world. The initial diagnosis and surveillance of BC require a combination of invasive and non-invasive methods, which are costly and suffer from several limitations. Cystoscopy with urine cytology and histological examination presents the standard diagnostic approach. Various biomarkers (e.g., proteins, genes, and RNAs) have been extensively studied in relation to BC. However, the new trend of liquid biopsy slowly proves to be almost equally effective. Cell-free DNA, non-coding RNA, and other subcellular structures are now being tested for the best predictive and diagnostic value. In this review, we focused on published gene mutations, especially in DNA fragments, but also epigenetic modifications, and non-coding RNA (ncRNA) molecules acquired by liquid biopsy. We performed an online search in PubMed/Medline, Scopus, and Web of Science databases using the terms "bladder cancer", in combination with "markers" or "biomarkers" published until August 2022. If applicable, we set the sensitivity and specificity threshold to 80%. In the era of precision medicine, the development of complex laboratory techniques fuels the search and development of more sensitive and specific biomarkers for diagnosis, follow-up, and screening of BC. Future efforts will be focused on the validation of their sensitivity, specificity, predictive value, and their utility in everyday clinical practice.
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Affiliation(s)
- Stefan Harsanyi
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Zuzana Varchulova Novakova
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Katarina Bevizova
- Institute of Anatomy, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 2, 811 08 Bratislava, Slovakia
| | - Lubos Danisovic
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Stanislav Ziaran
- Department of Urology, Faculty of Medicine, Comenius University in Bratislava, Limbova 5, 833 05 Bratislava, Slovakia
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17
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Li N, Wang L, Liang H, Lin C, Yi J, Yang Q, Luo H, Luo T, Zhang L, Li X, Wu K, Li F, Li N. Detecting and monitoring bladder cancer with exfoliated cells in urine. Front Oncol 2022; 12:986692. [PMID: 36158668 PMCID: PMC9491100 DOI: 10.3389/fonc.2022.986692] [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: 07/05/2022] [Accepted: 08/15/2022] [Indexed: 12/24/2022] Open
Abstract
Current methods for the diagnosis and monitoring of bladder cancer are invasive and have suboptimal sensitivity. Liquid biopsy as a non-invasive approach has been capturing attentions recently. To explore the ability of urine-based liquid biopsy in detecting and monitoring genitourinary tumors, we developed a method based on promoter-targeted DNA methylation of urine sediment DNA. We used samples from a primary bladder cancer cohort (n=40) and a healthy cohort (n=40) to train a model and obtained an integrated area under the curve (AUC) > 0.96 in the 10-fold cross-validation, which demonstrated the ability of our method for detecting bladder cancer from the healthy. We next validated the model with samples from a recurrent cohort (n=21) and a non-recurrent cohort (n=19) and obtained an AUC > 0.91, which demonstrated the ability of our model in monitoring the progress of bladder cancer. Moreover, 80% (4/5) of samples from patients with benign urothelial diseases had been considered to be healthy sample rather than cancer sample, preliminarily demonstrating the potential of distinguishing benign urothelial diseases from cancer. Further analysis basing on multiple-time point sampling revealed that the cancer signal in 80% (4/5) patients had decreased as expected when they achieved the recurrent-free state. All the results suggested that our method is a promising approach for noninvasive detection and prognostic monitoring of bladder cancer.
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Affiliation(s)
- Nannan Li
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
| | - Lei Wang
- Department of Urology, Peking University Shougang Hospital, Beijing, China
- Peking University Wu-jieping Urology Center, Peking University Health Science Center, Beijing, China
| | - Han Liang
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
| | - Cong Lin
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
| | - Ji Yi
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
| | - Qin Yang
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
| | - Huijuan Luo
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
| | - Tian Luo
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
| | - Liwei Zhang
- Department of Urology, Peking University Shougang Hospital, Beijing, China
- Peking University Wu-jieping Urology Center, Peking University Health Science Center, Beijing, China
| | - Xiaojian Li
- Department of Urology, Peking University Shougang Hospital, Beijing, China
- Peking University Wu-jieping Urology Center, Peking University Health Science Center, Beijing, China
| | - Kui Wu
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- *Correspondence: Kui Wu, ; Fuqiang Li, ; Ningchen Li,
| | - Fuqiang Li
- Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China
- *Correspondence: Kui Wu, ; Fuqiang Li, ; Ningchen Li,
| | - Ningchen Li
- Department of Urology, Peking University Shougang Hospital, Beijing, China
- Peking University Wu-jieping Urology Center, Peking University Health Science Center, Beijing, China
- *Correspondence: Kui Wu, ; Fuqiang Li, ; Ningchen Li,
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18
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Tulsyan S, Aftab M, Sisodiya S, Khan A, Chikara A, Tanwar P, Hussain S. Molecular basis of epigenetic regulation in cancer diagnosis and treatment. Front Genet 2022; 13:885635. [PMID: 36092905 PMCID: PMC9449878 DOI: 10.3389/fgene.2022.885635] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 07/19/2022] [Indexed: 02/01/2023] Open
Abstract
The global cancer cases and mortality rates are increasing and demand efficient biomarkers for accurate screening, detection, diagnosis, and prognosis. Recent studies have demonstrated that variations in epigenetic mechanisms like aberrant promoter methylation, altered histone modification and mutations in ATP-dependent chromatin remodelling complexes play an important role in the development of carcinogenic events. However, the influence of other epigenetic alterations in various cancers was confirmed with evolving research and the emergence of high throughput technologies. Therefore, alterations in epigenetic marks may have clinical utility as potential biomarkers for early cancer detection and diagnosis. In this review, an outline of the key epigenetic mechanism(s), and their deregulation in cancer etiology have been discussed to decipher the future prospects in cancer therapeutics including precision medicine. Also, this review attempts to highlight the gaps in epigenetic drug development with emphasis on integrative analysis of epigenetic biomarkers to establish minimally non-invasive biomarkers with clinical applications.
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Affiliation(s)
- Sonam Tulsyan
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
| | - Mehreen Aftab
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
| | - Sandeep Sisodiya
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Asiya Khan
- Laboratory Oncology Unit, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Atul Chikara
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Pranay Tanwar
- Laboratory Oncology Unit, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Showket Hussain
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
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19
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Hou CP, Tsui KH, Chen ST, Chang KS, Sung HC, Hsu SY, Lin YH, Feng TH, Juang HH. The Upregulation of Caffeic Acid Phenethyl Ester on Growth Differentiation Factor 15 Inhibits Transforming Growth Factor β/Smad Signaling in Bladder Carcinoma Cells. Biomedicines 2022; 10:biomedicines10071625. [PMID: 35884930 PMCID: PMC9312961 DOI: 10.3390/biomedicines10071625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 11/16/2022] Open
Abstract
Growth differentiation factor 15 (GDF15) is known as a TGFβ-like cytokine acting on the TGFβ receptor to modulate target genes. GDF15 is regarded as a tumor suppressor gene in the human bladder and the caffeic acid phenethyl ester (CAPE) induces GDF15 expression to inhibit the tumor growth in vitro and in vivo. However, the interactions among GDF15, CAPE, and TGFβ/Smads signaling in the human bladder carcinoma cells remain unexplored. Results revealed that TGFβ downregulated the expression of GDF15 via the activation of Smad 2/3 and Smad 1/5. Induction of GDF15 on its downstream genes, NDRG1 and maspin, is dependent on the TGFβ/Smad pathways. Moreover, TGFβ blocked the CAPE-inducing expressions of GDF15, maspin, and NDRG1. Pretreatment of TGF receptor kinase inhibitor not only blocked the activation of TGFβ but also attenuated the activation of GDF15 on the expressions of maspin and NDRG1. The CAPE treatment attenuated the activation of TGFβ on cell proliferation and invasion. Our findings indicate that TGFβ downregulated the expressions of GDF15, maspin, and NDRG1 via TGFβ/Smad signaling. Whereas, CAPE acts as an antagonist on TGFβ/Smad signaling to block the effect of TGFβ on the GDF15 expression and cell proliferation and invasion in bladder carcinoma cells.
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Affiliation(s)
- Chen-Pang Hou
- Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan;
- Department of Urology, Chang Gung Memorial Hospital-Linkou, Kwei-Shan, Taoyuan 33302, Taiwan;
- Department of Healthcare Management, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
| | - Ke-Hung Tsui
- Department of Urology, Shuang Ho Hospital, New Taipei City 235041, Taiwan;
- TMU Research Center of Urology and Kindey, Department of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Syue-Ting Chen
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan; (S.-T.C.); (K.-S.C.); (H.-C.S.); (S.-Y.H.)
- Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan
| | - Kang-Shuo Chang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan; (S.-T.C.); (K.-S.C.); (H.-C.S.); (S.-Y.H.)
| | - Hsin-Ching Sung
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan; (S.-T.C.); (K.-S.C.); (H.-C.S.); (S.-Y.H.)
- Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan
| | - Shu-Yuan Hsu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan; (S.-T.C.); (K.-S.C.); (H.-C.S.); (S.-Y.H.)
- Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan
| | - Yu-Hsiang Lin
- Department of Urology, Chang Gung Memorial Hospital-Linkou, Kwei-Shan, Taoyuan 33302, Taiwan;
| | - Tsui-Hsia Feng
- School of Nursing, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan;
| | - Horng-Heng Juang
- Department of Urology, Chang Gung Memorial Hospital-Linkou, Kwei-Shan, Taoyuan 33302, Taiwan;
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan; (S.-T.C.); (K.-S.C.); (H.-C.S.); (S.-Y.H.)
- Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan
- Correspondence: ; Tel.: +886-3-2118800; Fax: +886-3-2118112
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20
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Identification of an immune gene-associated prognostic signature in patients with bladder cancer. Cancer Gene Ther 2022; 29:494-504. [PMID: 35169299 DOI: 10.1038/s41417-022-00438-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/19/2021] [Accepted: 02/01/2022] [Indexed: 02/02/2023]
Abstract
A deeper understanding of the interaction between tumor cell and the immune microenvironment in bladder cancer may help select predictive and prognostic biomarkers. The current study aims to construct a prognostic signature for bladder cancer by analysis of molecular characteristics, as well as tumor-immune interactions. RNA-sequencing and clinical information from bladder cancer patients were downloaded from the TCGA database. The single sample Gene Sets Enrichment Analysis (ssGSEA) and Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) were employed to separate the samples into two clusters. Lasso Cox regression was performed to construct an immune gene signature for bladder cancer. The correlation between key target genes of immune checkpoint blockade and the prognostic signature was also analyzed. Dataset from Gene Expression Omnibus (GEO) was retrieved for validation. Two immunophenotypes and immunological characteristics were identified, and a 17-immune gene signature was constructed to provide an independent prognostic signature for bladder cancer. The signature was verified through external validation and correlated with genomic characteristics and clinicopathologic features. Finally, a nomogram was generated from the clinical characteristics and immune signature. Our study reveals a tumor-immune microenvironment signature useful for prognosis in bladder cancer. The results provide information on the potential development of treatment strategies for bladder cancer patients. Prospective studies are warranted to validate the prognostic capability of this model, but these data highlight the role of the microenvironment in the clinical outcome of patients.
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21
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Białek Ł, Bilski K, Dobruch J, Krajewski W, Szydełko T, Kryst P, Poletajew S. Non-Invasive Biomarkers in the Diagnosis of Upper Urinary Tract Urothelial Carcinoma-A Systematic Review. Cancers (Basel) 2022; 14:cancers14061520. [PMID: 35326672 PMCID: PMC8945959 DOI: 10.3390/cancers14061520] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/11/2022] [Accepted: 03/14/2022] [Indexed: 01/06/2023] Open
Abstract
Beyond laboratory, imaging and endoscopic procedures, new diagnostic tools are increasingly being sought for the diagnosis of upper urinary tract urothelial carcinoma (UTUC), especially those that are non-invasive. In this systematic review, we aimed to determine the effectiveness of non-invasive tests in the diagnosis of UTUC. PubMed and Embase electronic databases were searched to identify studies assessing effectiveness of non-invasive tests in the primary diagnosis of UTUC. The study protocol was registered with PROSPERO (CRD42020216480). Among 10,084 screened publications, 25 were eligible and included in the analysis. Most of them were conducted on small samples of patients and the control groups were heterogenous. The test used in the largest number of studies was voided urinary cytology, which has poor sensitivity (11-71.1%) with favorable specificity (54-100%). Fluorescence in situ hybridization in diagnostic cytology showed higher sensitivity (35-85.7%) with equally good specificity (80-100%). There were also studies on the use of tests known to diagnose bladder cancer such as NMP22, uCYT or BTA test. Other urine or blood tests have been the subject of only isolated studies, with varying results. To conclude, currently there is a lack of high-quality data that could confirm good effectiveness of non-invasive tests used in the diagnosis of UTUC.
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Affiliation(s)
- Łukasz Białek
- Department of Urology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland; (K.B.); (J.D.)
- Correspondence:
| | - Konrad Bilski
- Department of Urology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland; (K.B.); (J.D.)
| | - Jakub Dobruch
- Department of Urology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland; (K.B.); (J.D.)
| | - Wojciech Krajewski
- Department of Minimally Invasive and Robotic Urology, Wroclaw Medical University, 50-556 Wrocław, Poland; (W.K.); (T.S.)
| | - Tomasz Szydełko
- Department of Minimally Invasive and Robotic Urology, Wroclaw Medical University, 50-556 Wrocław, Poland; (W.K.); (T.S.)
| | - Piotr Kryst
- Second Department of Urology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland; (P.K.); (S.P.)
| | - Sławomir Poletajew
- Second Department of Urology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland; (P.K.); (S.P.)
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22
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Fang Q, Zhang X, Nie Q, Hu J, Zhou S, Wang C. Improved urine DNA methylation panel for early bladder cancer detection. BMC Cancer 2022; 22:237. [PMID: 35241014 PMCID: PMC8895640 DOI: 10.1186/s12885-022-09268-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 02/02/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Bladder cancer is one of the most common malignancies but the corresponding diagnostic methods are either invasive or limited in specificity and/or sensitivity. This study aimed to develop a urine-based methylation panel for bladder cancer detection by improving published panels and validate performance of the new panel with clinical samples. METHODS Related researches were reviewed and 19 potential panels were selected. RRBS was performed on a cohort with 45 samples to reassess these panels and a new panel inherited best markers was developed. The new panel was applied with qMSP platform to 33 samples from the RRBS cohort and the results were compared to those of RRBS. Lastly, another larger cohort with 207 samples was used to validate new panel performance with qMSP. RESULTS Three biomarkers (PCDH17, POU4F2 and PENK) were selected to construct a new panel P3. P3 panel achieved 100% specificity and 71% sensitivity with RRBS in corresponding cohort and then showed a better performance of 100% specificity and 84% sensitivity with qMSP platforms in a balanced cohort. When validated with 207-sample cohort, P3 with qMSP showed a performance of 97% specificity and 87% sensitivity which was modestly improved compared to the panels it derided from. CONCLUSIONS Overall, the P3 panel achieved relatively high sensitivity and accuracy in bladder cancer detection.
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Affiliation(s)
- Qixun Fang
- Yaneng Bioscience, Co., Ltd, Shenzhen, 518100, China.,South China University of Technology, Guangzhou, 510641, China
| | - Xu Zhang
- Department of Urology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Qing Nie
- Yaneng Bioscience, Co., Ltd, Shenzhen, 518100, China
| | - Jianqiang Hu
- South China University of Technology, Guangzhou, 510641, China
| | - Shujun Zhou
- Yaneng Bioscience, Co., Ltd, Shenzhen, 518100, China. .,South China University of Technology, Guangzhou, 510641, China.
| | - Chaojun Wang
- Department of Urology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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23
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El Azzouzi M, El Ahanidi H, Hafidi Alaoui C, Chaoui I, Benbacer L, Tetou M, Hassan I, Bensaid M, Oukabli M, Ameur A, Al Bouzidi A, El Mzibri M, Attaleb M. Evaluation of DNA methylation in promoter regions of hTERT, TWIST1, VIM and NID2 genes in Moroccan bladder cancer patients. Cancer Genet 2021; 260-261:41-45. [PMID: 34922269 DOI: 10.1016/j.cancergen.2021.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 11/08/2021] [Accepted: 12/05/2021] [Indexed: 12/11/2022]
Abstract
Promoter hypermethylation have been reported to play a key role in bladder cancer development and progression. The aim of this study is to evaluate the methylation status of hTERT, TWIST1, VIM and NID2 genes in bladder cancer. The methylation status was evaluated using the Methylation-Specific PCR (MSP) approach on 70 tumour biopsies from Moroccan bladder cancer patients. Overall, methylation frequencies of hTERT, TWIST1, VIM and NID2 genes, were 90%, 85.71%, 67.14% and 67.14%, respectively. Hypermethylation of all studied genes was found in all pathological grades and stages of bladder cancer. Nevertheless, statistical analysis showed no significant association between promoter methylation of hTERT, TWIST1, VIM and NID2 genes and tumours stage/grade (p value >0.05). Moreover, we have investigated the association between the methylation pattern of selected genes and the treatment outcome in a sub-group of non-muscle-invasive bladder cancer cases (52/70). Hypermethylation of hTERT, TWIST1, VIM and NID2 was detected in 83.34%; 66.67%; 83.34% and 58.34% of recurrent cases, respectively, and in 80%; 80%; 80% and 60% of progressive cases, respectively. Statistical analysis highlighted a significant association between TWIST1 hypermethylation and tumour recurrence (p = 0.041<0.05). Our results indicate that hypermethylation of hTERT, TWIST1, VIM and NID2 genes is a frequent epigenetic event in bladder cancer and could be a promising therapeutic target to prevent bladder cancer progression and metastasis.
