|
1
|
Kasmirski JA, Roy R, Wu C, Wheeler L, Kerrick Akinola K, Chen H, Bart Rose J, Cheng C, Bhatia S, Gillis A. Unraveling the clinical impact of differential DNA methylation in PDAC: A systematic review. Eur J Cancer 2025; 220:115384. [PMID: 40154213 DOI: 10.1016/j.ejca.2025.115384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 03/03/2025] [Accepted: 03/16/2025] [Indexed: 04/01/2025]
Abstract
INTRODUCTION Despite significant efforts to improve clinical outcomes, pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate. The poor prognosis associated with this disease is multifactorial and associated with a highly variable genetic profile associated with its pathogenesis. Epigenetic modifications including DNA methylation further affect the expression of genetic material. However, there is no comprehensive understanding of the clinical impact of DNA methylation in PDAC. METHODS A systematic literature review was registered on the International Prospective Register of Systematic Reviews database (CRD42023451955) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. An electronic search was conducted using the following databases: CINAHL Plus, Cochrane Library, Embase, Web of Science, Ovid Medline, and Google Scholar. Inclusion criteria included studies of patients with a PDAC diagnosis and information regarding genes or CpG sites that potentially affect diagnosis, prognosis, or survival of PDAC. RESULTS The initial search retrieved 2402 articles, and 423 duplicates were excluded. After exclusion criteria was applied, 19 studies were included. The most common genes recorded as affecting tumor pathogenesis were SFRP1 (n = 3/19, 15.7 %) and NPTX2 (n = 2/19, 10,5 %). Studies indicated that hypermethylation of SFRP1 and NPTX2 were associated with poor prognosis. CONCLUSIONS PDAC is associated with a range of epigenetic modifications. Methylation of specific genes related to PDAC may influence survival and prognosis and be a therapeutic target. Individual patient epigenetic analysis may be a future direction in directing PDAC treatment and prognosis.
Collapse
Affiliation(s)
| | - Raj Roy
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Christopher Wu
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lauren Wheeler
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - K Kerrick Akinola
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Herbert Chen
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - J Bart Rose
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Changde Cheng
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Smita Bhatia
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Andrea Gillis
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
| |
Collapse
|
|
2
|
Fanijavadi S, Thomassen M, Jensen LH. Targeting Triple NK Cell Suppression Mechanisms: A Comprehensive Review of Biomarkers in Pancreatic Cancer Therapy. Int J Mol Sci 2025; 26:515. [PMID: 39859231 PMCID: PMC11765000 DOI: 10.3390/ijms26020515] [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: 12/10/2024] [Revised: 01/04/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes due to frequent recurrence, metastasis, and resistance to treatment. A major contributor to this resistance is the tumor's ability to suppress natural killer (NK) cells, which are key players in the immune system's fight against cancer. In PDAC, the tumor microenvironment (TME) creates conditions that impair NK cell function, including reduced proliferation, weakened cytotoxicity, and limited tumor infiltration. This review examines how interactions between tumor-derived factors, NK cells, and the TME contribute to tumor progression and treatment resistance. To address these challenges, we propose a new "Triple NK Cell Biomarker Approach". This strategy focuses on identifying biomarkers from three critical areas: tumor characteristics, TME factors, and NK cell suppression mechanisms. This approach could guide personalized treatments to enhance NK cell activity. Additionally, we highlight the potential of combining NK cell-based therapies with conventional treatments and repurposed drugs to improve outcomes for PDAC patients. While progress has been made, more research is needed to better understand NK cell dysfunction and develop effective therapies to overcome these barriers.
Collapse
Affiliation(s)
- Sara Fanijavadi
- Cancer Polyclinic, Levanger Hospital, 7601 Levanger, Norway
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark;
| | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark;
- Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark
| | - Lars Henrik Jensen
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark;
- Department of Oncology, Institute of Regional Health Research, University of Southern Denmark, 7100 Vejle, Denmark
| |
Collapse
|
|
3
|
Kondo K, Muguruma K, Soejima S, Takai C, Kenzaki K, Kawakita N, Toba H, Takizawa H. Aberrant DNA Methylation of NPTX2 as an Indicator of Malignant Behavior in Thymic Epithelial Tumors. Cancers (Basel) 2024; 16:329. [PMID: 38254821 PMCID: PMC10813937 DOI: 10.3390/cancers16020329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/28/2023] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Thymic epithelial tumors (TET) consist of thymomas, thymic carcinoma (TC), and neuroendocrine tumors of the thymus (NECTT). Genetic and epigenetic alterations in TET have been the focus of recent research. In the present study, genome-wide screening was performed on aberrantly methylated CpG islands in TET, and this identified neuronal pentraxin 2 (NTPX2) as a significantly hypermethylated CpG island in TC relative to thymomas. NPTX2 is released from pre-synaptic cells in response to neuronal activity/seizure, and plays a role in host immunity and acute inflammation. TET samples were obtained from 38 thymomas, 25 TC, and 6 NECTT. The DNA methylation, mRNA, and protein expression levels of NPTX2 were examined. The DNA methylation rate of the NPTX2 gene was significantly higher in TC than in the normal thymus and thymomas, except B3. The mRNA expression level of NPTX2 was lower in TC than in the normal thymus. An inverse relationship was observed between mRNA expression levels and methylation levels. Relapse-free survival was shorter in patients with high NPTX2 DNA methylation levels than in those with low DNA methylation levels. NECTT showed very high mRNA and protein expression levels and low DNA methylation levels of NPTX2. NPTX2 may function as a tumor suppressor in TC, and have an oncogenic function in NECTT.
