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Cortellesi E, Savini I, Veneziano M, Gambacurta A, Catani MV, Gasperi V. Decoding the Epigenome of Breast Cancer. Int J Mol Sci 2025; 26:2605. [PMID: 40141248 PMCID: PMC11942310 DOI: 10.3390/ijms26062605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/06/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Breast cancer (BC) is the most prevalent malignancy among women, characterized by extensive heterogeneity stemming from molecular and genetic alterations. This review explores the intricate epigenetic landscape of BC, highlighting the significant role of epigenetic modifications-particularly DNA methylation, histone modifications, and the influence of non-coding RNAs-in the initiation, progression, and prognosis of the disease. Epigenetic alterations drive crucial processes, including gene expression regulation, cell differentiation, and tumor microenvironment interactions, contributing to tumorigenesis and metastatic potential. Notably, aberrations in DNA methylation patterns, including global hypomethylation and hypermethylation of CpG islands, have been associated with distinct BC subtypes, with implications for early detection and risk assessment. Furthermore, histone modifications, such as acetylation and methylation, affect cancer cell plasticity and aggressiveness by profoundly influencing chromatin dynamics and gene transcription. Finally, non-coding RNAs contribute by modulating epigenetic machinery and gene expression. Despite advances in our knowledge, clinical application of epigenetic therapies in BC is still challenging, often yielding limited efficacy when used alone. However, combining epi-drugs with established treatments shows promise for enhancing therapeutic outcomes. This review underscores the importance of integrating epigenetic insights into personalized BC treatment strategies, emphasizing the potential of epigenetic biomarkers for improving diagnosis, prognosis, and therapeutic response in affected patients.
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Affiliation(s)
- Elisa Cortellesi
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Isabella Savini
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Matteo Veneziano
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Alessandra Gambacurta
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
- NAST Centre (Nanoscience & Nanotechnology & Innovative Instrumentation), Tor Vergata University of Rome, 00133 Rome, Italy
| | - Maria Valeria Catani
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Valeria Gasperi
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
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2
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Keeler C, Krigbaum NY, Cohn B, Cirillo P. Parental loss at age birth to 21 years and daughters' breast cancer and tumor characteristics. JNCI Cancer Spectr 2025; 9:pkaf004. [PMID: 39820352 PMCID: PMC11892429 DOI: 10.1093/jncics/pkaf004] [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: 08/02/2024] [Revised: 12/10/2024] [Accepted: 01/06/2025] [Indexed: 01/19/2025] Open
Abstract
BACKGROUND Adverse events in childhood are linked to cancer risk across the life course, but evidence is lacking regarding parental death during childhood and breast cancer characteristics. We investigated whether women who experienced parental loss in childhood have a higher incidence of breast cancer and are at higher risk of aggressive disease. METHODS The Child Health and Development Studies (CHDS) consists of more than 15 000 families that enrolled during mothers' pregnancies between 1959 and 1967; family members were followed for cancer incidence and cause-specific mortality. We constructed an analytical cohort of all live-born CHDS daughters (N = 9169) linked to their parents' cause and date of death. We estimated adjusted hazard ratios of incident breast cancer, disease stage at diagnosis, and tumor hormone receptor expression for parental loss in Cox models adjusted for race, maternal breast cancer, and paternal age. Generalized linear models estimated associations between breast density and parental loss among a subsample of CHDS daughters (n = 610) with available mammography reports. RESULTS In total, 137 CHDS daughters were diagnosed with breast cancer by age 52 years, and 654 daughters had lost 1 or both parents when they were 21 years of age or younger. Loss of both parents was associated with breast cancer incidence (adjusted hazard ratio = 4.69, 95% CI = 1.68 to 13.04); late-stage disease at diagnosis (adjusted hazard ratio = 9.47, 95% CI = 1.38 to 64.84); and ERBB2 (formerly HER2)-positive, progesterone receptor-negative, and estrogen receptor-negative tumors. Loss of mother or father was associated with ERBB2-positive tumors. Breast density in the premenopause window was associated with loss of a mother or both parents. CONCLUSION In a multigenerational cohort with well-defined cancer outcomes and validated cause-of-death data, life-course risk of breast cancer was 4.69 times higher among participants who had lost both parents during childhood. Subanalyses showed that parental loss was associated with late stage at diagnosis and tumor hormone markers of aggressive disease. Parental death during childhood could be added to medical histories to indicate a need for counseling on prevention and early detection of breast cancer.
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Affiliation(s)
- Corinna Keeler
- Child Health and Development Studies, Public Health Institute, Berkeley, CA 94709, United States
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Nickilou Y Krigbaum
- Child Health and Development Studies, Public Health Institute, Berkeley, CA 94709, United States
| | - Barbara Cohn
- Child Health and Development Studies, Public Health Institute, Berkeley, CA 94709, United States
| | - Piera Cirillo
- Child Health and Development Studies, Public Health Institute, Berkeley, CA 94709, United States
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3
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Hu Y, Liu S, Cui C, Liu X, Li H, Liu H, Lu S, Lu Z, Chen Z, Pang D, Fan JB, Lin D, Zhang X, Sun Y. Enhanced HER2 status detection in breast and gastric cancers using surrogate DNA methylation markers. IUBMB Life 2025; 77:e70004. [PMID: 39988770 DOI: 10.1002/iub.70004] [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: 09/23/2024] [Accepted: 01/17/2025] [Indexed: 02/25/2025]
Abstract
There is a limited understanding of specific DNA methylation patterns associated with HER2 overexpression in breast and gastric cancers. Here we aim to solve the problem using inferred DNA methylation markers. DNA methylation data from The Cancer Genome Atlas (TCGA) were analyzed for breast and gastric cancers regarding HER2 status. We further applied a targeted bisulfite sequencing approach to elaborate the DNA methylation profile of the HER2 region, covering 7635 CpG sites. Based on these two sets of data, we selected specific DNA methylation markers inferring HER2 status for both breast and gastric cancers and validated their performance in assisting HER2-status determination on a retrospective cohort with 496 breast cancer and 372 gastric cancer. HER2-Meth could well distinguish HER2 IHC0/1+ from HER2 IHC3+ cases in both breast cancer (AUC = 0.983, n = 130) and gastric cancer (AUC = 0.974, n = 63), also could effectively discriminate HER2 IHC2+/FISH+ from HER2 IHC2+/FISH- cases in equivocal situations for both breast cancer (test set AUC = 0.879, n = 74; validation set AUC = 0.875, n = 75) and gastric cancer (test set AUC = 0.910, n = 70; validation set AUC = 0.941, n = 71), outperforming regular HER2 copy number test (An AUC of 0.793 for breast cancer and an AUC of 0.759 for gastric cancer) on HER2 IHC2+ cases. Furthermore, HER2-Meth demonstrated its potential for stratifying HER2-positive patients, enabling predictions regarding overall survivals, and the potential benefits of HER2-targeted therapies in breast cancer. The strong agreement observed between the methylation qPCR test and the results of IHC and FISH indicates significant potential for this approach as a complementary tool in guiding HER2-targeted therapies for patients with breast and gastric cancers.