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Affiliation(s)
- Meryem El Azzouzi
- Biology and Medical Research Unit, CNESTEN, Rabat, Morocco; Faculty of Medicine and Pharmacy of Rabat. Mohammed V University in Rabat, Rabat, Morocco
| | - Hajar El Ahanidi
- Biology and Medical Research Unit, CNESTEN, Rabat, Morocco; Faculty of Medicine and Pharmacy of Rabat. Mohammed V University in Rabat, Rabat, Morocco
| | - Chaimae Hafidi Alaoui
- Biology and Medical Research Unit, CNESTEN, Rabat, Morocco; Faculty of Sciences, Mohammed V University in Rabat, Rabat, Morocco
| | - Imane Chaoui
- Biology and Medical Research Unit, CNESTEN, Rabat, Morocco
| | - Laila Benbacer
- Biology and Medical Research Unit, CNESTEN, Rabat, Morocco
| | | | | | | | - Mohamed Oukabli
- Faculty of Medicine and Pharmacy of Rabat. Mohammed V University in Rabat, Rabat, Morocco; Mohammed V Military Hospital, Rabat, Morocco
| | - Ahmed Ameur
- Faculty of Medicine and Pharmacy of Rabat. Mohammed V University in Rabat, Rabat, Morocco; Mohammed V Military Hospital, Rabat, Morocco
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24
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Hou CP, Tsui KH, Chang KS, Sung HC, Hsu SY, Lin YH, Yang PS, Chen CL, Feng TH, Juang HH. Caffeic acid phenethyl ester inhibits the growth of bladder carcinoma cells by upregulating growth differentiation factor 15. Biomed J 2021; 45:763-775. [PMID: 34662721 DOI: 10.1016/j.bj.2021.10.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 09/30/2021] [Accepted: 10/07/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Caffeic acid phenethyl ester (CAPE), a bioactive component of propolis, has beneficial effects on cancer prevention. Growth differentiation factor 15 (GDF15) is an antitumor gene of bladder cancer. Therefore, this study investigated the anti-cancer effect of CAPE on bladder carcinoma cells and related mechanisms. METHODS The expressions of GDF15, N-myc downstream-regulated gene 1 (NDRG1), and maspin, and the activations of ERK, JNK, p38, and AMPKα1/2 in human bladder cells after gene transfection or knockdown were determined by immunoblot, RT-qPCR, and reporter assays. The assays of 5-ethynyl-2'-deoxyuridine (EdU), CyQUANT cell proliferation, and Matrigel invasion, and the xenograft animal study were used to assess the cell proliferation, invasion, and tumorigenesis. RESULTS GDF15 expression in epithelial cells was negatively correlated with neoplasia in vitro. Also, GDF15 exhibits in bladder fibroblasts and smooth muscle cells. CAPE-induced expressions of NDRG1 and maspin decreased cell proliferation and invasion of bladder carcinoma cells in a GDF15-dependent manner in vitro. The xenograft animal study suggesting CAPE attenuated tumor growth in vivo. CAPE increased phosphorylation of ERK, JNK, p38, and AMPKα1/2 to modulate the GDF15 expressions. Pretreatments with ERK, JNK, or p38 inhibitors partially inhibited the CAPE effects on the inductions of GDF15, NDRG1, or maspin. Knockdown of AMPKα1/2 attenuated the CAPE-induced GDF15 expression and cell proliferation in bladder carcinoma cells. CONCLUSIONS Our findings indicate that CAPE is a promising agent for anti-tumor growth in human bladder carcinoma cells via the upregulation of GDF15.
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Affiliation(s)
- Chen-Pang Hou
- Department of Urology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ke-Hung Tsui
- Department of Urology, Shuang Ho Hospital, New Taipei City, Taiwan; Department of Medicine; TMU Research Center of Urology and Kindey, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kang-Shuo Chang
- Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hsin-Ching Sung
- Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shu-Yuan Hsu
- Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Hsiang Lin
- Department of Urology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Pei-Shan Yang
- Department of Urology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chien-Lun Chen
- Department of Urology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Tsui-Hsia Feng
- Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan; School of Nursing, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Horng-Heng Juang
- Department of Urology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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25
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Sugeeta SS, Sharma A, Ng K, Nayak A, Vasdev N. Biomarkers in Bladder Cancer Surveillance. Front Surg 2021; 8:735868. [PMID: 34651010 PMCID: PMC8506024 DOI: 10.3389/fsurg.2021.735868] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 08/25/2021] [Indexed: 01/15/2023] Open
Abstract
Aim: This is a narrative review with an aim to summarise and describe urinary biomarkers in the surveillance of non-muscle-invasive bladder cancer (NMIBC). It provides a summary of FDA-approved protein biomarkers along with emerging ones which utilise genetic, epigenetic and exosomal markers. We discuss the current limitations of the available assays. Background: Current guidelines advice a combination of cystoscopy, imaging,and urine cytology in diagnosis and surveillance. Although cytology has a high specificity, it is limited by low sensitivity particularly in low grade tumours. There are six FDA-approved urinary assays for diagnosis and surveillance of bladder cancer. They have shown to improve sensitivity and specificity to be used alongside cytology and cystoscopy but have a lower specificity in comparison to cytology and false positives often occur in benign conditions. Recent developments in laboratory techniques has allowed for use of markers which are RNA-, DNA-based as well as extracellular vesicles in the past decade. Methods: Using the PubMed/Medline search engines as well as Google Scholar, we performed an online search using the terms "bladder cancer," "non-muscle invasive bladder cancer," and "urine biomarkers" with filter for articles in English published up to May 2021. Systematic reviews and original data of clinical trials or observational studies which contributed to the development of the biomarkers were collated. Results: Biomarkers identified were divided into FDA-approved molecular biomarkers, protein biomarkers and gene-related biomarker with a table summarising the findings of each marker with the most relevant studies. The studies conducted were mainly retrospective. Due to the early stages of development, only a few prospective studies have been done for more recently developed biomarkers and limited meta-analyses are available.Therefore a detailed evaluation of these markers are still required to decide on their clinical use. Conclusion: Advancements of analytical methods in BC has driven the research towards non-invasive liquid-based biomarkers in adjunct to urine cytology. Further large prospective studies are required to determine its feasibility in a clinical setting as they are not effective when used in isolation as they have their limitation. With the ongoing pandemic, other than reduction in costs and increased accuracy, the need for biomarkers to cope with delay in cystoscopies in diagnosis and surveillance is crucial. Thus clinical trials with direct comparison is required to improve patient care.
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Affiliation(s)
- Sukumar S. Sugeeta
- Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, United Kingdom
| | - Anand Sharma
- Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, United Kingdom
| | - Kenrick Ng
- Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, United Kingdom
| | - Arvind Nayak
- Department of Urology and Surgery, Lister Hospital, East and North Herts NHS Trust, Stevenage, United Kingdom
| | - Nikhil Vasdev
- Department of Urology and Surgery, Lister Hospital, East and North Herts NHS Trust, Stevenage, United Kingdom
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
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26
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Humayun-Zakaria N, Ward DG, Arnold R, Bryan RT. Trends in urine biomarker discovery for urothelial bladder cancer: DNA, RNA, or protein? Transl Androl Urol 2021; 10:2787-2808. [PMID: 34295762 PMCID: PMC8261432 DOI: 10.21037/tau-20-1327] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 04/23/2021] [Indexed: 02/01/2023] Open
Abstract
Urothelial bladder cancer is a complex disease displaying a landscape of heterogenous molecular subtypes, mutation profiles and clinical presentations. Diagnosis and surveillance rely on flexible cystoscopy which has high accuracy, albeit accompanied by a high-cost burden for healthcare providers and discomfort for patients. Advances in "omic" technologies and computational biology have provided insights into the molecular pathogenesis of bladder cancer and provided powerful tools to identify markers for disease detection, risk stratification, and predicting responses to therapy. To date, numerous attempts have been made to discover and validate diagnostic biomarkers that could be deployed as an adjunct to the cystoscopic diagnosis and long-term surveillance of bladder cancer. We report a comprehensive literature analysis using PubMed to assess the changing trends in investigating DNA, RNA, or proteins as diagnostic urinary biomarkers over a period of 5 decades: 1970-2020. A gradual shift has been observed in research away from protein biomarkers to nucleic acids including different classes of RNA, and DNA methylation and mutation markers. Until 2000, publications involving protein biomarker discovery constituted 87% of the total number of research articles with DNA comprising 6% and RNA 7%. Since 2000 the proportion of protein biomarker articles has fallen to 40%, and DNA and RNA studies increased to 32% and 28%, respectively. Clearly research focus, perhaps driven by technological innovation, has shifted from proteins to nucleic acids. We optimistically hypothesise that, following thorough validation, a clinically useful detection test for bladder cancer based on a panel of DNA or RNA markers could become reality within 5-10 years.
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Affiliation(s)
- Nada Humayun-Zakaria
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Douglas G Ward
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Roland Arnold
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Richard T Bryan
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
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27
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Du Y, Wang B, Jiang X, Cao J, Yu J, Wang Y, Wang X, Liu H. Identification and Validation of a Stromal EMT Related LncRNA Signature as a Potential Marker to Predict Bladder Cancer Outcome. Front Oncol 2021; 11:620674. [PMID: 33747932 PMCID: PMC7970757 DOI: 10.3389/fonc.2021.620674] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 01/25/2021] [Indexed: 12/19/2022] Open
Abstract
Bladder cancer (BLCA) has become one of the most common malignant tumors in the genitourinary system. BLCA is one of the tumors considered suitable for immunotherapy because of the large proportion of immune cells in TME. Epithelial to mesenchymal transition (EMT) is closely related to tumor immunity through its crosstalk with immune cells. A recent study validated that EMT-related genes were mainly expressed by stromal cells and could influence immunotherapy responsiveness. Stromal EMT-related gene signature was also demonstrated to affect the prognosis of multiple tumors, including BLCA. To further explore the prognostic roles of stromal components, we performed a comprehensive analysis of LncRNAs closely associated with stromal EMT-related genes in the TCGA BLCA cohort. We identified a signature including five stromal EMT gene-related LncRNAs that showed significant prognostic value for BLCA patients. By the CIBERSORT and MCP-COUNTER algorithm, we found the signature was markedly correlated with infiltrated immune cells and stromal components of the tumor microenvironment, which may further influence patient’s responsiveness to immune checkpoint blockade therapy. Through immunohistochemical analysis, we confirmed the correlation of the signature with macrophages M2 and CAFs. Meanwhile, key genes related to these LncRNAs, including VIM, MMP2, were also differentially expressed in the stromal components concerning the signature. Our research confirmed the prognostic and immune-associated role of stromal EMT-related LncRNAs. Meantime, we further confirmed that EMT-related genes were mainly expressed in stromal components. Targeting these LncRNAs as well as their related stromal EMT genes may provide potential therapeutic targets for BLCA immunotherapy and precision medicine.