Collapse
Affiliation(s)
- Kazuya Kondo
- Department of Oncological Medical Services, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8509, Japan; (K.M.); (S.S.); (C.T.)
| | - Kyoka Muguruma
- Department of Oncological Medical Services, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8509, Japan; (K.M.); (S.S.); (C.T.)
| | - Shiho Soejima
- Department of Oncological Medical Services, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8509, Japan; (K.M.); (S.S.); (C.T.)
| | - Chikako Takai
- Department of Oncological Medical Services, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8509, Japan; (K.M.); (S.S.); (C.T.)
| | - Koichiro Kenzaki
- Department of Chest and Breast Surgical Oncology, Takamatsu Red Cross Hospital, Takamatsu 760-0017, Japan;
| | - Naoya Kawakita
- Department of Thoracic, Endocrine Surgery and Oncology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan; (N.K.); (H.T.); (H.T.)
| | - Hiroaki Toba
- Department of Thoracic, Endocrine Surgery and Oncology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan; (N.K.); (H.T.); (H.T.)
| | - Hiromitsu Takizawa
- Department of Thoracic, Endocrine Surgery and Oncology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan; (N.K.); (H.T.); (H.T.)
| |
Collapse
|
|
4
|
Kang T, Zhang C, Lei H, Luo R, Liu M, Wang S, Zhang X, Duan Q, Xiao S, Zheng Y. NPTX2 Promotes Epithelial-Mesenchymal Transition in Cutaneous Squamous Cell Carcinoma through METTL3-Mediated N6-Methyladenosine Methylation of SNAIL. J Invest Dermatol 2023; 143:977-988.e2. [PMID: 36638907 DOI: 10.1016/j.jid.2022.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/29/2022] [Accepted: 12/13/2022] [Indexed: 01/12/2023]
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. NPTX2, a member of the neuronal pentraxin family, is reported to play inconsistent roles in different cancers. The role and mechanism of NPTX2 in cSCC remain unclear. In this study, we found that NPTX2 was overexpressed in both skin lesions and cell lines of cSCC. In vitro studies showed that NPTX2 facilitated cell proliferation, migration, invasion, colony formation, and epithelial‒mesenchymal translation in A431 and SCL-1 cells. NPTX2 interacted with METTL3, increased METTL3 expression, and improved N6-methyladenosine modification in cSCC cell lines. Mechanistically, NPTX2 facilitated epithelial‒mesenchymal translation by promoting METTL3-mediated N6-methyladenosine of SNAIL. METTL3 knockdown and N6-methyladenosine inhibition reversed the impacts of NPTX2 overexpression on cSCC cells. In vivo studies verified the role of NPTX2 as an oncogene in cSCC. Therefore, NPTX2 may be a potential therapeutic target for cSCC.
Collapse
Affiliation(s)
- Tong Kang
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Cheng Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hao Lei
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ruiting Luo
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Meng Liu
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shengbang Wang
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiu Zhang
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qiqi Duan
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shengxiang Xiao
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yan Zheng
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| |
Collapse
|
|
5
|
Hiratsuka K, Miyoshi T, Kroll KT, Gupta NR, Valerius MT, Ferrante T, Yamashita M, Lewis JA, Morizane R. Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery. SCIENCE ADVANCES 2022; 8:eabq0866. [PMID: 36129975 PMCID: PMC9491724 DOI: 10.1126/sciadv.abq0866] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 08/03/2022] [Indexed: 05/23/2023]
Abstract
Organoids serve as a novel tool for disease modeling in three-dimensional multicellular contexts. Static organoids, however, lack the requisite biophysical microenvironment such as fluid flow, limiting their ability to faithfully recapitulate disease pathology. Here, we unite organoids with organ-on-a-chip technology to unravel disease pathology and develop therapies for autosomal recessive polycystic kidney disease. PKHD1-mutant organoids-on-a-chip are subjected to flow that induces clinically relevant phenotypes of distal nephron dilatation. Transcriptomics discover 229 signal pathways that are not identified by static models. Mechanosensing molecules, RAC1 and FOS, are identified as potential therapeutic targets and validated by patient kidney samples. On the basis of this insight, we tested two U.S. Food and Drug Administration-approved and one investigational new drugs that target RAC1 and FOS in our organoid-on-a-chip model, which suppressed cyst formation. Our observations highlight the vast potential of organoid-on-a-chip models to elucidate complex disease mechanisms for therapeutic testing and discovery.
Collapse
Affiliation(s)
- Ken Hiratsuka
- Nephrology Division, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- John A. Paulson School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
- Division of Renal Medicine, Brigham and Women’s Hospital, Boston, MA, USA
| | - Tomoya Miyoshi
- Division of Renal Medicine, Brigham and Women’s Hospital, Boston, MA, USA
| | - Katharina T. Kroll
- John A. Paulson School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Navin R. Gupta
- Nephrology Division, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Division of Renal Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Stem Cell Institute (HSCI), Cambridge, MA, USA
| | - M. Todd Valerius
- Harvard Medical School, Boston, MA, USA
- Division of Renal Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Stem Cell Institute (HSCI), Cambridge, MA, USA
| | - Thomas Ferrante
- John A. Paulson School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Michifumi Yamashita
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jennifer A. Lewis
- John A. Paulson School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
- Harvard Stem Cell Institute (HSCI), Cambridge, MA, USA
| | - Ryuji Morizane
- Nephrology Division, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- John A. Paulson School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
- Division of Renal Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Stem Cell Institute (HSCI), Cambridge, MA, USA
| |
Collapse
|
|
6
|
Xu G, Fan L, Zhao S, OuYang C. Neuronal pentraxin II (NPTX2) hypermethylation promotes cell proliferation but inhibits cell cycle arrest and apoptosis in gastric cancer cells by suppressing the p53 signaling pathway. Bioengineered 2021; 12:1311-1323. [PMID: 33896384 PMCID: PMC8806217 DOI: 10.1080/21655979.2021.1915658] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 04/07/2021] [Accepted: 04/07/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is a considerable health burden worldwide. DNA methylation, a major epigenetic phenomenon, is closely related to the pathogenesis of cancer. Neuronal pentraxin II (NPTX2) has been found to be hypermethylated in several cancers such as glioblastoma and pancreatic cancer. However, the roles of NPTX2 in gastric cancer have not been reported. To explore this issue, NPTX2 expression in gastric cancer cells was assessed by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). The methylation analysis of NPTX2 was performed by qRT-PCR as well as methylation-specific PCR (MS-PCR). The effects of NPTX2 on gastric cancer cell proliferation, apoptosis and cell cycle were detected by colony formation, CCK-8 and flow cytometry assays, respectively. The interaction of NPTX2 with the p53 signaling pathway was evaluated by western blot. Our study found the down-regulated expression of NPTX2 in gastric cancer cells compared with human gastric mucosal cells. In addition, the hypermethylation of NPTX2 was observed in gastric cancer cells, which was correlated with the low expression of NPTX2. Moreover, NPTX2 inhibited gastric cancer cell proliferation, inhibited apoptosis and induced cell cycle arrest. Furthermore, NPTX2 enhanced the protein expression of p53, p21 and PTEN to activate the p53 signaling pathway. Therefore, NPTX2 hypermethylation caused the downregulation of NPTX2 expression, which could promote cell proliferation, inhibit apoptosis and cause cell cycle arrest in gastric cancer cells by suppressing the p53 signaling pathway. Therefore, NPTX2 may be crucial for the progression of gastric cancer.