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Affiliation(s)
- Yajie Hu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Siyu Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chunhui Cui
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xin Liu
- AnchorDx, Inc., Fremont, USA
| | - Hui Li
- AnchorDx Medical Co., Ltd., Guangzhou, China
| | - Hong Liu
- AnchorDx Medical Co., Ltd., Guangzhou, China
| | - Shiyao Lu
- AnchorDx Medical Co., Ltd., Guangzhou, China
| | - Zhipeng Lu
- AnchorDx Medical Co., Ltd., Guangzhou, China
| | - Zhiwei Chen
- AnchorDx, Inc., Fremont, USA
- AnchorDx Medical Co., Ltd., Guangzhou, China
| | - Da Pang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jian-Bing Fan
- AnchorDx Medical Co., Ltd., Guangzhou, China
- Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, China
| | - Dongmei Lin
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xianyu Zhang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yu Sun
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
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4
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El-Far M, Abdelrazek MA, Foda BM, Abouzid A, Swellam M. Potential Role of AKR1B1 Gene Methylation in Diagnosis of Patients With Breast Cancer. Clin Med Insights Oncol 2024; 18:11795549241290796. [PMID: 39445312 PMCID: PMC11497498 DOI: 10.1177/11795549241290796] [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: 05/29/2024] [Accepted: 09/22/2024] [Indexed: 10/25/2024] Open
Abstract
Background In addition to the great challenge of early diagnosis and prognosis in breast cancer (BC), the role of gene promoters in BC remains largely unexplored. This study aimed to evaluate aldo-keto reductase family 1 member B1 (AKR1B1) methylation as noninvasive biomarker for early BC diagnosis. Methods A total of 200 (120 with BC, 40 with benign breast diseases, 40 healthy) Egyptian women were enrolled. AKR1B1 methylation level was determined using EpiTect Methyl II QPCR assay quantitative polymerase chain reaction. Results Findings revealed that hypermethylation AKR1B1 was reported to be associated (P < .0001) with BC cases (93.2 [75.4-98.6]) compared with benign (23.9 [22.6-48.3]) or healthy (15.5 [10.6-16]) controls. It had a great diagnostic power (area under the curve [AUC] = 0.909) that was superior to cancer antigen (CA) 15-3 (AUC = 0.681) and carcinoembryonic antigen (CEA) (AUC = 0.539). Interestingly, AKR1B1 hypermethylation was reported to be significant in identifying BC early stages (AUC = 0.899) and grades (AUC = 0.903). Independent to hormonal status and HER2neu expression, AKR1B1 hypermethylation was related to some tumor severity features, including advanced stages, high histological grades, and lymph node invasion. Also, AKR1B1 high degrees of methylation were significantly correlated with the increase in CEA (r = .195; P = .027), CA-15.3 (r = .351; P = .0001) and tumor stages (r = .274; P = .014), grades (r = .253; P = .024), and lymph node invasion (r = .275; P = .014). Conclusions This study revealed that aberrant AKR1B1 methylation could facilitate early BC detection from benign br0east disorders. Hypermethylated AKR1B1 was related to BC aggressiveness suggesting its potential role as diagnostic and prognostic BC biomarker.
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Affiliation(s)
- Mohamed El-Far
- Biochemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Mohamed A Abdelrazek
- Research and Development Department, Biotechnology Research Center, New Damietta, Egypt
| | - Basma M Foda
- Biochemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Amr Abouzid
- Department of Surgical Oncology, Mansoura Oncology Centre, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Menha Swellam
- Biochemistry Department, Biotechnology Research Institute, High Throughput Molecular and Genetic Laboratory, Central Laboratories Network and the Centers of Excellence, National Research Centre, Giza, Egypt
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5
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Li C, Liu Y, Luo S, Yang M, Li L, Sun L. A review of CDKL: An underestimated protein kinase family. Int J Biol Macromol 2024; 277:133604. [PMID: 38964683 DOI: 10.1016/j.ijbiomac.2024.133604] [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: 06/25/2024] [Accepted: 06/30/2024] [Indexed: 07/06/2024]
Abstract
Cyclin-dependent kinase-like (CDKL) family proteins are serine/threonine protein kinases and is a specific branch of CMGC (including CDK, MAPK, GSK). Its name is due to the sequence similarity with CDK and it consists of 5 members. Their function in protein phosphorylation underpins their important role in cellular activities, including cell cycle, apoptosis, autophagy and microtubule dynamics. CDKL proteins have been demonstrated to regulate the length of primary cilium, which is a dynamic and diverse signaling hub and closely associated with multiple diseases. Furthermore, CDKL proteins have been shown to be involved in the development and progression of several diseases, including cancer, neurodegenerative diseases and kidney disease. In this review, we summarize the structural characteristics and discovered functions of CDKL proteins and their role in diseases, which might be helpful for the development of innovative therapeutic strategies for disease.
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Affiliation(s)
- Chenrui Li
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Yan Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Shilu Luo
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Li Li
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
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6
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Bashore F, Min SM, Chen X, Howell S, Rinderle CH, Morel G, Silvaroli JA, Wells CI, Bunnell BA, Drewry DH, Pabla NS, Ultanir SK, Bullock AN, Axtman AD. Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2. ACS Med Chem Lett 2024; 15:1325-1333. [PMID: 39140040 PMCID: PMC11318004 DOI: 10.1021/acsmedchemlett.4c00219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/20/2024] [Accepted: 06/24/2024] [Indexed: 08/15/2024] Open
Abstract
Acylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound 9 was selected as a CDKL2 chemical probe based on its potent inhibition of CDKL2 enzymatic activity, engagement of CDKL2 in cells, and excellent kinome-wide selectivity, especially when used in cells. Compound 16 was designed as a negative control to be used alongside compound 9 in experiments to interrogate CDKL2-mediated biology. A solved cocrystal structure of compound 9 bound to CDKL2 highlighted key interactions it makes within its ATP-binding site. Inhibition of downstream phosphorylation of EB2, a CDKL2 substrate, in rat primary neurons provided evidence that engagement of CDKL2 by compound 9 in cells resulted in inhibition of its activity. When used at relevant concentrations, compound 9 does not impact the viability of rat primary neurons or certain breast cancer cells nor elicit consistent changes in the expression of proteins involved in epithelial-mesenchymal transition.
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Affiliation(s)
- Frances
M. Bashore
- Structural
Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Sophia M. Min
- Structural
Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Xiangrong Chen
- Centre
for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, U.K.
| | - Stefanie Howell
- Structural
Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Caroline H. Rinderle
- Department
of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, Texas 76107, United States
| | - Gabriel Morel
- Kinases
and Brain Development Laboratory, The Francis
Crick Institute, London NW1 1AT, U.K.
| | - Josie A. Silvaroli
- Division
of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive
Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States
| | - Carrow I. Wells
- Structural
Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Bruce A. Bunnell
- Department
of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, Texas 76107, United States
| | - David H. Drewry
- Structural
Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- UNC
Lineberger
Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Navjot S. Pabla
- Division
of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive
Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States
| | - Sila K. Ultanir
- Kinases
and Brain Development Laboratory, The Francis
Crick Institute, London NW1 1AT, U.K.
| | - Alex N. Bullock
- Centre
for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, U.K.
| | - Alison D. Axtman
- Structural
Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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7
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Cheng X. A Comprehensive Review of HER2 in Cancer Biology and Therapeutics. Genes (Basel) 2024; 15:903. [PMID: 39062682 PMCID: PMC11275319 DOI: 10.3390/genes15070903] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 07/08/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Human epidermal growth factor receptor 2 (HER2), a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, plays a crucial role in cell proliferation, survival, and differentiation. Aberrant HER2 signaling is implicated in various cancers, particularly in breast and gastric cancers, where HER2 overexpression or amplification correlates with aggressive tumor behavior and poor prognosis. HER2-activating mutations contribute to accelerated tumorigenesis and metastasis. This review provides an overview of HER2 biology, signaling pathways, mechanisms of dysregulation, and diagnostic approaches, as well as therapeutic strategies targeting HER2 in cancer. Understanding the intricate details of HER2 regulation is essential for developing effective targeted therapies and improving patient outcomes.
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Affiliation(s)
- Xiaoqing Cheng
- Department of Oncology, School of Medicine, Washington University in Saint Louis, Saint Louis, MO 63108, USA
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8
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Bashore FM, Min SM, Chen X, Howell S, Rinderle CH, Morel G, Silvaroli JA, Wells CI, Bunnell BA, Drewry DH, Pabla NS, Ultanir SK, Bullock AN, Axtman AD. Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.12.593776. [PMID: 38798634 PMCID: PMC11118373 DOI: 10.1101/2024.05.12.593776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Acylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound 9 was selected as a CDKL2 chemical probe based on its potent inhibition of CDKL2 enzymatic activity, engagement of CDKL2 in cells, and excellent kinome-wide selectivity, especially when used in cells. Compound 16 was designed as a negative control to be used alongside compound 9 in experiments to interrogate CDKL2-mediated biology. A solved co-crystal structure of compound 9 bound to CDKL2 highlighted key interactions it makes within its ATP-binding site. Inhibition of downstream phosphorylation of EB2, a CDKL2 substrate, in rat primary neurons provided evidence that engagement of CDKL2 by compound 9 in cells resulted in inhibition of its activity. When used at relevant concentrations, compound 9 does not impact the viability of rat primary neurons or certain breast cancer cells nor elicit consistent changes in the expression of proteins involved in epithelial-mesenchymal transition.