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Affiliation(s)
- YiHeng Du
- Department of Urology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China
| | - Bo Wang
- Department of Urology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China
| | - Xiang Jiang
- Department of Pathology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China
| | - Jin Cao
- Department of Pathology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China
| | - Jiang Yu
- Department of Urology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China
| | - Yi Wang
- Department of Urology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China
| | - XiZhi Wang
- Department of Urology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China
| | - HaiTao Liu
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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28
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Chen Z, Liu G, Liu G, Bolkov MA, Shinwari K, Tuzankina IA, Chereshnev VA, Wang Z. Defining muscle-invasive bladder cancer immunotypes by introducing tumor mutation burden, CD8+ T cells, and molecular subtypes. Hereditas 2021; 158:1. [PMID: 33388091 PMCID: PMC7778803 DOI: 10.1186/s41065-020-00165-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 12/06/2020] [Indexed: 02/06/2023] Open
Abstract
Immunotherapy, especially anti-PD-1, is becoming a pillar of modern muscle-invasive bladder cancer (MIBC) treatment. However, the objective response rates (ORR) are relatively low due to the lack of precise biomarkers to select patients. Herein, the molecular subtype, tumor mutation burden (TMB), and CD8+ T cells were calculated by the gene expression and mutation profiles of MIBC patients. MIBC immunotypes were constructed using clustering analysis based on tumor mutation burden, CD8+ T cells, and molecular subtypes. Mutated genes, enriched functional KEGG pathways and GO terms, and co-expressed network-specific hub genes have been identified. We demonstrated that ORR of immunotype A patients identified by molecular subtype, CD8+ T cells, and TMB is about 36% predictable. PIK3CA, RB1, FGFR3, KMT2C, MACF1, RYR2, and EP300 are differentially mutated among three immunotypes. Pathways such as ECM-receptor interaction, PI3K-Akt signaling pathway, and TGF-beta signaling pathway are top-ranked in enrichment analysis. Low expression of ACTA2 was associated with the MIBC survival benefit. The current study constructs a model that could identify suitable MIBC patients for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers.
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Affiliation(s)
- Zihao Chen
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Guojun Liu
- Department of Medical Biochemistry and Biophysics, Institute of Natural Sciences and Mathematics, Ural Federal University, Ekaterinburg, 620000, Russia.
- School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, 014010, China.
| | - Guoqing Liu
- School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, 014010, China
| | - Mikhail A Bolkov
- Department of immunochemistry, Institute of Chemical Engineering, Ural Federal University, Ekaterinburg, 620000, Russia
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, 620000, Russia
| | - Khyber Shinwari
- Department of immunochemistry, Institute of Chemical Engineering, Ural Federal University, Ekaterinburg, 620000, Russia
| | - Irina A Tuzankina
- Department of immunochemistry, Institute of Chemical Engineering, Ural Federal University, Ekaterinburg, 620000, Russia
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, 620000, Russia
| | - Valery A Chereshnev
- Department of immunochemistry, Institute of Chemical Engineering, Ural Federal University, Ekaterinburg, 620000, Russia
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, 620000, Russia
| | - Zhifeng Wang
- Department of Urology, Henan Provincial People's Hospital, Zhengzhou, 450003, China
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29
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Harris T, Sheel A, Zong Y, Hutchinson LM, Cornejo KM, Bubendorf L, Yates J, Fischer AH. Cytologically targeted next-generation sequencing: a synergy for diagnosing urothelial carcinoma. J Am Soc Cytopathol 2020; 10:94-102. [PMID: 33184010 DOI: 10.1016/j.jasc.2020.10.001] [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] [Received: 09/15/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Cytology and cystoscopy are used to detect urothelial carcinoma (UC), but together they still fail to detect some UC cases and are not suitable for screening asymptomatic individuals. Mutations are present in more than 98% of UC, mutations have therapeutic significance, and they can be detected by next generation sequencing (NGS) in urine samples. We review the role of NGS in UC detection. MATERIALS AND METHODS Comprehensive literature review on UC genetics, economics of NGS, and previous reports of UC detection by NGS. RESULTS The raw costs of NGS have decreased to about 14,000 base pairs per penny, making it appear economically feasible to use NGS widely. Reported NGS assays fall short of predicted sensitivity. Decreased sensitivity is attributed to a low frequency of mutant alleles in many urine samples. Attempts to increase the percentage of mutant alleles, by using cell-free urinary DNA, or by using cell sorting and microfluidics, have been unsuccessful or remain unproven. However, cytologic examination can immediately enable NGS: Urine cytologies with sufficient proportions of abnormal cells could be directly triaged to NGS with high sensitivity for UC detection. For cases with a low proportion of abnormal cells, cytologically targeted microdissection of cells for NGS should maintain sensitivity and decrease sequencing costs. Cytologically targeted urothelial cells for NGS could allow a screening test for low grade UC. CONCLUSIONS Cytology is immediately poised to allow NGS to improve the diagnosis of UC, allowing NGS to be an ancillary test for atypical cytologies, and potentially allowing a screening test for low-grade UC.
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Affiliation(s)
- Taylor Harris
- University of Massachusetts Medical School, Worcester, Massachusetts
| | - Ankur Sheel
- University of Massachusetts Medical School, Worcester, Massachusetts
| | - Yang Zong
- Department of Pathology, University of Massachusetts Memorial Health Care, Worcester, Massachusetts
| | - Lloyd M Hutchinson
- Department of Pathology, University of Massachusetts Memorial Health Care, Worcester, Massachusetts
| | - Kristine M Cornejo
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Lukas Bubendorf
- Department of Pathology, University of Basel, Basel, Switzerland
| | - Jennifer Yates
- Department of Urology, University of Massachusetts Memorial Health Care, Worcester, Massachusetts
| | - Andrew H Fischer
- Department of Pathology, University of Massachusetts Memorial Health Care, Worcester, Massachusetts.
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30
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DNA Methylation as a Therapeutic Target for Bladder Cancer. Cells 2020; 9:cells9081850. [PMID: 32784599 PMCID: PMC7463638 DOI: 10.3390/cells9081850] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 02/06/2023] Open
Abstract
Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted by the current treatment options. Thus, the development of new therapeutic strategies, either alternative or complementary to the current ones, is of major importance. The disruption of normal epigenetic mechanisms, namely, DNA methylation, is a known early event in cancer development. Consequently, DNA methyltransferase (DNMT) inhibitors constitute a promising therapeutic target for the treatment of BC. Although these inhibitors, mainly nucleoside analogues such as 5-azacytidine (5-aza) and decitabine (DAC), cause re-expression of tumor suppressor genes, inhibition of tumor cell growth, and increased apoptosis in BC experimental models and clinical trials, they also show important drawbacks that prevent their use as a valuable option for the treatment of BC. However, their combination with chemotherapy and/or immune-checkpoint inhibitors could aid in their implementation in the clinical practice. Here, we provide a comprehensive review of the studies exploring the effects of DNA methylation inhibition using DNMTs inhibitors in BC, from in vitro and in vivo studies to clinical trials.
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31
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Cheng S, Jiang Z, Xiao J, Guo H, Wang Z, Wang Y. The prognostic value of six survival-related genes in bladder cancer. Cell Death Discov 2020; 6:58. [PMID: 32695477 PMCID: PMC7359373 DOI: 10.1038/s41420-020-00295-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/23/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023] Open
Abstract
This study was conducted to identify genes that are differentially expressed in paracancerous tissue and to determine the potential predictive value of selected gene panel. Gene transcriptome data of bladder tissue was downloaded from UCSC Xena browser and NCBI GEO repository, including GTEx (the Genotype-Tissue Expression project) data, TCGA (The Cancer Genome Atlas) data, and GEO (Gene Expression Omnibus) data. Differentially Expressed Genes (DEGs) analysis was performed to identify tumor-DEGs candidate genes, using the intersection of tumor-paracancerous DEGs genes and paracancerous-normal DEGs genes. The survival-related genes were screened by Kaplan-Meier (KM) survival analysis and univariable Cox regression with the cutoff criteria of KM < 0.05 and cox p-value < 0.05. The risk model was developed using Lasso regression. The clinical data were analyzed by univariate and multivariate Cox regression analysis. Gene Ontology (GO) and KEGG enrichment analysis were performed in the DEGs genes between the high-risk and low-risk subgroups. We identified six survival-related genes, EMP1, TPM1, NRP2, FGFR1, CAVIN1, and LATS2, found in the DEG analyses of both, tumor-paracancerous and paracancerous-normal differentially expressed data sets. Then, the patients were classified into two clusters, which can be distinguished by specific clinical characteristics. A three-gene risk prediction model (EMP1, FGFR1, and CAVIN1) was constructed in patients within cluster 1. The model was applied to categorize cluster 1 patients into high-risk and low-risk subgroups. The prognostic risk score was considered as an independent prognostic factor. The six identified survival-related genes can be used in molecular characterization of a specific subtype of bladder cancer. This subtype had distinct clinical features of T (topography), N (lymph node), stage, grade, and survival status, compared to the other subtype of bladder cancer. Among the six identified survival-related genes, three-genes, EMP1, FGFR1, and CAVIN1, were identified as potential independent prognostic markers for the specific bladder cancer subtype with clinical features described.