Collapse
Affiliation(s)
- Guofeng Xu
- Department of Gastroenterology, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Linfeng Fan
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Shufeng Zhao
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Canhui OuYang
- Department of Gastroenterology, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| |
Collapse
|
|
7
|
Huang W, Xue L, Xu H, Kong Z, Xu J, Zhao H, Nie Y. Diagnostic value of neuronal pentraxin II methylation in patients with pancreatic cancer: Meta-analysis. Int J Clin Pract 2021; 75:e14443. [PMID: 34105851 DOI: 10.1111/ijcp.14443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/01/2020] [Accepted: 05/24/2021] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is a devasting disease of which mortality almost parallels its incidence. PC tissue may express aberrantly methylated neuronal pentraxin II (NPTX2), but it is unclear what the consequences of this are. METHODS We systematically searched PubMed, Web of Science, the Chinese National Knowledge Infrastructure (CNKI), from inception to July 15, 2020, to identify if the detection of methylated NPTX2 have sufficient sensitivity and specificity to identify PC from other benign pancreatic diseases. RESULTS Majority of the studies obtained samples from pancreatic juice by endoscopy or surgery and composed of population with chronic pancreatitis, benign cystic lesion, intraductal papillary mucinous neoplasm, and healthy controls. Our results demonstrated that the diagnostic value of methylated NPTX2 is of widely various sensitivity and specificity and it shown higher specificity in differentiate PC from benign diseases. The lab method of quantitative real-time methylation-specific PCR (QMSP) has higher specificity than real-time methylation-specific PCR (MSP) in detecting the indicator. CONCLUSIONS NPTX2 methylation could serve as a promising molecular biomarker for pancreatic cancer diagnosis, for its high diagnostic value in differentiating pancreatic cancer from benign pancreatic disease with the lab method. The variable sensitivity of methylated NPTX2 was multifactorial, and it must be promoted before applied as screening test in clinical practice. Furthermore, experiments on methylated NPTX2 were needed to expanded for lower the heterogeneity.
Collapse
Affiliation(s)
- Wenqi Huang
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - LiFeng Xue
- Department of Gastroenterology, People's Hospital of Shenzhen, Guangzhou, China
| | - Haoming Xu
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Zhiqian Kong
- Dongguan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Dongguan, China
| | - Jing Xu
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Hailan Zhao
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yuqiang Nie
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| |
Collapse
|
|
8
|
Han X, Lu Y, Li X, Xia L, Wen H, Feng Z, Ju X, Chen X, Wu X. Overexpression of NPTX2 Promotes Malignant Phenotype of Epithelial Ovarian Carcinoma via IL6-JAK2/STAT3 Signaling Pathway Under Hypoxia. Front Oncol 2021; 11:643986. [PMID: 33768003 PMCID: PMC7985451 DOI: 10.3389/fonc.2021.643986] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 01/25/2021] [Indexed: 01/14/2023] Open
Abstract
Background Epithelial ovarian cancer (EOC) is the main subtype of ovarian cancer and shows an aggressive phenotype and poor prognosis. Neuronal pentraxin II (NPTX2) is a member of the neuronal pentraxin family and plays a contradictory role in different tumors. However, there has been no report about the possible role and effect of NPTX2 in EOC. Methods Bioinformatics analysis, qPCR, western blotting and immunohistochemistry were used to detect the expression of NPTX2 in EOC. Lentivirus-based transfection for NPTX2 overexpression or knockdown was performed on the EOC cell lines A2780, HEY, SKOV3 and OVCAR-3. The effect of NPTX2 on the malignant phenotype of EOC was examined through methods of MTS assay, Edu assay, transwell assay, western blotting analysis, qPCR analysis, luciferase reporter assay and xenograft experiment. Results EOC tissues showed higher NPTX2 expression than the normal tissues with poor prognosis. NPTX2 overexpression can promote the proliferation, invasion, migration and tumorigenesis of EOC via IL6-JAK2/STAT3 signaling pathway. Moreover, hypoxia-inducible factor-1(HIF-1) can promote the transcription and expression of NPTX2 under the hypoxic environment. NPTX2 knockdown abolished the hypoxia-induced malignant phenotypes in ECO. Conclusions The above results suggest that NPTX2 may play a novel role in ovarian cancer's malignant phenotype and act as a promising treatment target for EOC molecular therapy.