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Affiliation(s)
- Frances M. Bashore
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Sophia M. Min
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Xiangrong Chen
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
| | - Stefanie Howell
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Caroline H. Rinderle
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Gabriel Morel
- Kinases and Brain Development Laboratory, The Francis Crick Institute, London, NW1 1AT, UK
| | - Josie A. Silvaroli
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, 43210, United States of America
| | - Carrow I. Wells
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Bruce A. Bunnell
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - David H. Drewry
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Navjot S. Pabla
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, 43210, United States of America
| | - Sila K. Ultanir
- Kinases and Brain Development Laboratory, The Francis Crick Institute, London, NW1 1AT, UK
| | - Alex N. Bullock
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
| | - Alison D. Axtman
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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9
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Ochoa S, Hernández-Lemus E. Molecular mechanisms of multi-omic regulation in breast cancer. Front Oncol 2023; 13:1148861. [PMID: 37564937 PMCID: PMC10411627 DOI: 10.3389/fonc.2023.1148861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 07/05/2023] [Indexed: 08/12/2023] Open
Abstract
Breast cancer is a complex disease that is influenced by the concurrent influence of multiple genetic and environmental factors. Recent advances in genomics and other high throughput biomolecular techniques (-omics) have provided numerous insights into the molecular mechanisms underlying breast cancer development and progression. A number of these mechanisms involve multiple layers of regulation. In this review, we summarize the current knowledge on the role of multiple omics in the regulation of breast cancer, including the effects of DNA methylation, non-coding RNA, and other epigenomic changes. We comment on how integrating such diverse mechanisms is envisioned as key to a more comprehensive understanding of breast carcinogenesis and cancer biology with relevance to prognostics, diagnostics and therapeutics. We also discuss the potential clinical implications of these findings and highlight areas for future research. Overall, our understanding of the molecular mechanisms of multi-omic regulation in breast cancer is rapidly increasing and has the potential to inform the development of novel therapeutic approaches for this disease.
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Affiliation(s)
- Soledad Ochoa
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico
- Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Enrique Hernández-Lemus
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico
- Center for Complexity Sciences, Universidad Nacional Autónoma de México, Mexico City, Mexico
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10
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Wang H, Penaloza T, Manea AJ, Gao X. PFKP: More than phosphofructokinase. Adv Cancer Res 2023; 160:1-15. [PMID: 37704285 PMCID: PMC12125951 DOI: 10.1016/bs.acr.2023.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2023]
Abstract
Phosphofructokinase (PFK) is one of the key enzymes that functions in glycolysis. Studies show that PFKP regulates cell proliferation, apoptosis, autophagy, cell migration/metastasis, and stemness through glycolysis and glycolysis-independent functions. PFKP performs its function not only in the cytoplasm, but also at the cell membrane, on the mitochondria, at the lysosomal membrane, and in the nucleus. The functions of PFKP are extensively studied in cancer cells. PFKP is also highly expressed in certain immune cells; nevertheless, the study of the PFKP's role in immune cells is limited. In this review, we summarize how the expression and activity of PFKP are regulated in cancer cells. PFKP may be applied as a prognostic marker due to its overexpression and significant functions in cancer cells. As such, specifically targeting/inhibiting PFKP may be a critical and promising strategy for cancer therapy.
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Affiliation(s)
- Haizhen Wang
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States.
| | - Tiffany Penaloza
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States
| | - Amanda J Manea
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States
| | - Xueliang Gao
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States.
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11
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Controlling the confounding effect of metabolic gene expression to identify actual metabolite targets in microsatellite instability cancers. Hum Genomics 2023; 17:18. [PMID: 36879264 PMCID: PMC9990231 DOI: 10.1186/s40246-023-00465-9] [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: 12/12/2022] [Accepted: 02/22/2023] [Indexed: 03/08/2023] Open
Abstract
BACKGROUND The metabolome is the best representation of cancer phenotypes. Gene expression can be considered a confounding covariate affecting metabolite levels. Data integration across metabolomics and genomics to establish the biological relevance of cancer metabolism is challenging. This study aimed to eliminate the confounding effect of metabolic gene expression to reflect actual metabolite levels in microsatellite instability (MSI) cancers. METHODS In this study, we propose a new strategy using covariate-adjusted tensor classification in high dimensions (CATCH) models to integrate metabolite and metabolic gene expression data to classify MSI and microsatellite stability (MSS) cancers. We used datasets from the Cancer Cell Line Encyclopedia (CCLE) phase II project and treated metabolomic data as tensor predictors and data on gene expression of metabolic enzymes as confounding covariates. RESULTS The CATCH model performed well, with high accuracy (0.82), sensitivity (0.66), specificity (0.88), precision (0.65), and F1 score (0.65). Seven metabolite features adjusted for metabolic gene expression, namely, 3-phosphoglycerate, 6-phosphogluconate, cholesterol ester, lysophosphatidylethanolamine (LPE), phosphatidylcholine, reduced glutathione, and sarcosine, were found in MSI cancers. Only one metabolite, Hippurate, was present in MSS cancers. The gene expression of phosphofructokinase 1 (PFKP), which is involved in the glycolytic pathway, was related to 3-phosphoglycerate. ALDH4A1 and GPT2 were associated with sarcosine. LPE was associated with the expression of CHPT1, which is involved in lipid metabolism. The glycolysis, nucleotide, glutamate, and lipid metabolic pathways were enriched in MSI cancers. CONCLUSIONS We propose an effective CATCH model for predicting MSI cancer status. By controlling the confounding effect of metabolic gene expression, we identified cancer metabolic biomarkers and therapeutic targets. In addition, we provided the possible biology and genetics of MSI cancer metabolism.
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12
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Manoochehri M, Borhani N, Gerhäuser C, Assenov Y, Schönung M, Hielscher T, Christensen BC, Lee MK, Gröne HJ, Lipka DB, Brüning T, Brauch H, Ko YD, Hamann U. DNA methylation biomarkers for noninvasive detection of triple-negative breast cancer using liquid biopsy. Int J Cancer 2023; 152:1025-1035. [PMID: 36305646 DOI: 10.1002/ijc.34337] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 09/06/2022] [Accepted: 09/20/2022] [Indexed: 01/06/2023]
Abstract
Noninvasive detection of aberrant DNA methylation could provide invaluable biomarkers for earlier detection of triple-negative breast cancer (TNBC) which could help clinicians with easier and more efficient treatment options. We evaluated genome-wide DNA methylation data derived from TNBC and normal breast tissues, peripheral blood of TNBC cases and controls and reference samples of sorted blood and mammary cells. Differentially methylated regions (DMRs) between TNBC and normal breast tissues were stringently selected, verified and externally validated. A machine-learning algorithm was applied to select the top DMRs, which then were evaluated on plasma-derived circulating cell-free DNA (cfDNA) samples of TNBC patients and healthy controls. We identified 23 DMRs accounting for the methylation profile of blood cells and reference mammary cells and then selected six top DMRs for cfDNA analysis. We quantified un-/methylated copies of these DMRs by droplet digital PCR analysis in a plasma test set from TNBC patients and healthy controls and confirmed our findings obtained on tissues. Differential cfDNA methylation was confirmed in an independent validation set of plasma samples. A methylation score combining signatures of the top three DMRs overlapping with the SPAG6, LINC10606 and TBCD/ZNF750 genes had the best capability to discriminate TNBC patients from controls (AUC = 0.78 in the test set and AUC = 0.74 in validation set). Our findings demonstrate the usefulness of cfDNA-based methylation signatures as noninvasive liquid biopsy markers for the diagnosis of TNBC.