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Affiliation(s)
- Shuting Cheng
- Health Ministry Key Laboratory of Chronobiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, P.R. China
| | - Zhou Jiang
- Health Ministry Key Laboratory of Chronobiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, P.R. China
| | - Jing Xiao
- Health Ministry Key Laboratory of Chronobiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, P.R. China
| | - Huiling Guo
- Health Ministry Key Laboratory of Chronobiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, P.R. China
| | - Zhengrong Wang
- Health Ministry Key Laboratory of Chronobiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, P.R. China
| | - Yuhui Wang
- Health Ministry Key Laboratory of Chronobiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, P.R. China
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Yang Y, Zeng B, Li Y, Liang H, Yang Y, Yuan Q. Construction of MoS2 field effect transistor sensor array for the detection of bladder cancer biomarkers. Sci China Chem 2020. [DOI: 10.1007/s11426-020-9743-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Ahmed AA, Adam Essa ME. Epigenetic alterations in female urogenital organs cancer: Premise, properties, and perspectives. SCIENTIFIC AFRICAN 2020. [DOI: 10.1016/j.sciaf.2020.e00318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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A Multiplex Test Assessing MiR663ame and VIMme in Urine Accurately Discriminates Bladder Cancer from Inflammatory Conditions. J Clin Med 2020; 9:jcm9020605. [PMID: 32102337 PMCID: PMC7073678 DOI: 10.3390/jcm9020605] [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: 01/28/2020] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 01/03/2023] Open
Abstract
Bladder cancer (BlCa) is a common malignancy with significant morbidity and mortality. Current diagnostic methods are invasive and costly, showing the need for newer biomarkers. Although several epigenetic-based biomarkers have been proposed, their ability to discriminate BlCa from common benign conditions of the urinary tract, especially inflammatory diseases, has not been adequately explored. Herein, we sought to determine whether VIMme and miR663ame might accurately discriminate those two conditions, using a multiplex test. Performance of VIMme and miR663ame in tissue samples and urines in testing set confirmed previous results (96.3% sensitivity, 88.2% specificity, area under de curve (AUC) 0.98 and 92.6% sensitivity, 75% specificity, AUC 0.83, respectively). In the validation sets, VIMme-miR663ame multiplex test in urine discriminated BlCa patients from healthy donors or patients with inflammatory conditions, with 87% sensitivity, 86% specificity and 80% sensitivity, 75% specificity, respectively. Furthermore, positive likelihood ratio (LR) of 2.41 and negative LR of 0.21 were also disclosed. Compared to urinary cytology, VIMme-miR663ame multiplex panel correctly detected 87% of the analysed cases, whereas cytology only forecasted 41%. Furthermore, high miR663ame independently predicted worse clinical outcome, especially in patients with invasive BlCa. We concluded that the implementation of this panel might better stratify patients for confirmatory, invasive examinations, ultimately improving the cost-effectiveness of BlCa diagnosis and management. Moreover, miR663ame analysis might provide relevant information for patient monitoring, identifying patients at higher risk for cancer progression.
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Methylation silencing of TGF-β receptor type II is involved in malignant transformation of esophageal squamous cell carcinoma. Clin Epigenetics 2020; 12:25. [PMID: 32046777 PMCID: PMC7014638 DOI: 10.1186/s13148-020-0819-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 01/28/2020] [Indexed: 12/24/2022] Open
Abstract
Background Although massive studies have been conducted to investigate the mechanisms of esophageal squamous cell carcinoma (ESCC) carcinogenesis, the understanding of molecular alterations during the malignant transformation of epithelial dysplasia is still lacking, especially regarding epigenetic changes. Results To better characterize the methylation changes during the malignant transformation of epithelial dysplasia, a whole-genome bisulfite sequencing analysis was performed on a series of tumor, dysplastic, and non-neoplastic epithelial tissue samples from esophageal squamous cell carcinoma (ESCC) patients. Promoter hypermethylation in TGF-β receptor type II (TGFBR2), an important mediator of TGF-β signaling, was identified. Further, we evaluated the methylation and expression of TGFBR2 in tumor samples through The Cancer Genome Atlas multiplatform data as well as immunohistochemistry. Moreover, treatment of ESCC cell lines with5-Aza-2′-deoxycytidine, a DNA methyltransferase inhibitor, reactivated the expression of TGFBR2. The lentiviral mediating the overexpression of TGFBR2 inhibited the proliferation of ESCC cell line by inducing cell cycle G2/M arrest. Furthermore, the overexpression of TGFBR2 inhibited the tumor growth obviously in vivo. Conclusions The characterization of methylation silencing of TGFBR2 in ESCC will enable us to further explore whether this epigenetic change could be considered as a predictor of malignant transformation in esophageal epithelial dysplasia and whether use of a TGFBR2 agonist may lead to a new therapeutic strategy in patients with ESCC.
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Ma Y, He S, Gao A, Zhang Y, Zhu Q, Wang P, Yang B, Yin H, Li Y, Song J, Yue P, Li M, Zhang D, Liu Y, Wang X, Guo M, Jiao Y. Methylation silencing of TGF-β receptor type II is involved in malignant transformation of esophageal squamous cell carcinoma. Clin Epigenetics 2020. [PMID: 32046777 DOI: 10.1186/s13148-020-0819-6.pmid:32046777;pmcid:pmc7014638] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2023] Open
Abstract
BACKGROUND Although massive studies have been conducted to investigate the mechanisms of esophageal squamous cell carcinoma (ESCC) carcinogenesis, the understanding of molecular alterations during the malignant transformation of epithelial dysplasia is still lacking, especially regarding epigenetic changes. RESULTS To better characterize the methylation changes during the malignant transformation of epithelial dysplasia, a whole-genome bisulfite sequencing analysis was performed on a series of tumor, dysplastic, and non-neoplastic epithelial tissue samples from esophageal squamous cell carcinoma (ESCC) patients. Promoter hypermethylation in TGF-β receptor type II (TGFBR2), an important mediator of TGF-β signaling, was identified. Further, we evaluated the methylation and expression of TGFBR2 in tumor samples through The Cancer Genome Atlas multiplatform data as well as immunohistochemistry. Moreover, treatment of ESCC cell lines with5-Aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, reactivated the expression of TGFBR2. The lentiviral mediating the overexpression of TGFBR2 inhibited the proliferation of ESCC cell line by inducing cell cycle G2/M arrest. Furthermore, the overexpression of TGFBR2 inhibited the tumor growth obviously in vivo. CONCLUSIONS The characterization of methylation silencing of TGFBR2 in ESCC will enable us to further explore whether this epigenetic change could be considered as a predictor of malignant transformation in esophageal epithelial dysplasia and whether use of a TGFBR2 agonist may lead to a new therapeutic strategy in patients with ESCC.
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Affiliation(s)
- Yarui Ma
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Siyuan He
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Aiai Gao
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Research Building, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Ying Zhang
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Qing Zhu
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Pei Wang
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Beibei Yang
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Huihui Yin
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Yifei Li
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Jinge Song
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Pinli Yue
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Mo Li
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Dandan Zhang
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yun Liu
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiaobing Wang
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
| | - Mingzhou Guo
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Research Building, No.28 Fuxing Road, Haidian District, Beijing, 100853, China.
| | - Yuchen Jiao
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
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Rose M, Bringezu S, Godfrey L, Fiedler D, Gaisa NT, Koch M, Bach C, Füssel S, Herr A, Hübner D, Ellinger J, Pfister D, Knüchel R, Wirth MP, Böhme M, Dahl E. ITIH5 and ECRG4 DNA Methylation Biomarker Test (EI-BLA) for Urine-Based Non-Invasive Detection of Bladder Cancer. Int J Mol Sci 2020; 21:ijms21031117. [PMID: 32046186 PMCID: PMC7036997 DOI: 10.3390/ijms21031117] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/05/2020] [Accepted: 02/05/2020] [Indexed: 02/07/2023] Open
Abstract
Bladder cancer is one of the more common malignancies in humans and the most expensive tumor for treating in the Unites States (US) and Europe due to the need for lifelong surveillance. Non-invasive tests approved by the FDA have not been widely adopted in routine diagnosis so far. Therefore, we aimed to characterize the two putative tumor suppressor genes ECRG4 and ITIH5 as novel urinary DNA methylation biomarkers that are suitable for non-invasive detection of bladder cancer. While assessing the analytical performance, a spiking experiment was performed by determining the limit of RT112 tumor cell detection (range: 100-10,000 cells) in the urine of healthy donors in dependency of the processing protocols of the RWTH cBMB. Clinically, urine sediments of 474 patients were analyzed by using quantitative methylation-specific PCR (qMSP) and Methylation Sensitive Restriction Enzyme (MSRE) qPCR techniques. Overall, ECRG4-ITIH5 showed a sensitivity of 64% to 70% with a specificity ranging between 80% and 92%, i.e., discriminating healthy, benign lesions, and/or inflammatory diseases from bladder tumors. When comparing single biomarkers, ECRG4 achieved a sensitivity of 73%, which was increased by combination with the known biomarker candidate NID2 up to 76% at a specificity of 97%. Hence, ITIH5 and, in particular, ECRG4 might be promising candidates for further optimizing current bladder cancer biomarker panels and platforms.
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Affiliation(s)
- Michael Rose
- Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany; (S.B.); (L.G.); (D.F.); (N.T.G.); (M.K.); (R.K.)