Collapse
Affiliation(s)
- Xiaotian Han
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yechen Lu
- Wound Repair Center, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Xiaoqi Li
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lingfang Xia
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hao Wen
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zheng Feng
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xingzhu Ju
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaojun Chen
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaohua Wu
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| |
Collapse
|
|
9
|
Chakma K, Gu Z, Abudurexiti Y, Hata T, Motoi F, Unno M, Horii A, Fukushige S. Epigenetic inactivation of IRX4 is responsible for acceleration of cell growth in human pancreatic cancer. Cancer Sci 2020; 111:4594-4604. [PMID: 32894817 PMCID: PMC7734003 DOI: 10.1111/cas.14644] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 08/29/2020] [Accepted: 09/01/2020] [Indexed: 12/19/2022] Open
Abstract
Epigenetic gene silencing by aberrant DNA methylation is one of the important mechanisms leading to loss of key cellular pathways in tumorigenesis. Methyl-CpG-targeted transcriptional activation (MeTA) reactivates hypermethylation-mediated silenced genes in a different way from DNA-demethylating agents. Microarray coupled with MeTA (MeTA-array) identified seven commonly hypermethylation-mediated silenced genes in 12 pancreatic ductal adenocarcinoma (PDAC) cell lines. Among these, we focused on IRX4 (Iroquois homeobox 4) because IRX4 is located at chromosome 5p15.33 where PDAC susceptibility loci have been identified through genome-wide association study. IRX4 was greatly downregulated in all of the analyzed 12 PDAC cell lines by promoter hypermethylation. In addition, the IRX4 promoter region was found to be frequently and specifically hypermethylated in primary resected PDACs (18/28: 64%). Reexpression of IRX4 inhibited colony formation and proliferation in two PDAC cell lines, PK-1 and PK-9. In contrast, knockdown of IRX4 accelerated cell proliferation in an IRX4-expressing normal pancreatic ductal epithelial cell line, HPDE-1. Because IRX4 is a sequence-specific transcription factor, downstream molecules of IRX4 were pursued by microarray analyses utilizing tetracycline-mediated IRX4 inducible PK-1 and PK-9 cells; CRYAB, CD69, and IL32 were identified as IRX4 downstream candidate genes. Forced expression of these genes suppressed colony formation abilities for both PK-1 and PK-9. These results suggest that DNA methylation-mediated silencing of IRX4 contributes to pancreatic tumorigenesis through aberrant transcriptional regulation of several cancer-related genes.
Collapse
MESH Headings
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Differentiation, T-Lymphocyte/genetics
- Antigens, Differentiation, T-Lymphocyte/metabolism
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- Cell Proliferation/genetics
- DNA Methylation
- Down-Regulation
- Gene Knockdown Techniques/methods
- Gene Silencing
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Humans
- Interleukins/genetics
- Interleukins/metabolism
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Plasmids
- Protein Array Analysis
- Tumor Stem Cell Assay
- Up-Regulation
- alpha-Crystallin B Chain/genetics
- alpha-Crystallin B Chain/metabolism
- Pancreatic Neoplasms
Collapse
Affiliation(s)
- Kanchan Chakma
- Division of PathologyTohoku University School of MedicineSendaiJapan
- Present address:
Department of Biochemistry and Molecular BiologyUniversity of ChittagongChittagongBangladesh
| | - Zhaodi Gu
- Division of PathologyTohoku University School of MedicineSendaiJapan
| | | | - Tatsuo Hata
- Department of Gastroenterological SurgeryTohoku University School of MedicineSendaiJapan
| | - Fuyuhiko Motoi
- Department of Gastroenterological SurgeryTohoku University School of MedicineSendaiJapan
- Present address:
Department of Surgery IYamagata University Graduate School of Medical ScienceYamagataJapan
| | - Michiaki Unno
- Department of Gastroenterological SurgeryTohoku University School of MedicineSendaiJapan
| | - Akira Horii
- Division of PathologyTohoku University School of MedicineSendaiJapan
- Present address:
Saka General HospitalShiogamaJapan
| | - Shinichi Fukushige
- Division of PathologyTohoku University School of MedicineSendaiJapan
- Center for Regulatory Epigenome and DiseasesTohoku University School of MedicineSendaiJapan
| |
Collapse
|
|
10
|
Avrahami D, Wang YJ, Schug J, Feleke E, Gao L, Liu C, Naji A, Glaser B, Kaestner KH. Single-cell transcriptomics of human islet ontogeny defines the molecular basis of β-cell dedifferentiation in T2D. Mol Metab 2020; 42:101057. [PMID: 32739450 PMCID: PMC7471622 DOI: 10.1016/j.molmet.2020.101057] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 07/20/2020] [Accepted: 07/27/2020] [Indexed: 01/03/2023] Open
Abstract
OBJECTIVE Dedifferentiation of pancreatic β-cells may reduce islet function in type 2 diabetes (T2D). However, the prevalence, plasticity and functional consequences of this cellular state remain unknown. METHODS We employed single-cell RNAseq to detail the maturation program of α- and β-cells during human ontogeny. We also compared islets from non-diabetic and T2D individuals. RESULTS Both α- and β-cells mature in part by repressing non-endocrine genes; however, α-cells retain hallmarks of an immature state, while β-cells attain a full β-cell specific gene expression program. In islets from T2D donors, both α- and β-cells have a less mature expression profile, de-repressing the juvenile genetic program and exocrine genes and increasing expression of exocytosis, inflammation and stress response signalling pathways. These changes are consistent with the increased proportion of β-cells displaying suboptimal function observed in T2D islets. CONCLUSIONS These findings provide new insights into the molecular program underlying islet cell maturation during human ontogeny and the loss of transcriptomic maturity that occurs in islets of type 2 diabetics.
Collapse
Affiliation(s)
- Dana Avrahami
- Endocrinology and Metabolism Department, Hadassah-Hebrew University Medical Centre, Jerusalem, Israel
| | - Yue J Wang
- Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jonathan Schug
- Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Eseye Feleke
- Endocrinology and Metabolism Department, Hadassah-Hebrew University Medical Centre, Jerusalem, Israel
| | - Long Gao
- Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Chengyang Liu
- Department of Surgery and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ali Naji
- Department of Surgery and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Benjamin Glaser
- Endocrinology and Metabolism Department, Hadassah-Hebrew University Medical Centre, Jerusalem, Israel.
| | - Klaus H Kaestner
- Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
| |
Collapse
|
|
11
|
Wang Z, Wang X, Zou H, Dai Z, Feng S, Zhang M, Xiao G, Liu Z, Cheng Q. The Basic Characteristics of the Pentraxin Family and Their Functions in Tumor Progression. Front Immunol 2020; 11:1757. [PMID: 33013829 PMCID: PMC7461825 DOI: 10.3389/fimmu.2020.01757] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 06/30/2020] [Indexed: 02/05/2023] Open
Abstract
The pentraxin is a superfamily of proteins with the same domain known as the pentraxin domain at C-terminal. This family has two subgroups, namely; short pentraxins (C-reactive protein and serum amyloid P component) and long pentraxins (neuronal pentraxin 1, neuronal pentraxin 2, neuronal pentraxin receptor, pentraxin 3 and pentraxin 4). Each group shares a similar structure with the pentameric complexes arranged in a discoid shape. Previous studies revealed the functions of different pentraxin family members. Most of them are associated with human innate immunity. Inflammation has commonly been associated with tumor progression, implying that the pentraxin family might also participate in tumor progression. Therefore, we reviewed the basic characteristics and functions of the pentraxin family and their role in tumor progression.