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Affiliation(s)
- Mehdi Manoochehri
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of In Vitro Diagnostics, Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Stuttgart, Germany
| | - Nasim Borhani
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Clarissa Gerhäuser
- Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Yassen Assenov
- Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Maximilian Schönung
- Section Translational Cancer Epigenomics, Translational Medical Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,National Center for Tumor Diseases (NCT), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Thomas Hielscher
- Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Brock C Christensen
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, USA
| | - Min Kyung Lee
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, USA
| | | | - Daniel B Lipka
- Section Translational Cancer Epigenomics, Translational Medical Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Thomas Brüning
- Institute for Prevention & Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany
| | - Hiltrud Brauch
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,iFIT Cluster of Excellence, University of Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Tübingen, Germany
| | - Yon-Dschun Ko
- Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany
| | - Ute Hamann
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
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13
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Abdul Razzaq EA, Bajbouj K, Bouzid A, Alkhayyal N, Hamoudi R, Bendardaf R. Transcriptomic Changes Associated with ERBB2 Overexpression in Colorectal Cancer Implicate a Potential Role of the Wnt Signaling Pathway in Tumorigenesis. Cancers (Basel) 2022; 15:130. [PMID: 36612126 PMCID: PMC9817785 DOI: 10.3390/cancers15010130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/16/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
Colorectal cancer (CRC) remains the third most common cause of cancer mortality worldwide. Precision medicine using OMICs guided by transcriptomic profiling has improved disease diagnosis and prognosis by identifying many CRC targets. One such target that has been actively pursued is an erbb2 receptor tyrosine kinase 2 (ERBB2) (Human Epidermal Growth Factor Receptor 2 (HER2)), which is overexpressed in around 3-5% of patients with CRC worldwide. Despite targeted therapies against HER2 showing significant improvement in disease outcomes in multiple clinical trials, to date, no HER2-based treatment has been clinically approved for CRC. In this study we performed whole transcriptome ribonucleic acid (RNA) sequencing on 11 HER2+ and 3 HER2- CRC patients with advanced stages II, III and IV of the disease. In addition, transcriptomic profiling was carried out on CRC cell lines (HCT116 and HT29) and normal colon cell lines (CCD841 and CCD33), ectopically overexpressing ERBB2. Our analysis revealed transcriptomic changes involving many genes in both CRC cell lines overexpressing ERBB2 and in HER2+ patients, compared to normal colon cell lines and HER2- patients, respectively. Gene Set Enrichment Analysis indicated a role for HER2 in regulating CRC pathogenesis, with Wnt/β-catenin signaling being mediated via a HER2-dependent regulatory pathway impacting expression of the homeobox gene NK2 homeobox 5 (NKX2-5). Results from this study thus identified putative targets that are co-expressed with HER2 in CRC warranting further investigation into their role in CRC pathogenesis.
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Affiliation(s)
- Eman A. Abdul Razzaq
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
| | - Khuloud Bajbouj
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
| | - Amal Bouzid
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
| | - Noura Alkhayyal
- Oncology Unit, University Hospital Sharjah, Sharjah P.O. Box 72772, United Arab Emirates
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London WC1E 6BT, UK
| | - Riyad Bendardaf
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Oncology Unit, University Hospital Sharjah, Sharjah P.O. Box 72772, United Arab Emirates
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14
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Ansar M, Thu LTA, Hung CS, Su CM, Huang MH, Liao LM, Chung YM, Lin RK. Promoter hypomethylation and overexpression of TSTD1 mediate poor treatment response in breast cancer. Front Oncol 2022; 12:1004261. [PMID: 36419875 PMCID: PMC9676938 DOI: 10.3389/fonc.2022.1004261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/19/2022] [Indexed: 11/09/2022] Open
Abstract
Epigenetic alterations play a pivotal role in cancer treatment outcomes. Using the methylation array data and The Cancer Genome Atlas (TCGA) dataset, we observed the hypomethylation and upregulation of thiosulfate sulfurtransferase–like domain containing 1 (TSTD1) in patients with breast cancer. We examined paired tissues from Taiwanese patients and observed that 65.09% and 68.25% of patients exhibited TSTD1 hypomethylation and overexpression, respectively. A significant correlation was found between TSTD1 hypomethylation and overexpression in Taiwanese (74.2%, p = 0.040) and Western (88.0%, p < 0.001) cohorts. High expression of TSTD1 protein was observed in 68.8% of Taiwanese and Korean breast cancer patients. Overexpression of TSTD1 in tumors of breast cancer patients was significantly associated with poor 5-year overall survival (p = 0.021) and poor chemotherapy response (p = 0.008). T47D cells treated with TSTD1 siRNA exhibited lower proliferation than the control group, and transfection of TSTD1 in MDA-MB-231 induced the growth of MDA-MB-231 cells compared to the vector control. Additionally, overexpression of TSTD1 in MCF7 cells mediated a poor response to chemotherapy by epirubicin (p < 0.001) and docetaxel (p < 0.001) and hormone therapy by tamoxifen (p =0.025). Circulating cell-free hypomethylated TSTD1 was detected in plasma of Taiwanese breast cancer patients with disease progression and poor chemotherapy efficacy. Our results indicate that promoter hypomethylation and overexpression of TSTD1 in patients with breast cancer are potential biomarkers for poor 5-year overall survival and poor treatment response.
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Affiliation(s)
- Muhamad Ansar
- Ph.D Program in the Clinical Drug Development of Herbal Medicine, Taipei Medical University, Taipei, Taiwan
| | - Le Thi Anh Thu
- Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Quang Tri Medical College, Dong Ha, Quang Tri, Vietnam
| | - Chin-Sheng Hung
- Division of Breast Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Chih-Ming Su
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Man-Hsu Huang
- Department of Pathology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Li-Min Liao
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Yu-Mei Chung
- Master Program in Clinical Genomics and Proteomics; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Ruo-Kai Lin
- Ph.D Program in the Clinical Drug Development of Herbal Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Master Program in Clinical Genomics and Proteomics; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Clinical Trial Center, Taipei Medical University Hospital, Taipei, Taiwan
- *Correspondence: Ruo-Kai Lin,
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15
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Huang L, Liu X, Li L, Wang L, Wu N, Liu Z. Novel immune subtypes identification of HER2-positive breast cancer based on immunogenomic landscape. Med Oncol 2022; 39:92. [PMID: 35568771 DOI: 10.1007/s12032-022-01690-3] [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: 11/17/2021] [Accepted: 02/21/2022] [Indexed: 11/28/2022]
Abstract
HER2 positive BC is heterogeneous. But few studies discussed the classification of HER2-positive BC based on immune-related signatures. Using three publicly BC genomics datasets, we classified HER2 positive BC based on 33 immune-related signatures and used unsupervised machine learning methods to predict and perform the classification. We grouped three HER2-positive BC subtypes that we called Immune-High (IM-H), Immune-Medium (IM-M), and Immune-Low (IM-L), and manifested this categorization was predictable, duplicable and reliable by analyzing another dataset. Compared to other subtypes, IM-H had a higher immune cell infiltration level and stronger anti-tumor immune activities, as well as better clinical survival outcome. Besides these signatures, there were some cancer-related pathways which were hyperactivated in IM-H, including cytokine-cytokine receptor interactions, antigen processing and presentation pathways, natural killer cell-mediated cytotoxicity, Th1 and Th2 cell differentiation, chemokine signaling pathway, Th17 cell differentiation, B and T cell receptor signaling, NF-kappa B signaling, PD-L1 expression and PD-1 checkpoint pathway in cancer, TNF signaling, IL-17 signaling, NOD-like receptor signaling and Toll-like receptor signaling. By contrast, IM-L showed depressed immune-related signatures and enhanced activation of lycosylphosphatidylinositol-anchor biosynthesis and mismatch repair. Moreover, we discovered a gene co-expression network focused on eight transcription factor genes (EOMES, TBX21, GFI1, IRF4, POU2AF1, CIITA, FOXP3 and TOX) and one tumor suppress gene (PRF1), which were closely related with tumor immune. We identified three HER2-positive BC subtypes based on immune-related signatures, which had potential clinical implications and promoted the optimal stratification of HER2-positive BC responsive to immunotherapy.