- RWTH Centralized Biomaterial Bank (RWTH cBMB), Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
- Correspondence: (M.R.); (E.D.); Tel.: +49-241-808-9715 (M.R.); +49-241-808-8431 (E.D.); Fax: +49-241-808-2439 (M.R.); +49-241-808-2439 (E.D.)
| | - Sarah Bringezu
- Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany; (S.B.); (L.G.); (D.F.); (N.T.G.); (M.K.); (R.K.)
| | - Laura Godfrey
- Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany; (S.B.); (L.G.); (D.F.); (N.T.G.); (M.K.); (R.K.)
| | - David Fiedler
- Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany; (S.B.); (L.G.); (D.F.); (N.T.G.); (M.K.); (R.K.)
| | - Nadine T. Gaisa
- Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany; (S.B.); (L.G.); (D.F.); (N.T.G.); (M.K.); (R.K.)
| | - Maximilian Koch
- Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany; (S.B.); (L.G.); (D.F.); (N.T.G.); (M.K.); (R.K.)
| | - Christian Bach
- Department of Urology, RWTH Aachen University, 52074 Aachen, Germany; (C.B.); (D.P.)
| | - Susanne Füssel
- Department of Urology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (S.F.); (D.H.); (M.P.W.)
| | | | - Doreen Hübner
- Department of Urology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (S.F.); (D.H.); (M.P.W.)
| | - Jörg Ellinger
- Department of Urology, University Hospital Bonn, 53105 Bonn, Germany;
| | - David Pfister
- Department of Urology, RWTH Aachen University, 52074 Aachen, Germany; (C.B.); (D.P.)
- Department of Urology, Uro-Oncology, Robot Assisted and Reconstructive Urologic Surgery, University Hospital Cologne, 50937 Cologne, Germany
| | - Ruth Knüchel
- Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany; (S.B.); (L.G.); (D.F.); (N.T.G.); (M.K.); (R.K.)
| | - Manfred P. Wirth
- Department of Urology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (S.F.); (D.H.); (M.P.W.)
| | - Manja Böhme
- Biotype GmbH, 01109 Dresden, Germany; (A.H.); (M.B.)
| | - Edgar Dahl
- Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany; (S.B.); (L.G.); (D.F.); (N.T.G.); (M.K.); (R.K.)
- RWTH Centralized Biomaterial Bank (RWTH cBMB), Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
- Correspondence: (M.R.); (E.D.); Tel.: +49-241-808-9715 (M.R.); +49-241-808-8431 (E.D.); Fax: +49-241-808-2439 (M.R.); +49-241-808-2439 (E.D.)
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Kim J, Kim WT, Kim WJ. Advances in urinary biomarker discovery in urological research. Investig Clin Urol 2020; 61:S8-S22. [PMID: 32055750 PMCID: PMC7004831 DOI: 10.4111/icu.2020.61.s1.s8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 10/22/2019] [Indexed: 12/27/2022] Open
Abstract
A disease-specific biomarker (or biomarkers) is a characteristic reflecting a pathological condition in human body, which can be used as a diagnostic or prognostic tool for the clinical management. A urine-based biomarker(s) may provide a clinical value as attractive tools for clinicians to utilize in the clinical setting in particular to bladder diseases including bladder cancer and other bladder benign dysfunctions. Urine can be easily obtained by patients with no preparation or painful procedures required from patients' side. Currently advanced omics technologies and computational power identified potential omics-based novel biomarkers. An unbiased profiling based on transcriptomics, proteomics, epigenetics, metabolomics approaches et al. found that expression at RNA, protein, and metabolite levels are linked with specific bladder diseases and outcomes. In this review, we will discuss about the urine-based biomarkers reported by many investigators including us and how these biomarkers can be applied as a diagnostic and prognostic tool in clinical trials and patient care to promote bladder health. Furthermore, we will discuss how these promising biomarkers can be developed into a smart medical device and what we should be cautious about toward being used in real clinical setting.
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Affiliation(s)
- Jayoung Kim
- Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Medicine, University of California Los Angeles, CA, USA
| | - Won Tae Kim
- Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea
- Department of Urology, Chungbuk National University Hospital, Cheongju, Korea
| | - Wun-Jae Kim
- Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea
- Department of Urology, Chungbuk National University Hospital, Cheongju, Korea
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Xu X, Yu H. Ras-PI3K pathway promotes osteosarcoma progression via regulating VRK1-mediated H2A phosphorylation at threonine 120. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:4274-4283. [PMID: 31810390 DOI: 10.1080/21691401.2019.1687506] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Background: Ras-PI3K pathway aberrant activation plays an important role in the occurrence and development of osteosarcoma. This study investigated the functions of Ras-PI3K pathway specific activation on histone H2A phosphorylation at threonine 120 (H2AT120ph) in osteosarcoma cells, along with the possible internal molecular mechanisms.Methods: Cell transfection was done to alter RasG12V/Y40C, H2AT120ph and vaccinia-related kinase 1 (VRK1) expression. Then, cell viability, proliferation, migration and cell cycle distribution were assessed, respectively. qRT-PCR was utilized to measure the VRK1 and Ras-PI3K pathway downstream genes (CYR61, IGFBP3, WNT16B, NT5E, GDF15 and CARD16) expression. Chromatin immunoprecipitation (ChIP) was conducted to evaluate the input levels of H2AT120ph and VRK1 in the promoter regions of Ras-PI3K pathway downstream genes.Results: Ras-PI3K specific activation promoted histone H2AT120ph. H2AT120ph participated in the oncogenic functions of Ras-PI3K pathway on osteosarcoma by modulating the transcription of Ras-PI3K-targeted genes. Moreover, VRK1 contributed to the Ras-PI3K specific activation-induced up-regulation of H2AT120ph and osteosarcoma progression. Ras-PI3K pathway-specific activation-induced up-regulation of H2AT120ph was achieved by up-regulation of VRK1.Conclusions: Ras-PI3K pathway activation promoted osteosarcoma progression might be via up-regulating VRK1-mediated H2AT120ph. We proposed that VRK1 and H2AT120ph could be the potential targets for osteosarcoma diagnosis and treatment.HighlightsH2AT120ph is specifically promoted by Ras-PI3K pathway activation.H2AT120ph joins in the oncogenic effects of Ras-PI3K pathway on osteosarcoma.H2AT120ph regulates the transcription of Ras-PI3K-targeted genes.VRK1 takes part in the regulatory function of Ras-PI3K pathway on H2AT120ph.
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Affiliation(s)
- Xianlun Xu
- Department of Traumatology, Jining No.1 People's Hospital, Jining, Shandong, China.,Affiliated Jining No. 1 People's Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Hao Yu
- Department of Traumatology, Jining No.1 People's Hospital, Jining, Shandong, China.,Affiliated Jining No. 1 People's Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
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Martinez VG, Munera-Maravilla E, Bernardini A, Rubio C, Suarez-Cabrera C, Segovia C, Lodewijk I, Dueñas M, Martínez-Fernández M, Paramio JM. Epigenetics of Bladder Cancer: Where Biomarkers and Therapeutic Targets Meet. Front Genet 2019; 10:1125. [PMID: 31850055 PMCID: PMC6902278 DOI: 10.3389/fgene.2019.01125] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 10/17/2019] [Indexed: 12/12/2022] Open
Abstract
Bladder cancer (BC) is the most common neoplasia of the urothelial tract. Due to its high incidence, prevalence, recurrence and mortality, it remains an unsolved clinical and social problem. The treatment of BC is challenging and, although immunotherapies have revealed potential benefit in a percentage of patients, it remains mostly an incurable disease at its advanced state. Epigenetic alterations, including aberrant DNA methylation, altered chromatin remodeling and deregulated expression of non-coding RNAs are common events in BC and can be driver events in BC pathogenesis. Accordingly, these epigenetic alterations are now being used as potential biomarkers for these disorders and are being envisioned as potential therapeutic targets for the future management of BC. In this review, we summarize the recent findings in these emerging and exciting new aspects paving the way for future clinical treatment of this disease.
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Affiliation(s)
- Victor G. Martinez
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
| | - Ester Munera-Maravilla
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Alejandra Bernardini
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Carolina Rubio
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Cristian Suarez-Cabrera
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
| | - Cristina Segovia
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
| | - Iris Lodewijk
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
| | - Marta Dueñas
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Mónica Martínez-Fernández
- Genomes & Disease Lab, CiMUS (Center for Research in Molecular Medicine and Chronic Diseases), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Jesus Maria Paramio
- Biomedical Research Institute I + 12, University Hospital 12 de Octubre, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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Sottnik JL, Mallaredy V, Chauca-Diaz A, Ritterson Lew C, Owens C, Dancik GM, Pagliarani S, Lucchiari S, Moggio M, Ripolone M, Comi GP, Frierson HF, Clouthier D, Theodorescu D. Elucidating the role of Agl in bladder carcinogenesis by generation and characterization of genetically engineered mice. Carcinogenesis 2019; 40:194-201. [PMID: 30403777 DOI: 10.1093/carcin/bgy139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 09/06/2018] [Indexed: 12/17/2022] Open
Abstract
Amylo-α-1,6-glucosidase,4-α-glucanotransferase (AGL) is an enzyme primarily responsible for glycogen debranching. Germline mutations lead to glycogen storage disease type III (GSDIII). We recently found AGL to be a tumor suppressor in xenograft models of human bladder cancer (BC) and low levels of AGL expression in BC are associated with poor patient prognosis. However, the impact of low AGL expression on the susceptibility of normal bladder to carcinogenesis is unknown. We address this gap by developing a germline Agl knockout (Agl-/-) mouse that recapitulates biochemical and histological features of GSDIII. Agl-/- mice exposed to N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) had a higher BC incidence compared with wild-type mice (Agl+/+). To determine if the increased BC incidence observed was due to decreased Agl expression in the urothelium specifically, we developed a urothelium-specific conditional Agl knockout (Aglcko) mouse using a Uroplakin II-Cre allele. BBN-induced carcinogenesis experiments repeated in Aglcko mice revealed that Aglcko mice had a higher BC incidence than control (Aglfl/fl) mice. RNA sequencing revealed that tumors from Agl-/- mice had 19 differentially expressed genes compared with control mice. An 'Agl Loss' gene signature was developed and found to successfully stratify normal and tumor samples in two BC patient datasets. These results support the role of AGL loss in promoting carcinogenesis and provide a rationale for evaluating Agl expression levels, or Agl Loss gene signature scores, in normal urothelium of populations at risk of BC development such as older male smokers.