Collapse
Affiliation(s)
- Zeyu Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Xing Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Hecun Zou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Ziyu Dai
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Songshan Feng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Mingyu Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Gelei Xiao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Zhixiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
12
|
Singh N, Rashid S, Rashid S, Dash NR, Gupta S, Saraya A. Clinical significance of promoter methylation status of tumor suppressor genes in circulating DNA of pancreatic cancer patients. J Cancer Res Clin Oncol 2020; 146:897-907. [PMID: 32146565 DOI: 10.1007/s00432-020-03169-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 02/27/2020] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive cancer. There are various sub-cellular events (both genetic and epigenetic) that get dysregulated leading to tumorigenesis. Methylation in promoters of tumor suppressor genes is one of these epigenetic phenomena contributing to the pathogenesis of cancer. Genes analyzed for promoter methylation status in this study namely SPARC (Secreted Protein Acidic and Rich in Cysteine, UCHL1 (ubiquitin carboxy-terminal hydrolase L1), NPTX2 (neuronal pentraxin 2), PENK (proenkephalin) had been studied in pancreatic cancer, but there is a need to check methylation in these genes as circulatory non-invasive markers. This study analyzed the absolute quantification of methylation levels of SPARC, UCHL1, PENK, and NPTX2 genes promoters in PDAC patients as well as in chronic pancreatitis (CP) patients and healthy subjects (HC) and evaluated its clinical significance in PDAC. MATERIALS AND METHODS The study included 65 PDAC patients, 25 CP patients, and 25 healthy controls. DNA was extracted from their plasma samples and subsequently given bisulfite treatment. Absolute quantization of methylated and unmethylated copies of gene promoters of all the four genes was performed using real-time PCR (SYBR green) by the standard curve method. Methylation levels were expressed as methylation index (MI) for each gene in each patient. MI was calculated from absolute copy numbers as follows: MI-methylated copy number/methylated copy number + unmethylated copy number). These indices were used to compare gene methylation levels within different groups and to correlate with clinicopathological features and survival of pancreatic cancer patients. An appropriate statistical analysis was applied. RESULTS Methylation indices for all the four genes in PDAC cases were found to be significantly higher as compared to that in healthy individuals. SPARC MI values were found to differentiate early-stage PDAC patients from CP patients. PDAC patients with the metastasized disease and stage IV disease were found to have high MI for the SPARC gene as well as for the NPTX2 gene, while a higher UCHL1 methylation index was found to correlate with an advanced stage of the disease. Higher MI values for SPARC and NPTX2 genes were found to associate with poor survival in patients with PDAC. CONCLUSION Methylation load in the form of MI for each of the four genes assessed in plasma may emerge as a non-invasive biomarker to differentiate pancreatic cancer from healthy individuals. But only SPARC and NPTX2 hypermethylation were able to distinguish pancreatic cancer from chronic pancreatitis. Association of aberrant methylation in SPARC and NPTX2 gene with metastasis and poor survival of patients suggest the role of methylation in these genes as prognostic markers.
Collapse
Affiliation(s)
- Nidhi Singh
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sumaira Rashid
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Safoora Rashid
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Nihar Ranjan Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Surabhi Gupta
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India.
| |
Collapse
|
|
13
|
Zubair H, Azim S, Khan MA, Patel GK, Ahmad A, Pai S, Singh S, Singh AP. Epigenetic Control of Pancreatic Carcinogenesis and Its Regulation by Natural Products. EPIGENETICS OF CANCER PREVENTION 2019:251-270. [DOI: 10.1016/b978-0-12-812494-9.00012-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
14
|
Novel Diagnostic and Predictive Biomarkers in Pancreatic Adenocarcinoma. Int J Mol Sci 2017; 18:ijms18030667. [PMID: 28335509 PMCID: PMC5372679 DOI: 10.3390/ijms18030667] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 03/07/2017] [Accepted: 03/10/2017] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for a multitude of reasons including very late diagnosis. This in part is due to the lack of understanding of the biological behavior of PDAC and the ineffective screening for this disease. Significant efforts have been dedicated to finding the appropriate serum and imaging biomarkers to help early detection and predict response to treatment of PDAC. Carbohydrate antigen 19-9 (CA 19-9) has been the most validated serum marker and has the highest positive predictive value as a stand-alone marker. When combined with carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA 125), CA 19-9 can help predict the outcome of patients to surgery and chemotherapy. A slew of novel serum markers including multimarker panels as well as genetic and epigenetic materials have potential for early detection of pancreatic cancer, although these remain to be validated in larger trials. Imaging studies may not correlate with elevated serum markers. Critical features for determining PDAC include the presence of a mass, dilated pancreatic duct, and a duct cut-off sign. Features that are indicative of early metastasis includes neurovascular bundle involvement, duodenal invasion, and greater post contrast enhancement. 18-F-fluorodeoxyglucose (18-FDG) radiotracer uptake and changes following treatment may predict patient overall survival following treatment. Similarly, pretreatment apparent diffusion coefficient (ADC) values may predict prognosis with lower ADC lesions having worse outcome. Although these markers have provided significant improvement in the care of pancreatic cancer patients, further advancements can be made with perhaps better combination of markers or discovery of unique marker(s) to pancreatic cancer.
Collapse
|
|
15
|
Singh R, Lillard JW, Singh S. Epigenetic Changes and Potential Targets in Pancreatic Cancer. EPIGENETIC ADVANCEMENTS IN CANCER 2016:27-63. [DOI: 10.1007/978-3-319-24951-3_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
16
|
Jin T, Zhang XY, Hao JY. Abnormal methylation in pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:5581-5590. [DOI: 10.11569/wcjd.v23.i35.5581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive malignancies in the world and has a poor prognosis. Since most cases have already had local invasion or distant metastasis at diagnosis, they usually lost the opportunity for effective surgical resection. Thus, early detection and treatment are of great clinical significance for reducing mortality. Epigenetic changes play an important role in the occurrence of cancers. Abnormal methylation is an important part of epigenetic theory. Here we discuss abnormal methylation of multiple genes in pancreatic cancer, with an aim to find methods of early diagnosis and treatment for this devastating disease.