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Affiliation(s)
- Lingli Huang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
| | - Xin Liu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
| | - Li Li
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
| | - Lei Wang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
| | - Nan Wu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
| | - Zhixian Liu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
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16
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Chen Z, Lv Y, He L, Wu S, Wu Z. Decreased CDKL2 Expression in Clear Cell Renal Cell Carcinoma Predicts Worse Overall Survival. Front Mol Biosci 2022; 8:657672. [PMID: 35096961 PMCID: PMC8793634 DOI: 10.3389/fmolb.2021.657672] [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: 07/27/2021] [Accepted: 12/24/2021] [Indexed: 11/26/2022] Open
Abstract
Background: Clear cell renal cell carcinoma (ccRCC) is the most frequent and lethal type of kidney cancer. Although differential expression of cyclin-dependent kinase-like 2 (CDKL2) has been reported to be associated with tumor progression in other cancers, its prognostic value, and potential mechanism in patients with ccRCC still remain unknown. Methods: Gene expression analysis was conducted using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus, and International Cancer Genome Consortium databases. Further, clinicopathologic analysis; Kaplan–Meier survival analysis; weighted gene co-expression network analysis; gene set enrichment analysis; gene ontology enrichment; methylation; and immune infiltration analyses were performed using TCGA-kidney renal clear cell carcinoma profiles. CDKL2 translational levels were analyzed using The Human Protein Atlas database. Results:CDKL2 expression was decreased in ccRCC samples retrieved from the four databases. Gender, survival status, histologic grade, clinical stage, TNM classification, and tumor status were closely related to CDKL2 expression. In addition, CDKL2 downregulation was an independent prognostic factor for poor prognosis in multivariate analysis. Enrichment analyses using multiple tests revealed that CDKL2 is not just closely related to immune response but this association is highly correlated as well. Further, we found that CDKL2 expression was significantly correlated with the infiltration levels of T cell CD4 memory resting; monocytes; macrophages M0, M1, and M2; dendritic cells resting; mast cells resting; plasma cells; T cell CD8; and T cell regulatory. Conclusion: This is the first report to study the expression of CDKL2 in ccRCC, wherein we suggest that decreased CDKL2 expression is closely correlated with poor prognosis in ccRCC. We consider that CDKL2 is a novel and potential prognostic biomarker associated with immune infiltrates in ccRCC.
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17
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Pereira Zambalde E, Bayraktar R, Schultz Jucoski T, Ivan C, Rodrigues AC, Mathias C, knutsen E, Silveira de Lima R, Fiori Gradia D, de Souza Fonseca Ribeiro EM, Hannash S, Adrian Calin G, Carvalhode Oliveira J. A novel lncRNA derived from an ultraconserved region: lnc- uc.147, a potential biomarker in luminal A breast cancer. RNA Biol 2021; 18:416-429. [PMID: 34387142 PMCID: PMC8677017 DOI: 10.1080/15476286.2021.1952757] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 06/02/2021] [Accepted: 07/04/2021] [Indexed: 02/06/2023] Open
Abstract
The human genome contains 481 ultraconserved regions (UCRs), which are genomic stretches of over 200 base pairs conserved among human, rat, and mouse. The majority of these regions are transcriptionally active (T-UCRs), and several have been found to be differentially expressed in tumours. Some T-UCRs have been functionally characterized, but of those few have been associated to breast cancer (BC). Using TCGA data, we found 302 T-UCRs related to clinical features in BC: 43% were associated with molecular subtypes, 36% with oestrogen-receptor positivity, 17% with HER2 expression, 12% with stage, and 10% with overall survival. The expression levels of 12 T-UCRs were further analysed in a cohort of 82 Brazilian BC patients using RT-qPCR. We found that uc.147 is high expressed in luminal A and B patients. For luminal A, a subtype usually associated with better prognosis, high uc.147 expression was associated with a poor prognosis and suggested as an independent prognostic factor. The lncRNA from uc.147 (lnc-uc.147) is located in the nucleus. Northern blotting results show that uc.147 is a 2,8 kb monoexonic trancript, and its sequence was confirmed by RACE. The silencing of uc.147 increases apoptosis, arrests cell cycle, and reduces cell viability and colony formation in BC cell lines. Additionally, we identifed 19 proteins that interact with lnc-uc.147 through mass spectrometry and demonstrated a high correlation of lnc-uc.147 with the neighbour gene expression and miR-18 and miR-190b. This is the first study to analyse the expression of all T-UCRs in BC and to functionally assess the lnc-uc.147.
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Affiliation(s)
- Erika Pereira Zambalde
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
- Department of Experimental Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - Recep Bayraktar
- Department of Experimental Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - Tayana Schultz Jucoski
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
| | - Cristina Ivan
- Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ana Carolina Rodrigues
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
| | - Carolina Mathias
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
| | - Erik knutsen
- Department of Experimental Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
- Department of Medical Biology, Faculty of Health Sciences, UiT - the Arctic University of Norway, Tromsø, Norway
| | | | - Daniela Fiori Gradia
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
| | | | - Samir Hannash
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - George Adrian Calin
- Department of Experimental Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
- Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaqueline Carvalhode Oliveira
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
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18
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Meurer L, Ferdman L, Belcher B, Camarata T. The SIX Family of Transcription Factors: Common Themes Integrating Developmental and Cancer Biology. Front Cell Dev Biol 2021; 9:707854. [PMID: 34490256 PMCID: PMC8417317 DOI: 10.3389/fcell.2021.707854] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 06/28/2021] [Indexed: 01/19/2023] Open
Abstract
The sine oculis (SIX) family of transcription factors are key regulators of developmental processes during embryogenesis. Members of this family control gene expression to promote self-renewal of progenitor cell populations and govern mechanisms of cell differentiation. When the function of SIX genes becomes disrupted, distinct congenital defects develops both in animal models and humans. In addition to the embryonic setting, members of the SIX family have been found to be critical regulators of tumorigenesis, promoting cell proliferation, epithelial-to-mesenchymal transition, and metastasis. Research in both the fields of developmental biology and cancer research have provided an extensive understanding of SIX family transcription factor functions. Here we review recent progress in elucidating the role of SIX family genes in congenital disease as well as in the promotion of cancer. Common themes arise when comparing SIX transcription factor function during embryonic and cancer development. We highlight the complementary nature of these two fields and how knowledge in one area can open new aspects of experimentation in the other.
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Affiliation(s)
- Logan Meurer
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
| | - Leonard Ferdman
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
| | - Beau Belcher
- Department of Biological Sciences, Arkansas State University, Jonesboro, AR, United States
| | - Troy Camarata
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
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Zhang X, Wang Y, Zhao S, Qin Q, Zhang M, Jiang Y, Zhu H, Li H. Low expression of developing brain homeobox 2 (Dbx2) may serve as a biomarker to predict poor prognosis in endometrial cancer. Am J Transl Res 2021; 13:4738-4748. [PMID: 34150054 PMCID: PMC8205784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 02/02/2021] [Indexed: 06/12/2023]
Abstract
OBJECTIVE For investigating Dbx2's expression in endometrial cancer (EC) and its effect on prognosis of patients with EC. METHODS A comparison was performed in the Cancer Genome Atlas (TCGA) database in terms of the expression profiling of EC and the survival data. To obtain differential expression genes (DEGs), Volcano plot and Venn analysis were adopted. DEGs function was performed by carrying out the GO annotation analysis (GO) and gene set enrichment analysis (GSEA). In clinical EC samples, PCR was applied to the verification of Dbx2's expression. RESULTS Dbx2 was a downregulated expression in tumor tissues. Dbx2 can have a poor prognosis role in EC by regulating the apoptotic signaling pathway and the immune pathway. Lower expression of Dbx2 was related to lymph node metastasis and FIGO stage. CONCLUSION Dbx2 is downregulated in endometrial cancer, which serves as a biomarker to predict poor prognosis.