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Affiliation(s)
- Joseph L Sottnik
- Department of Surgery, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
| | - Vandana Mallaredy
- Department of Surgery, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
| | - Ana Chauca-Diaz
- Department of Surgery, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
| | - Carolyn Ritterson Lew
- Department of Surgery, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
| | - Charles Owens
- Department of Surgery, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA
| | - Garrett M Dancik
- Department of Computer Science, Eastern Connecticut State University, Willimantic, CT, USA
| | - Serena Pagliarani
- Neuromuscular and Rare Diseases Unit, Department of Neuroscience and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Sabrina Lucchiari
- Neuromuscular and Rare Diseases Unit, Department of Neuroscience and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Maurizio Moggio
- Neuromuscular and Rare Diseases Unit, Department of Neuroscience and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Michela Ripolone
- Neuromuscular and Rare Diseases Unit, Department of Neuroscience and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giacomo P Comi
- Department of Pathophysiology and Transplantation, University of Milan, and Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Henry F Frierson
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
| | | | - Dan Theodorescu
- Department of Surgery, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.,Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA
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Xiong X, Yuan J, Zhang N, Zheng Y, Liu J, Yang M. Silencing of lncRNA PVT1 by miR-214 inhibits the oncogenic GDF15 signaling and suppresses hepatocarcinogenesis. Biochem Biophys Res Commun 2019; 521:478-484. [PMID: 31677796 DOI: 10.1016/j.bbrc.2019.10.137] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Accepted: 10/18/2019] [Indexed: 12/12/2022]
Abstract
The prognosis for hepatocellular carcinoma (HCC) is dismal. Long noncoding RNA PVT1 has been linked to malignancies and might be a deleterious therapy target. However, the key events controlling its expression in HCC remain undetermined. Here, we address how PVT1 is fine-regulated and its downstream signaling in hepatoma cells. Interestingly, we found that c-Myc and P53 could divergently regulate PVT1 transcription. Oncoprotein c-Myc enhances PVT1 expression, whereas P53 suppresses its expression. We also identified miR-214 as a crucial, negative regulator of PVT1. Consistently, high miR-214 levels were significantly correlated with diminished PVT1 expression in HCC specimens. Silencing of PVT1 by ectopic miR-214 or siRNAs markedly inhibited viability and invasion of HCC cells. In opposition, inhibition of endogenous miR-214 promoted PVT1 expression and enhanced cell proliferation. Notably, oncogenic GDF15 is a potential downstream target of the miR-214-PVT1 signaling. Collectively, our results show that the c-Myc/P53/miR-214-PVT1-GDF15 axis is implicated in HCC development, shedding light on the mechanistic actions of PVT1 and representing potential targets for HCC clinical intervention.
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Affiliation(s)
- Xiangyu Xiong
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Jupeng Yuan
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Nasha Zhang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Yan Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Jibing Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
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High Detection Rate for Non-Muscle-Invasive Bladder Cancer Using an Approved DNA Methylation Signature Test. Clin Genitourin Cancer 2019; 18:210-221. [PMID: 32139301 DOI: 10.1016/j.clgc.2019.10.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/25/2019] [Accepted: 10/06/2019] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Cystoscopy and transurethral resection are the current reference standard tests to diagnose and histologically confirm non-muscle-invasive bladder cancer (NMIBC). In other tumor entities (ie, colon carcinoma, cervical cancer), DNA methylation markers have been approved as diagnostic tests with high diagnostic power. In our case-control study, we used an approved molecular cervical cancer diagnostics test that includes 6 DNA methylation markers (GynTect) for the detection of bladder cancer. PATIENTS AND METHODS We included samples from 40 patients with bladder cancer and 34 control subjects. In a pilot study, we analyzed DNA methylation in 38 tumor tissues and 4 healthy ureters using methylation-specific polymerase chain reaction. Subsequently, we determined the sensitivity and specificity of the GynTect for the detection of bladder cancer in urine sediments from 40 patients with bladder cancer and 30 control subjects with benign prostatic hyperplasia or urolithiasis. RESULTS The markers showed very different methylation rates in the NMIBC tissues, ranging from 2.6% to 78.9%. No methylation of any of the markers was detectable in the healthy ureters. Using the urine sediments from the patients with cancer and control subjects, we found surprisingly high sensitivity and specificity for the GynTect assay (60% and 96.7%, respectively). The application of different algorithms for evaluation of the markers included in GynTect resulted in a sensitivity of ≤ 90% and specificity of ≤ 100%. CONCLUSION The GynTect assay, originally designed for cervical cancer diagnostics, showed unexpectedly high diagnostic accuracy for bladder cancer detection. The inclusion of additional methylation markers might allow for the development of a suitable diagnostic marker set based on the GynTect test for NMIBC diagnostics.
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Thakur GK, Sharma T, Krishna Latha T, Banerjee BD, Shah HK, Guleria K. High Resolution Based Quantitative Determination of Methylation Status of CDH1 and VIM Gene in Epithelial Ovarian Cancer. Asian Pac J Cancer Prev 2019; 20:2923-2928. [PMID: 31653136 PMCID: PMC6982649 DOI: 10.31557/apjcp.2019.20.10.2923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND DNA promoter methylation is widely explored epigenetic phenomena, known to effect gene expression and further perturbation in cellular homeostasis. Myriad of studies have leveraged promoter methylation and its potential as biomarker for various types of cancer. Aim of present study is to investigate promoter methylation of CDH1 and VIM gene and etiology of epithelial ovarian cancer (EOC). METHODS Most of previous studies were qualitative; we have quantitatively assessed methylation levels in 50 EOC cases and control each through high recognition melt (HRM) technique. RESULTS At 10 % cutoff for CDH1 94% of EOC cases were found to be methylated with mean methylation of 45±13.8, whereas for control mean methylation was found to be 7.3±3.7 amongst 16 % methylation positive control samples. For VIM methylation was detected in 96% of cases with mean of 50.44±11.7 in EOC and in 12% methylation positive samples for control mean methylation was 6.24±4.3. CONCLUSION In short HRM based DNA methylation can serve as a robust and sensitive diagnostic method for promoter methylation detection and as a biomarker for early epithelial ovarian cancer detection.
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Affiliation(s)
- Gaurav Kr Thakur
- Environmental and Molecular Biology Laboratory, Department of Biochemistry, University College of Medical Sciences (Delhi University) and GTB Hospital, Dilshad Garden, Delhi, India
| | - Tusha Sharma
- Environmental and Molecular Biology Laboratory, Department of Biochemistry, University College of Medical Sciences (Delhi University) and GTB Hospital, Dilshad Garden, Delhi, India
| | - T Krishna Latha
- Environmental and Molecular Biology Laboratory, Department of Biochemistry, University College of Medical Sciences (Delhi University) and GTB Hospital, Dilshad Garden, Delhi, India
| | - B D Banerjee
- Environmental and Molecular Biology Laboratory, Department of Biochemistry, University College of Medical Sciences (Delhi University) and GTB Hospital, Dilshad Garden, Delhi, India
| | - Harendra Kr Shah
- Environmental and Molecular Biology Laboratory, Department of Biochemistry, University College of Medical Sciences (Delhi University) and GTB Hospital, Dilshad Garden, Delhi, India
| | - Kiran Guleria
- Department of Obst and Gynae, University College of Medical Sciences (Delhi University) and GTB Hospital, Dilshad Garden, Delhi, India
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Hu J, Zhou L, Song Z, Xiong M, Zhang Y, Yang Y, Chen K, Chen Z. The identification of new biomarkers for bladder cancer: A study based on TCGA and GEO datasets. J Cell Physiol 2019; 234:15607-15618. [PMID: 30779109 DOI: 10.1002/jcp.28208] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/08/2019] [Accepted: 01/10/2019] [Indexed: 01/24/2023]
Abstract
Bladder cancer (BC) is one of the most common neoplastic diseases worldwide. With the highest recurrence rate among all cancers, treatment of BC only improved a little in the last 30 years. Available biomarkers are not sensitive enough for the diagnosis of BC, whereas the standard diagnostic method, cystoscopy, is an invasive test and expensive. Hence, seeking new biomarkers of BC is urgent and challenging. With that order, we screened the overlapped differentially expressed genes (DEGs) of GSE13507 and TCGA BLCA datasets. Subsequent protein-protein interactions network analysis recognized the hub genes among these DEGs. Further functional analysis including Gene Ontology and KEGG pathway analysis and gene set enrichment analysis were processed to investigate the role of these genes and potential underlying mechanisms in BC. Kaplan-Meier analysis and Cox hazard ratio analysis were carried out to clarify the diagnostic and prognostic role of these genes. In conclusion, our present study demonstrated that ACTA2, CDC20, MYH11, TGFB3, TPM1, VIM, and DCN are all potential diagnostic biomarkers for BC. And may also be potential treatment targets for clinical implication in the future.