Collapse
|
|
17
|
Pancreatic cancer: diagnosis and treatments. Tumour Biol 2015; 36:1375-84. [PMID: 25680410 DOI: 10.1007/s13277-015-3223-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 02/03/2015] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is one of the deadliest cancers, with exceptionally high mortality. Despite the relatively low incidence rate (10th), it is the fourth leading cause of cancer-related deaths in most developed countries. To improve the early diagnosis of pancreatic cancer and strengthen the standardized comprehensive treatment are still the main focus of pancreatic cancer research. Here, we summarized the rapid developments in the diagnosis and treatments of pancreatic cancer. Regarding diagnosis, we reviewed advances in medical imaging technology, tumor markers, molecular biology (e.g., gene mutation), and proteomics. Moreover, great progress has also been made in the treatments of this disease, including surgical resection, chemotherapy, targeted radiotherapy, targeted minimally invasive treatment, and molecular targeted therapy. Therefore, we also recapitulated the development, advantages, and disadvantages of each of the treatment methods in this review.
Collapse
|
|
18
|
Zhou C, Qin Y, Xie Z, Zhang J, Yang M, Li S, Chen R. NPTX1 is a novel epigenetic regulation gene and associated with prognosis in lung cancer. Biochem Biophys Res Commun 2015; 458:381-6. [PMID: 25646694 DOI: 10.1016/j.bbrc.2015.01.124] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Accepted: 01/24/2015] [Indexed: 12/29/2022]
Abstract
BACKGROUND CpG island hypermethylation of gene promoters is a well-known mechanism of epigenetic regulation of tumor related-genes and is directly linked to lung carcinogenesis. Alterations in the pattern of methylation of the NPTX1 gene have not yet been studied in detail in human lung cancer. METHODS Methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) were used to analyze promoter methylation status, and real-time quantitative reverse transcription-PCR (qRT-PCR) examined mRNA levels. Subsequently, we compared the methylation profile of NPTX1 in samples of neoplastic and non-neoplastic lung tissue taken from the same patients by using quantitative methylation specific PCR (QMSP). RESULTS CpG island hypermethylation in promoter of NPTX1 was confirmed in lung cancer cell lines. A significant increase in NPTX1 methylation was identified in lung cancer specimens compared to adjacent noncancerous tissues and that it was negatively correlated with its mRNA expression. The overall survival time among patients carrying methylated NPTX1 tumors was significantly shorter as compared to those with unmethylated NPTX1 tumors (P = 0.011). Moreover, methylation of NPTX1 gene was found to be an independent prognostic factor for poor overall survival based on multivariate analysis models (p = 0.021), as was age ≥60 years old (p = 0.012) and TNM stage (p < 0.001). CONCLUSIONS These results suggest that NPTX1 hypermethylation and consequent mRNA changes might be an important molecular mechanism in lung cancer. Epigenetic alterations in NPTX1 may serve as potential diagnostic and prognostic biomarkers in lung cancer.
Collapse
Affiliation(s)
- Chengzhi Zhou
- Department of Medicine, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510120, China
| | - Yinyin Qin
- Department of Medicine, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510120, China
| | - Zhanhong Xie
- Department of Medicine, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510120, China
| | - Jiexia Zhang
- Department of Medicine, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510120, China
| | - Mingou Yang
- Department of Medicine, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510120, China
| | - Shiyue Li
- Department of Medicine, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510120, China.
| | - Rongchang Chen
- Department of Medicine, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510120, China.
| |
Collapse
|
|
19
|
Botlagunta M. Neuronal pentraxin 1 expression is regulated by hypoxia inducible factor-1α. Biochem Biophys Res Commun 2015; 456:662-5. [DOI: 10.1016/j.bbrc.2014.12.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 12/04/2014] [Indexed: 10/25/2022]
|
|
20
|
Neureiter D, Jäger T, Ocker M, Kiesslich T. Epigenetics and pancreatic cancer: Pathophysiology and novel treatment aspects. World J Gastroenterol 2014; 20:7830-7848. [PMID: 24976721 PMCID: PMC4069312 DOI: 10.3748/wjg.v20.i24.7830] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 02/07/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023] Open
Abstract
An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades. Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations, such as mutations of K-ras, and especially epigenetic dysregulation of tumor-associated genes, such as silencing of the tumor suppressor p16ink4a, are hallmarks of pancreatic cancer. Here, we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation, histone acetylation or miRNA (microRNA) expression, and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition, morphological pattern formation, or cancer stem cell regulation during carcinogenesis from PanIN (pancreatic intraepithelial lesions) to invasive cancer and resistance development. Epigenetic drugs, such as DNA methyltransferases or histone deactylase inhibitors, have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development. Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.
Collapse
|
|
21
|
von Roemeling CA, Radisky DC, Marlow LA, Cooper SJ, Grebe SK, Anastasiadis PZ, Tun HW, Copland JA. Neuronal pentraxin 2 supports clear cell renal cell carcinoma by activating the AMPA-selective glutamate receptor-4. Cancer Res 2014; 74:4796-810. [PMID: 24962026 DOI: 10.1158/0008-5472.can-14-0210] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and has the highest propensity to manifest as metastatic disease. Recent characterizations of the genetic signature of ccRCC have revealed several factors correlated with tumor cell migration and invasion; however, the specific events driving malignancy are not well defined. Furthermore, there remains a lack of targeted therapies that result in long-term, sustainable response in patients with metastatic disease. We show here that neuronal pentraxin 2 (NPTX2) is overexpressed specifically in ccRCC primary tumors and metastases, and that it contributes to tumor cell viability and promotes cell migration through its interaction with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR4. We propose NPTX2 as a novel molecular target for therapy for patients with ccRCC diagnosed with or at risk of developing metastatic disease.