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Affiliation(s)
- Xinlu Zhang
- Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, P. R. China
| | - Yaping Wang
- Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, P. R. China
| | - Shujun Zhao
- Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, P. R. China
- Zhengzhou Key Laboratory of Gynecological Oncology, The Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, P. R. China
| | - Qiaohong Qin
- Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, P. R. China
- Zhengzhou Key Laboratory of Gynecological Oncology, The Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, P. R. China
| | - Min Zhang
- Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, P. R. China
| | - Yi Jiang
- Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, P. R. China
| | - Hai Zhu
- Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, P. R. China
| | - Hongyu Li
- Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, P. R. China
- Zhengzhou Key Laboratory of Gynecological Oncology, The Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, P. R. China
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20
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Li JJ, Chen YE, Tong X. A flexible model-free prediction-based framework for feature ranking. JOURNAL OF MACHINE LEARNING RESEARCH : JMLR 2021; 22:124. [PMID: 35321091 PMCID: PMC8939838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Despite the availability of numerous statistical and machine learning tools for joint feature modeling, many scientists investigate features marginally, i.e., one feature at a time. This is partly due to training and convention but also roots in scientists' strong interests in simple visualization and interpretability. As such, marginal feature ranking for some predictive tasks, e.g., prediction of cancer driver genes, is widely practiced in the process of scientific discoveries. In this work, we focus on marginal ranking for binary classification, one of the most common predictive tasks. We argue that the most widely used marginal ranking criteria, including the Pearson correlation, the two-sample t test, and two-sample Wilcoxon rank-sum test, do not fully take feature distributions and prediction objectives into account. To address this gap in practice, we propose two ranking criteria corresponding to two prediction objectives: the classical criterion (CC) and the Neyman-Pearson criterion (NPC), both of which use model-free nonparametric implementations to accommodate diverse feature distributions. Theoretically, we show that under regularity conditions, both criteria achieve sample-level ranking that is consistent with their population-level counterpart with high probability. Moreover, NPC is robust to sampling bias when the two class proportions in a sample deviate from those in the population. This property endows NPC good potential in biomedical research where sampling biases are ubiquitous. We demonstrate the use and relative advantages of CC and NPC in simulation and real data studies. Our model-free objective-based ranking idea is extendable to ranking feature subsets and generalizable to other prediction tasks and learning objectives.
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Affiliation(s)
| | | | - Xin Tong
- Department of Data Sciences and Operations, Marshall Business School, University of Southern California
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21
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Wang SC, Liao LM, Ansar M, Lin SY, Hsu WW, Su CM, Chung YM, Liu CC, Hung CS, Lin RK. Automatic Detection of the Circulating Cell-Free Methylated DNA Pattern of GCM2, ITPRIPL1 and CCDC181 for Detection of Early Breast Cancer and Surgical Treatment Response. Cancers (Basel) 2021; 13:cancers13061375. [PMID: 33803633 PMCID: PMC8002961 DOI: 10.3390/cancers13061375] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/12/2021] [Accepted: 03/16/2021] [Indexed: 12/31/2022] Open
Abstract
The early detection of cancer can reduce cancer-related mortality. There is no clinically useful noninvasive biomarker for early detection of breast cancer. The aim of this study was to develop accurate and precise early detection biomarkers and a dynamic monitoring system following treatment. We analyzed a genome-wide methylation array in Taiwanese and The Cancer Genome Atlas (TCGA) breast cancer (BC) patients. Most breast cancer-specific circulating methylated CCDC181, GCM2 and ITPRIPL1 biomarkers were found in the plasma. An automatic analysis process of methylated ccfDNA was established. A combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was performed in R using Recursive Partitioning and Regression Trees to establish a new prediction model. Combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was found to have a sensitivity level of 97% and an area under the curve (AUC) of 0.955 in the training set, and a sensitivity level of 100% and an AUC of 0.961 in the test set. The circulating methylated CCDC181, GCM2 and ITPRIPL1 was also significantly decreased after surgery (all p < 0.001). The aberrant methylation patterns of the CCDC181, GCM2 and ITPRIPL1 genes means that they are potential biomarkers for the detection of early BC and can be combined with breast imaging data to achieve higher accuracy, sensitivity and specificity, facilitating breast cancer detection. They may also be applied to monitor the surgical treatment response.
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Affiliation(s)
- Sheng-Chao Wang
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, No. 250, Wuxing Street, Taipei 110, Taiwan;
| | - Li-Min Liao
- Division of General Surgery, Department of Surgery, Taipei Medical University Shuang Ho Hospital, No.291, Zhongzheng Rd., Zhonghe District, New Taipei City 23561, Taiwan; (L.-M.L.); (C.-M.S.)
| | - Muhamad Ansar
- Ph.D. Program in the Clinical Drug Development of Herbal Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan;
| | - Shih-Yun Lin
- Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan;
| | - Wei-Wen Hsu
- Department of Statistics, College of Arts and Sciences, Kansas State University, 101 Dickens Hall, 1116 Mid-Campus Drive N, Manhattan, KS 66506-0802, USA;
| | - Chih-Ming Su
- Division of General Surgery, Department of Surgery, Taipei Medical University Shuang Ho Hospital, No.291, Zhongzheng Rd., Zhonghe District, New Taipei City 23561, Taiwan; (L.-M.L.); (C.-M.S.)
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wuxing Street, Taipei 110, Taiwan
| | - Yu-Mei Chung
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan;
| | - Cai-Cing Liu
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan;
| | - Chin-Sheng Hung
- Division of General Surgery, Department of Surgery, Taipei Medical University Shuang Ho Hospital, No.291, Zhongzheng Rd., Zhonghe District, New Taipei City 23561, Taiwan; (L.-M.L.); (C.-M.S.)
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wuxing Street, Taipei 110, Taiwan
- Correspondence: (C.-S.H.); (R.-K.L.); Tel.: +886-970-405-127 (C.-S.H.); +886-2-2736-1661 (ext. 6162) (R.-K.L.)
| | - Ruo-Kai Lin
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, No. 250, Wuxing Street, Taipei 110, Taiwan;
- Ph.D. Program in the Clinical Drug Development of Herbal Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan;
- Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan;
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan;
- Clinical trial center, Taipei Medical University Hospital, 252 Wu-Hsing Street, Taipei 110, Taiwan
- Correspondence: (C.-S.H.); (R.-K.L.); Tel.: +886-970-405-127 (C.-S.H.); +886-2-2736-1661 (ext. 6162) (R.-K.L.)
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22
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Ochoa S, de Anda-Jáuregui G, Hernández-Lemus E. An Information Theoretical Multilayer Network Approach to Breast Cancer Transcriptional Regulation. Front Genet 2021; 12:617512. [PMID: 33815463 PMCID: PMC8014033 DOI: 10.3389/fgene.2021.617512] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 02/05/2021] [Indexed: 12/13/2022] Open
Abstract
Breast cancer is a complex, highly heterogeneous disease at multiple levels ranging from its genetic origins and molecular processes to clinical manifestations. This heterogeneity has given rise to the so-called intrinsic or molecular breast cancer subtypes. Aside from classification, these subtypes have set a basis for differential prognosis and treatment. Multiple regulatory mechanisms-involving a variety of biomolecular entities-suffer from alterations leading to the diseased phenotypes. Information theoretical approaches have been found to be useful in the description of these complex regulatory programs. In this work, we identified the interactions occurring between three main mechanisms of regulation of the gene expression program: transcription factor regulation, regulation via noncoding RNA, and epigenetic regulation through DNA methylation. Using data from The Cancer Genome Atlas, we inferred probabilistic multilayer networks, identifying key regulatory circuits able to (partially) explain the alterations that lead from a healthy phenotype to different manifestations of breast cancer, as captured by its molecular subtype classification. We also found some general trends in the topology of the multi-omic regulatory networks: Tumor subtype networks present longer shortest paths than their normal tissue counterpart; epigenomic regulation has frequently focused on genes enriched for certain biological processes; CpG methylation and miRNA interactions are often part of a regulatory core of conserved interactions. The use of probabilistic measures to infer information regarding theoretical-derived multilayer networks based on multi-omic high-throughput data is hence presented as a useful methodological approach to capture some of the molecular heterogeneity behind regulatory phenomena in breast cancer, and potentially other diseases.
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Affiliation(s)
- Soledad Ochoa
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Guillermo de Anda-Jáuregui
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico.,Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico.,Conacyt Research Chairs, National Council on Science and Technology, Mexico City, Mexico
| | - Enrique Hernández-Lemus
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico.,Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico
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23
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Guo Y, Mao X, Qiao Z, Chen B, Jin F. A Novel Promoter CpG-Based Signature for Long-Term Survival Prediction of Breast Cancer Patients. Front Oncol 2020; 10:579692. [PMID: 33194705 PMCID: PMC7606941 DOI: 10.3389/fonc.2020.579692] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/08/2020] [Indexed: 11/20/2022] Open
Abstract
DNA methylation has been reported as one of the most critical epigenetic aberrations during the tumorigenesis and development of breast cancer (BC). This study explored a novel promoter CpG-based signature for long-term survival prediction of BC patients. We used The Cancer Genome Atlas (TCGA) data as training set, and results were validated in an independent dataset from Gene Expression Omnibus (GEO). First, the differential methylation CpG sites were screened in TCGA dataset, of which the candidate promoter CpG sites were preliminarily identified with the univariate Cox regression analysis and the least absolute shrinkage and selection operator regression analysis. Second, the signature was constructed with stepwise regression analysis and multivariate Cox proportional hazards model, which was validated with the survival analysis of two cohorts each from TCGA and GEO databases. The 10-year receiver operating characteristic curves of risk score presented an area under the curve of over 0.7 for both cohorts. A nomogram was also constructed and released. Moreover, Gene Set Enrichment Analysis was performed to identify the more active pathways in high-risk patients. The CpG sites-target gene correlations and differential methylation regions were further explored. In conclusion, the promoter CpG-based signature exhibited good prognostic prediction efficacy in the long-term overall survival of BC patients.