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Affiliation(s)
- Junyi Hu
- 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
| | - Zhengshuai Song
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ming Xiong
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Youpeng Zhang
- 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, Indiana
| | - Ke Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhaohui Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Cervena K, Vodicka P, Vymetalkova V. Diagnostic and prognostic impact of cell-free DNA in human cancers: Systematic review. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:100-129. [PMID: 31416571 DOI: 10.1016/j.mrrev.2019.05.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 05/03/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023]
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Larsen LK, Lind GE, Guldberg P, Dahl C. DNA-Methylation-Based Detection of Urological Cancer in Urine: Overview of Biomarkers and Considerations on Biomarker Design, Source of DNA, and Detection Technologies. Int J Mol Sci 2019; 20:ijms20112657. [PMID: 31151158 PMCID: PMC6600406 DOI: 10.3390/ijms20112657] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 05/23/2019] [Accepted: 05/24/2019] [Indexed: 12/11/2022] Open
Abstract
Changes in DNA methylation have been causally linked with cancer and provide promising biomarkers for detection in biological fluids such as blood, urine, and saliva. The field has been fueled by genome-wide characterization of DNA methylation across cancer types as well as new technologies for sensitive detection of aberrantly methylated DNA molecules. For urological cancers, urine is in many situations the preferred "liquid biopsy" source because it contains exfoliated tumor cells and cell-free tumor DNA and can be obtained easily, noninvasively, and repeatedly. Here, we review recent advances made in the development of DNA-methylation-based biomarkers for detection of bladder, prostate, renal, and upper urinary tract cancers, with an emphasis on the performance characteristics of biomarkers in urine. For most biomarkers evaluated in independent studies, there was great variability in sensitivity and specificity. We discuss issues that impact the outcome of DNA-methylation-based detection of urological cancer and account for the great variability in performance, including genomic location of biomarkers, source of DNA, and technical issues related to the detection of rare aberrantly methylated DNA molecules. Finally, we discuss issues that remain to be addressed to fully exploit the potential of DNA-methylation-based biomarkers in the clinic, including the need for prospective trials and careful selection of control groups.
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Affiliation(s)
| | - Guro Elisabeth Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, the Norwegian Radium Hospital, NO-0424 Oslo, Norway.
| | - Per Guldberg
- Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
| | - Christina Dahl
- Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
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Köhler CU, Bonberg N, Ahrens M, Behrens T, Hovanec J, Eisenacher M, Noldus J, Deix T, Braun K, Gohlke H, Walter M, Tannapfel A, Tam Y, Sommerer F, Marcus K, Jöckel KH, Erbel R, Cantor CR, Käfferlein HU, Brüning T. Noninvasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures-Gender matters. Int J Cancer 2019; 145:2861-2872. [PMID: 31008534 DOI: 10.1002/ijc.32356] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 04/01/2019] [Indexed: 01/28/2023]
Abstract
Urothelial cancer (UCa) is the most predominant cancer of the urinary tract and noninvasive diagnosis using hypermethylation signatures in urinary cells is promising. Here, we assess gender differences in a newly identified set of methylation biomarkers. UCa-associated hypermethylated sites were identified in urine of a male screening cohort (n = 24) applying Infinium-450K-methylation arrays and verified in two separate mixed-gender study groups (n = 617 in total) using mass spectrometry as an independent technique. Additionally, tissue samples (n = 56) of mixed-gender UCa and urological controls (UCt) were analyzed. The hypermethylation signature of UCa in urine was specific and sensitive across all stages and grades of UCa and independent on hematuria. Individual CpG sensitivities reached up to 81.3% at 95% specificity. Albeit similar methylation differences in tissue of both genders, differences were less pronounced in urine from women, most likely due to the frequent presence of squamous epithelial cells and leukocytes. Increased repression of methylation levels was observed at leukocyte counts ≥500/μl urine which was apparent in 30% of female and 7% of male UCa cases, further confirming the significance of the relative amounts of cancerous and noncancerous cells in urine. Our study shows that gender difference is a most relevant issue when evaluating the performance of urinary biomarkers in cancer diagnostics. In case of UCa, the clinical benefits of methylation signatures to male patients may outweigh those in females due to the general composition of women's urine. Accordingly, these markers offer a diagnostic option specifically in males to decrease the number of invasive cystoscopies.
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Affiliation(s)
- Christina U Köhler
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bochum, Germany
| | - Nadine Bonberg
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bochum, Germany
| | - Maike Ahrens
- Medical Proteome Center, Ruhr University Bochum, Bochum, Germany
| | - Thomas Behrens
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bochum, Germany
| | - Jan Hovanec
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bochum, Germany
| | | | - Joachim Noldus
- Department of Urology, Marien Hospital Herne, Ruhr-University Bochum, Herne, Germany
| | - Thomas Deix
- Department of Urology, Marien Hospital Herne, Ruhr-University Bochum, Herne, Germany
| | - Katharina Braun
- Department of Urology, Marien Hospital Herne, Ruhr-University Bochum, Herne, Germany
| | | | - Michael Walter
- c.ATG Core Facility for NGS and Microarrays, University of Tübingen, Tübingen, Germany
| | - Andrea Tannapfel
- Institute of Pathology, Georgius Agricola Foundation, Ruhr-University Bochum, Bochum, Germany
| | - Yu Tam
- Institute of Pathology, Georgius Agricola Foundation, Ruhr-University Bochum, Bochum, Germany
| | - Florian Sommerer
- Institute of Pathology, Georgius Agricola Foundation, Ruhr-University Bochum, Bochum, Germany
| | - Katrin Marcus
- Medical Proteome Center, Ruhr University Bochum, Bochum, Germany
| | - Karl-Heinz Jöckel
- Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Raimund Erbel
- Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Charles R Cantor
- Department of Biomedical Engineering, School of Medicine, Boston University, Boston, MA
| | - Heiko U Käfferlein
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bochum, Germany
| | - Thomas Brüning
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bochum, Germany
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Li K, Gu W, Xu J, Wang A, Han H. Expression of TMEFF2 in Human Pancreatic Cancer Tissue and the Effects of TMEFF2 Knockdown on Cell, Proliferation, and Apoptosis in Human Pancreatic Cell Lines. Med Sci Monit 2019; 25:3238-3246. [PMID: 31044775 PMCID: PMC6510056 DOI: 10.12659/msm.913974] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Background The TMEFF2 gene encodes the transmembrane protein with EGF like and two follistatin-like domains 2 and has been reported to be a tumor suppressor gene, but its role remains unknown in pancreatic cancer. This study aimed to investigate the expression of TMEFF2 in human pancreatic cancer tissue and the effects of knockdown of TMEFF2 on cell, proliferation, and apoptosis in human pancreatic cell lines. Material/Methods Thirty-five samples of human pancreatic tissue and adjacent normal pancreatic tissue, and five human pancreatic cancer cell lines, CAPAN1, ASPC1, BXPC3, SW1990, and CFPAC were studied. RNA expression, protein expression, cell proliferation, and apoptosis were studied using real-time polymerase chain reaction (RT-PCR), Western blot, the cell counting kit-8 (CCK-8) assay, and flow cytometry, respectively. A co-immunoprecipitation assay evaluated protein interactions. Results TMEFF2 expression was down-regulated in pancreatic cancer tissue compared with normal pancreas. In human pancreatic cancer cell lines, overexpression of TMEFF2 suppressed cell proliferation and enhanced apoptosis, suppressed the expression of p-STAT3, MCL1, VEGF and increased the expression of the tyrosine-specific protein phosphatase, SHP-1. The co-immunoprecipitation assay showed that TMEFF2 interacted with SHP-1. Knockdown of expression of TMEFF2 resulted in the increased expression of p-STAT3, MCL1, and VEGF, increased cell proliferation and decreased cell apoptosis, which were reversed by overexpression of SHP-1. Conclusions In pancreatic cancer, TMEFF2 exerted as a tumor suppressor effect by regulating p-STAT3, MCL1, and VEGF via SHP-1.
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Affiliation(s)
- Kailiang Li
- Department of Hepatobiliary Pancreatic Surgery, Jilin Province Peoples' Hospital, Changchun, Jilin, China (mainland)
| | - Wenjing Gu
- Department of Otolaryngology Head and Neck Surgery, First Bethune Hospital of Jilin University, Changchun, Jilin, China (mainland)
| | - Jie Xu
- Department of Gynecology and Obstetrics, Yancheng Third Peoples' Hospital, Yancheng, Jiangsu, China (mainland)
| | - Aikun Wang
- Department of General Surgery, Yancheng Third Peoples' Hospital, Yancheng, Jiangsu, China (mainland)
| | - Hongchao Han
- Department of General Surgery, Yancheng Third Peoples' Hospital, Yancheng, Jiangsu, China (mainland)
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50
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Franczak C, Filhine-Tresarrieu P, Gilson P, Merlin JL, Au L, Harlé A. Technical considerations for circulating tumor DNA detection in oncology. Expert Rev Mol Diagn 2019; 19:121-135. [DOI: 10.1080/14737159.2019.1568873] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Claire Franczak
- Service de Biopathologie, Institut de Cancérologie de Lorraine, Vandoeuvre les Nancy, France
| | | | - Pauline Gilson
- Service de Biopathologie, Institut de Cancérologie de Lorraine, Université de Lorraine, CNRS UMR 7039 CRAN, Nancy, France
| | - Jean-Louis Merlin
- Service de Biopathologie, Institut de Cancérologie de Lorraine, Université de Lorraine, CNRS UMR 7039 CRAN, Nancy, France
| | - Lewis Au
- Skin and Renal Units, The Royal Marsden NHS Foundation Trust, London, UK
| | - Alexandre Harlé
- Service de Biopathologie, Institut de Cancérologie de Lorraine, Université de Lorraine, CNRS UMR 7039 CRAN, Nancy, France
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