Collapse
Affiliation(s)
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida
| | - Laura A Marlow
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida
| | - Simon J Cooper
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida
| | - Stefan K Grebe
- Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Han W Tun
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida. Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida
| | - John A Copland
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida.
| |
Collapse
|
|
22
|
Abstract
Embryonic stem (ES) cells have been shown to recapitulate normal developmental stages. They are therefore a highly useful tool in the study of developmental biology. Profiling of ES cell-derived cells has yielded important information about the characteristics of differentiated cells, and allowed the identification of novel marker genes and pathways of differentiation. In this review, we focus on recent results from profiling studies of mouse embryos, human islets, and human ES cell-derived differentiated cells from several research groups. Global gene expression data from mouse embryos have been used to identify novel genes or pathways involved in the developmental process, and to search for transcription factors that regulate direct reprogramming. We introduce gene expression databases of human pancreas cells (Beta Cell Gene Atlas, EuroDia database), and summarize profiling studies of islet- or human ES cell-derived pancreatic cells, with a focus on gene expression, microRNAs, epigenetics, and protein expression. Then, we describe our gene expression profile analyses and our search for novel endoderm, or pancreatic, progenitor marker genes. We differentiated mouse ES cells into mesendoderm, definitive endoderm (DE), mesoderm, ectoderm, and Pdx1-expressing pancreatic lineages, and performed DNA microarray analyses. Genes specifically expressed in DE, and/or in Pdx1-expressing cells, were extracted and their expression patterns in normal embryonic development were studied by in situ hybridization. Out of 54 genes examined, 27 were expressed in the DE of E8.5 mouse embryos, and 15 genes were expressed in distinct domains in the pancreatic buds of E14.5 mouse embryos. Akr1c19, Aebp2, Pbxip1, and Creb3l1 were all novel, and none has been described as being expressed, either in the DE, or in the pancreas. By introducing the profiling results of ES cell-derived cells, the benefits of using ES cells to study early embryonic development will be discussed.
Collapse
Affiliation(s)
- Nobuaki Shiraki
- Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan
| | - Soichiro Ogaki
- Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan
| | - Shoen Kume
- Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan
| |
Collapse
|
|
23
|
Hinton J, Callan R, Bodine C, Glasgow W, Brower S, Jiang SW, Li J. Potential epigenetic biomarkers for the diagnosis and prognosis of pancreatic ductal adenocarcinomas. Expert Rev Mol Diagn 2014; 13:431-43. [DOI: 10.1586/erm.13.38] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
24
|
Shukla S, Pia Patric IR, Thinagararjan S, Srinivasan S, Mondal B, Hegde AS, Chandramouli BA, Santosh V, Arivazhagan A, Somasundaram K. A DNA methylation prognostic signature of glioblastoma: identification of NPTX2-PTEN-NF-κB nexus. Cancer Res 2013; 73:6563-73. [PMID: 24078801 DOI: 10.1158/0008-5472.can-13-0298] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Glioblastoma (GBM) is the most common, malignant adult primary tumor with dismal patient survival, yet the molecular determinants of patient survival are poorly characterized. Global methylation profile of GBM samples (our cohort; n = 44) using high-resolution methylation microarrays was carried out. Cox regression analysis identified a 9-gene methylation signature that predicted survival in GBM patients. A risk-score derived from methylation signature predicted survival in univariate analysis in our and The Cancer Genome Atlas (TCGA) cohort. Multivariate analysis identified methylation risk score as an independent survival predictor in TCGA cohort. Methylation risk score stratified the patients into low-risk and high-risk groups with significant survival difference. Network analysis revealed an activated NF-κB pathway association with high-risk group. NF-κB inhibition reversed glioma chemoresistance, and RNA interference studies identified interleukin-6 and intercellular adhesion molecule-1 as key NF-κB targets in imparting chemoresistance. Promoter hypermethylation of neuronal pentraxin II (NPTX2), a risky methylated gene, was confirmed by bisulfite sequencing in GBMs. GBMs and glioma cell lines had low levels of NPTX2 transcripts, which could be reversed upon methylation inhibitor treatment. NPTX2 overexpression induced apoptosis, inhibited proliferation and anchorage-independent growth, and rendered glioma cells chemosensitive. Furthermore, NPTX2 repressed NF-κB activity by inhibiting AKT through a p53-PTEN-dependent pathway, thus explaining the hypermethylation and downregulation of NPTX2 in NF-κB-activated high-risk GBMs. Taken together, a 9-gene methylation signature was identified as an independent GBM prognosticator and could be used for GBM risk stratification. Prosurvival NF-κB pathway activation characterized high-risk patients with poor prognosis, indicating it to be a therapeutic target.
Collapse
Affiliation(s)
- Sudhanshu Shukla
- Authors' Affiliations: Department of Microbiology and Cell Biology, Indian Institute of Science; Sri SatyaSai Institute of Higher Medical Sciences; Departments of Neurosurgery and Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Alholle A, Brini AT, Gharanei S, Vaiyapuri S, Arrigoni E, Dallol A, Gentle D, Kishida T, Hiruma T, Avigad S, Grimer R, Maher ER, Latif F. Functional epigenetic approach identifies frequently methylated genes in Ewing sarcoma. Epigenetics 2013; 8:1198-204. [PMID: 24005033 DOI: 10.4161/epi.26266] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Using a candidate gene approach we recently identified frequent methylation of the RASSF2 gene associated with poor overall survival in Ewing sarcoma (ES). To identify effective biomarkers in ES on a genome-wide scale, we used a functionally proven epigenetic approach, in which gene expression was induced in ES cell lines by treatment with a demethylating agent followed by hybridization onto high density gene expression microarrays. After following a strict selection criterion, 34 genes were selected for expression and methylation analysis in ES cell lines and primary ES. Eight genes (CTHRC1, DNAJA4, ECHDC2, NEFH, NPTX2, PHF11, RARRES2, TSGA14) showed methylation frequencies of>20% in ES tumors (range 24-71%), these genes were expressed in human bone marrow derived mesenchymal stem cells (hBMSC) and hypermethylation was associated with transcriptional silencing. Methylation of NPTX2 or PHF11 was associated with poorer prognosis in ES. In addition, six of the above genes also showed methylation frequency of>20% (range 36-50%) in osteosarcomas. Identification of these genes may provide insights into bone cancer tumorigenesis and development of epigenetic biomarkers for prognosis and detection of these rare tumor types.