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Affiliation(s)
| | - Xiaoyun Mao
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
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24
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Vernier M, McGuirk S, Dufour CR, Wan L, Audet-Walsh E, St-Pierre J, Giguère V. Inhibition of DNMT1 and ERRα crosstalk suppresses breast cancer via derepression of IRF4. Oncogene 2020; 39:6406-6420. [PMID: 32855526 PMCID: PMC7544553 DOI: 10.1038/s41388-020-01438-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/10/2020] [Accepted: 08/17/2020] [Indexed: 12/15/2022]
Abstract
DNA methylation is implicated in the acquisition of malignant phenotypes, and the use of epigenetic modulating drugs is a promising anti-cancer therapeutic strategy. 5-aza-2'deoxycytidine (decitabine, 5-azadC) is an FDA-approved DNA methyltransferase (DNMT) inhibitor with proven effectiveness against hematological malignancies and more recently triple-negative breast cancer (BC). Herein, genetic or pharmacological studies uncovered a hitherto unknown feedforward molecular link between DNMT1 and the estrogen related receptor α (ERRα), a key transcriptional regulator of cellular metabolism. Mechanistically, DNMT1 promotes ERRα stability which in turn couples DNMT1 transcription with that of the methionine cycle and S-adenosylmethionine synthesis to drive DNA methylation. In vitro and in vivo investigation using a pre-clinical mouse model of BC demonstrated a clear therapeutic advantage for combined administration of the ERRα inhibitor C29 with 5-azadC. A large-scale bisulfite genomic sequencing analysis revealed specific methylation perturbations fostering the discovery that reversal of promoter hypermethylation and consequently derepression of the tumor suppressor gene, IRF4, is a factor underlying the observed BC suppressive effects. This work thus uncovers a critical role of ERRα in the crosstalk between transcriptional control of metabolism and epigenetics and illustrates the potential for targeting ERRα in combination with DNMT inhibitors for BC treatment and other epigenetics-driven malignancies.
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Affiliation(s)
- Mathieu Vernier
- Goodman Cancer Research Centre, McGill University, Montréal, H3A 1A3, QC, Canada.
| | - Shawn McGuirk
- Goodman Cancer Research Centre, McGill University, Montréal, H3A 1A3, QC, Canada
| | - Catherine R Dufour
- Goodman Cancer Research Centre, McGill University, Montréal, H3A 1A3, QC, Canada
| | - Liangxinyi Wan
- Goodman Cancer Research Centre, McGill University, Montréal, H3A 1A3, QC, Canada
| | - Etienne Audet-Walsh
- Goodman Cancer Research Centre, McGill University, Montréal, H3A 1A3, QC, Canada
- Département de Médecine Moléculaire, Faculté de Médicine, Centre de Recherche du CHU de Québec, Université Laval, Québec, QC, G1V 4G2, Canada
| | - Julie St-Pierre
- Goodman Cancer Research Centre, McGill University, Montréal, H3A 1A3, QC, Canada
- Departments of Biochemistry, Medicine and Oncology, Faculty of Medicine, McGill University, Montréal, H3G 1Y6, QC, Canada
- Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada
| | - Vincent Giguère
- Goodman Cancer Research Centre, McGill University, Montréal, H3A 1A3, QC, Canada.
- Departments of Biochemistry, Medicine and Oncology, Faculty of Medicine, McGill University, Montréal, H3G 1Y6, QC, Canada.
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25
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Wu D, Jia HY, Wei N, Li SJ. POU4F1 confers trastuzumab resistance in HER2-positive breast cancer through regulating ERK1/2 signaling pathway. Biochem Biophys Res Commun 2020; 533:533-539. [PMID: 32988584 DOI: 10.1016/j.bbrc.2020.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 09/02/2020] [Indexed: 12/11/2022]
Abstract
Over-expression of the human epidermal growth factor receptor-2 (HER2) is related to aggressive tumors and poor prognosis in breast cancer. Trastuzumab (TRA) resistance leads to tumor recurrence and metastasis, resulting in poor prognosis in HER2-positive breast cancer. POU Class 4 Homeobox 1 (POU4F1) is a member of the POU domain family transcription factors, and has a key role in regulating cancers. However, its effects on TRA-resistant HER2-positive breast cancer are still vague. In the present study, we found that POU4F1 expression was dramatically increased in clinical breast cancer specimens with TRA resistance. Higher POU4F1 was also detected in HER2-positive breast cancer cells with TRA resistance than that of the parental ones. Poor prognosis was detected in breast cancer patients with high POU4F1 expression. Under TRA treatment, POU4F1 knockdown significantly reduced the proliferative capacity of HER2-positive breast cancer cells with TRA resistance. POU4F1 silence also sensitized resistant HER-positive breast cancer cells to TRA treatment in vivo using a xenograft mouse model, along with the markedly reduced tumor growth rate and tumor weight. Moreover, we found that POU4F1 deletion greatly decreased the activation of mitogen-activated or extracellular signal-regulated protein kinase kinases 1 and 2 (MEK1/2) and extracellular-regulated kinase 1/2 (ERK1/2) signaling pathways in breast cancer cells with TRA resistance. Migration and invasion were also effectively hindered by POU4F1 knockdown in TRA-resistant HER2-positive breast cancer cells. Notably, we found that POU4F1 deletion-improved chemosensitivity of HER2-positive breast cancer cells with drug-resistance to TRA treatment was closely associated with the blockage of ERK1/2 signaling. Collectively, our findings reported a critical role of POU4F1 in regulating TRA resistance, and demonstrated the underlying molecular mechanisms in HER2-positive breast cancer. Thus, POU4F1 may be a promising prognostic and therapeutic target to develop effective treatment for overcoming TRA resistance.
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Affiliation(s)
- Di Wu
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China
| | - Hong-Yao Jia
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China
| | - Na Wei
- The First Operating Room, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China
| | - Si-Jie Li
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China.
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26
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Khayami R, Hashemi SR, Kerachian MA. Role of aldo-keto reductase family 1 member B1 (AKR1B1) in the cancer process and its therapeutic potential. J Cell Mol Med 2020; 24:8890-8902. [PMID: 32633024 PMCID: PMC7417692 DOI: 10.1111/jcmm.15581] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/21/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
The role of aldo‐keto reductase family 1 member B1 (AKR1B1) in cancer is not totally clear but growing evidence is suggesting to have a great impact on cancer progression. AKR1B1 could participate in a complicated network of signalling pathways, proteins and miRNAs such as mir‐21 mediating mechanisms like inflammatory responses, cell cycle, epithelial to mesenchymal transition, cell survival and apoptosis. AKR1B1 has been shown to be mostly overexpressed in cancer. This overexpression has been associated with inflammatory mediators including nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB), cell cycle mediators such as cyclins and cyclin‐dependent kinases (CDKs), survival proteins and pathways like mammalian target of rapamycin (mTOR) and protein kinase B (PKB) or AKT, and other regulatory factors in response to reactive oxygen species (ROS) and prostaglandin synthesis. In addition, inhibition of AKR1B1 has been shown to mostly have anti‐cancer effects. Several studies have also suggested that AKR1B1 inhibition as an adjuvant therapy could render tumour cells more sensitive to anti‐cancer therapy or alleviate the adverse effects of therapy. AKR1B1 could also be considered as a potential cancer diagnostic biomarker since its promoter has shown high levels of methylation. Although pre‐clinical investigations on the role of AKR1B1 in cancer and the application of its inhibitors have shown promising results, the lack of clinical studies on AKR1B1 inhibitors has hampered the use of these drugs to treat cancer. Thus, there is a need to conduct more clinical studies on the application of AKR1B1 inhibitors as adjuvant therapy on different cancers.