Collapse
Affiliation(s)
- Abdullah Alholle
- Centre for Rare Diseases and Personalized Medicine; School of Clinical and Experimental Medicine; University of Birmingham; Birmingham, UK
| | - Anna T Brini
- Department of Biomedical, Surgical, and Dental Sciences; University of Milan; Milan, Italy; I.R.C.C.S. Istituto Ortopedico Galeazzi; Milano, Italy
| | - Seley Gharanei
- Centre for Rare Diseases and Personalized Medicine; School of Clinical and Experimental Medicine; University of Birmingham; Birmingham, UK
| | - Sumathi Vaiyapuri
- Royal Orthopaedic Hospital Foundation Trust; Robert Aitken Institute of Clinical Research; University of Birmingham; Birmingham, UK
| | - Elena Arrigoni
- Department of Biomedical, Surgical, and Dental Sciences; University of Milan; Milan, Italy
| | - Ashraf Dallol
- Center of Excellence in Genomic Medicine Research and KACST Technology Innovation Center in Personalized Medicine; King Abdulaziz University; Jeddah, Kingdom of Saudi Arabia
| | - Dean Gentle
- Centre for Rare Diseases and Personalized Medicine; School of Clinical and Experimental Medicine; University of Birmingham; Birmingham, UK
| | | | - Toru Hiruma
- Department of Musculoskeletal tumor surgery; Kanagawa Cancer Center; Kanagawa, Japan
| | - Smadar Avigad
- Molecular Oncology; Felsenstein Medial Research Center; Pediatric Hematology Oncology; Schneider Children's Medical Center of Israel; Tel Aviv University; Tel Aviv, Israel
| | - Robert Grimer
- Royal Orthopaedic Hospital Foundation Trust; Robert Aitken Institute of Clinical Research; University of Birmingham; Birmingham, UK
| | - Eamonn R Maher
- Centre for Rare Diseases and Personalized Medicine; School of Clinical and Experimental Medicine; University of Birmingham; Birmingham, UK
| | - Farida Latif
- Centre for Rare Diseases and Personalized Medicine; School of Clinical and Experimental Medicine; University of Birmingham; Birmingham, UK
| |
Collapse
|
|
26
|
Bu X, Zhao C. Significant association between GSTT1 null genotype and susceptibility to pancreatic cancer. Mol Biol Rep 2013; 40:4295-9. [PMID: 23720024 DOI: 10.1007/s11033-013-2516-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 04/27/2013] [Indexed: 12/20/2022]
Abstract
Many studies have investigated the association between glutathione S-transferase T1 (GSTT1) polymorphism and risk for pancreatic cancer, but those studies have yielded contradictory findings on the association. We performed a comprehensive search in the PubMed, EMBASE, and the Chinese National Knowledge Infrastructure databases to identify relevant studies. A meta-analysis was performed to examine the association between GSTT1 polymorphism and susceptibility to pancreatic cancer by calculating the pooled odds ratios (ORs) and corresponding 95 % confidence intervals (95 % CIs). Eight studies involving a total of 4,437 individuals were included. Overall, significantly increased pancreatic cancer risk was associated with GSTT1 null genotype when all studies were pooled into the meta-analysis (random effects OR = 1.61, 95 % CI 1.06-2.44; P = 0.025). Significantly increased risk of pancreatic cancer was also found for GSTT1 null genotype in Asians when stratified by ethnicity (fixed effects OR = 2.67, 95 % CI 1.74-4.09; P < 0.001). The findings demonstrate that GSTT1 null genotype have a modest effect on the genetic susceptibility to pancreatic cancer, and GSTT1 null genotype is associated with increased risk of pancreatic cancer.
Collapse
Affiliation(s)
- Xianmin Bu
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping, Shenyang, 110004, China.
| | | |
Collapse
|
|
27
|
Zhang L, Gao J, Li Z, Gong Y. Neuronal pentraxin II (NPTX2) is frequently down-regulated by promoter hypermethylation in pancreatic cancers. Dig Dis Sci 2012; 57:2608-14. [PMID: 22806544 DOI: 10.1007/s10620-012-2202-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 04/14/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND Gene silencing via promoter hypermethylation plays a crucial role in the pathogenesis of cancers. Neuronal pentraxin II (NPTX2) has been observed to be hypermethylated in pancreatic cancers. Methylation of NPTX2 might provide a novel diagnostic marker for pancreatic cancers. AIM The objective of this study is to investigate the abnormal patterns of DNA methylation of NPTX2 in pancreatic cancers, and its role in the transcriptional silencing of NPTX2. METHODS NPTX2 expression was detected by reverse-transcription polymerase chain reaction (RT-PCR), and the methylation status of NPTX2 was assessed by methylation-specific polymerase chain reaction (MSP). Immunohistochemistry was used to examine the NPTX2 protein expression. The pancreatic cancer cell lines were treated with the DNA methyltransferase inhibitor, histone deacetylase inhibitors, either alone or in combination. RESULTS The MSP analysis revealed that the promoter region of NPTX2 gene was largely unmethylated in normal pancreatic tissues, while NPTX2 was frequently hypermethylated in pancreatic cancer cells and in primary pancreatic carcinomas. Quantitative RT-PCR revealed that the mean mRNA expression level of NPTX2 in the pancreatic cancer tissues was significantly lower than that in the paired adjacent normal tissues (0.96 ± 0.91 vs. 2.78 ± 1.42, P < 0.001). Consistent with RT-PCR detection, treatment with 5Aza-dC resulted in different degrees of induction of NPTX2 protein in the various cancer cell lines. CONCLUSION We demonstrate that the NPTX2 protein is down-regulated in human primary pancreatic cancers and in pancreatic cancer cell lines. This study provides the first evidence that the down-regulation of NPTX2 tightly correlates with its promoter hypermethylation.
Collapse
Affiliation(s)
- Ling Zhang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | | | | | | |
Collapse
|
|
28
|
Oparina NY, Sadritdinova AF, Snezhkina AV, Dmitriev AA, Krasnov GS, Senchenko VN, Melnikova NV, Belenikin MS, Lakunina VA, Veselovsky VA, Stepanov OA, Kudryavtseva AV. Increase in NETO2 gene expression is a potential molecular genetic marker in renal and lung cancers. RUSS J GENET+ 2012. [DOI: 10.1134/s1022795412050171] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
|