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Affiliation(s)
- Reza Khayami
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyyed Reza Hashemi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Amin Kerachian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Genetics Research Unit, Reza Radiotherapy and Oncology Center, Mashhad, Iran
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27
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DiNardo AR, Rajapakshe K, Nishiguchi T, Grimm SL, Mtetwa G, Dlamini Q, Kahari J, Mahapatra S, Kay A, Maphalala G, Mace EM, Makedonas G, Cirillo JD, Netea MG, van Crevel R, Coarfa C, Mandalakas AM. DNA hypermethylation during tuberculosis dampens host immune responsiveness. J Clin Invest 2020; 130:3113-3123. [PMID: 32125282 PMCID: PMC7260034 DOI: 10.1172/jci134622] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 02/27/2020] [Indexed: 12/21/2022] Open
Abstract
Mycobacterium tuberculosis (M. tuberculosis) has coevolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to improve outcomes and potentially shorten existing therapy will require identification of the full complement by which host immunity is inhibited. Perturbation of host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, lymphocytic choriomeningitis virus (LCMV), and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of patients with tuberculosis (TB) and their asymptomatic household contacts and found that the patients with TB have DNA hypermethylation of the IL-2/STAT5, TNF/NF-κB, and IFN-γ signaling pathways. We performed methylation-sensitive restriction enzyme-quantitative PCR (MSRE-qPCR) and observed that multiple genes of the IL-12/IFN-γ signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1, and JAK2) were hypermethylated in patients with TB. The DNA hypermethylation of these pathways was associated with decreased immune responsiveness with decreased mitogen-induced upregulation of IFN-γ, TNF, IL-6, CXCL9, CXCL10, and IL-1β production. The DNA hypermethylation of the IL-12/IFN-γ pathway was associated with decreased IFN-γ-induced gene expression and decreased IL-12-inducible upregulation of IFN-γ. This study demonstrates that immune cells from patients with TB are characterized by DNA hypermethylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and nonspecific immune responsiveness.
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Affiliation(s)
- Andrew R. DiNardo
- Global Tuberculosis Program, Texas Children’s Hospital, Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Kimal Rajapakshe
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Tomoki Nishiguchi
- Global Tuberculosis Program, Texas Children’s Hospital, Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Sandra L. Grimm
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Godwin Mtetwa
- Baylor-Swaziland Children’s Foundation, Mbabane, Swaziland
| | - Qiniso Dlamini
- Baylor-Swaziland Children’s Foundation, Mbabane, Swaziland
| | | | - Sanjana Mahapatra
- Global Tuberculosis Program, Texas Children’s Hospital, Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Alexander Kay
- Baylor-Swaziland Children’s Foundation, Mbabane, Swaziland
| | | | - Emily M. Mace
- Department of Pediatrics, Columbia University Medical Center, New York, New York, USA
| | | | - Jeffrey D. Cirillo
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, Texas, USA
| | - Mihai G. Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
| | - Reinout van Crevel
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
| | - Cristian Coarfa
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Anna M. Mandalakas
- Global Tuberculosis Program, Texas Children’s Hospital, Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
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28
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Stastny I, Zubor P, Kajo K, Kubatka P, Golubnitschaja O, Dankova Z. Aberrantly Methylated cfDNA in Body Fluids as a Promising Diagnostic Tool for Early Detection of Breast Cancer. Clin Breast Cancer 2020; 20:e711-e722. [PMID: 32792225 DOI: 10.1016/j.clbc.2020.05.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/29/2020] [Accepted: 05/11/2020] [Indexed: 12/24/2022]
Abstract
Breast malignancies are the leading type of cancer among women. Its prevention and early detection, particularly in young women, remains challenging. To this end, cell-free DNA (cfDNA) detected in body fluids demonstrates great potential for early detection of tissue transformation and altered molecular setup, such as epigenetic profiles. Aberrantly methylated cfDNA in body fluids could therefore serve as a potential diagnostic and prognostic tool in breast cancer management. Abnormal methylation may lead to both an activation of oncogenes via hypomethylation and an inactivation of tumor suppressor genes by hypermethylation. We update the state of the art in the area of aberrant cfDNA methylation analyses as a diagnostic and prognostic tool in breast cancer, report on the main technological challenges, and provide an outlook for advancing the overall management of breast malignancies based on cfDNA as a target for diagnosis and tailored therapies.
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Affiliation(s)
- Igor Stastny
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic; Department of Obstetrics and Gynaecology, Martin University Hospital and Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic.
| | - Pavol Zubor
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic; Department of Gynecologic Oncology, The Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway
| | - Karol Kajo
- Department of Pathology, St Elizabeth Cancer Institute Hospital, Bratislava, Slovak Republic; Biomedical Research Centre, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Peter Kubatka
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic; Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovak Republic
| | - Olga Golubnitschaja
- Radiological Hospital, Rheinische, Excellence University of Bonn, Bonn, Germany; Breast Cancer Research Centre, Rheinische, Excellence University of Bonn, Bonn, Germany; Centre for Integrated Oncology, Cologne-Bonn, Excellence University of Bonn, Bonn, Germany
| | - Zuzana Dankova
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic
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29
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Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and Its Relation to Epigenomic Subtypes and HER2 Overexpression. Biomedicines 2020; 8:biomedicines8050116. [PMID: 32397602 PMCID: PMC7277193 DOI: 10.3390/biomedicines8050116] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/06/2020] [Accepted: 05/08/2020] [Indexed: 01/09/2023] Open
Abstract
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) substantially contribute to the regulation of intercellular interactions and thereby play a role in maintaining the tissue structure and function. We examined methylation of a subset of 5'-cytosine-phosphate-guanine-3' (CpG) dinucleotides in promoter regions of the MMP2, MMP11, MMP14, MMP15, MMP16, MMP17, MMP21, MMP23B, MMP24, MMP25, MMP28, TIMP1, TIMP2, TIMP3, and TIMP4 genes by methylation-sensitive restriction enzyme digestion PCR. In our collection of 183 breast cancer samples, abnormal hypermethylation was observed for CpGs in MMP2, MMP23B, MMP24, MMP25, and MMP28 promoter regions. The non-methylated status of the examined CpGs in promoter regions of MMP2, MMP23B, MMP24, MMP25, and MMP28 in tumors was associated with low HER2 expression, while the group of samples with abnormal hypermethylation of at least two of these MMP genes was significantly enriched with HER2-positive tumors. Abnormal methylation of MMP24 and MMP25 was significantly associated with a CpG island hypermethylated breast cancer subtype discovered by genome-wide DNA bisulfite sequencing. Our results indicate that abnormal hypermethylation of at least several MMP genes promoters is a secondary event not directly functional in breast cancer (BC) pathogenesis. We suggest that it is elevated and/or ectopic expression, rather than methylation-driven silencing, that might link MMPs to tumorigenesis.
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30
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Decreased CDKL2 expression is correlated with the progression and poor prognosis of glioma. Pathol Res Pract 2020; 216:152920. [DOI: 10.1016/j.prp.2020.152920] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 02/19/2020] [Accepted: 03/07/2020] [Indexed: 01/23/2023]
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31
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Fan J, Li J, Guo S, Tao C, Zhang H, Wang W, Zhang Y, Zhang D, Ding S, Zeng C. Genome-wide DNA methylation profiles of low- and high-grade adenoma reveals potential biomarkers for early detection of colorectal carcinoma. Clin Epigenetics 2020; 12:56. [PMID: 32317010 PMCID: PMC7175491 DOI: 10.1186/s13148-020-00851-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/08/2020] [Indexed: 02/07/2023] Open
Abstract
Background Abnormal DNA methylation is a hallmark of human cancers and may be a promising biomarker for early diagnosis of human cancers. However, the majority of DNA methylation biomarkers that have been identified are based on the hypothesis that early differential methylation regions (DMRs) are maintained throughout carcinogenesis and could be detected at all stages of cancer. Methods In this study, we identified potential early biomarkers of colorectal cancer (CRC) development by genome-wide DNA methylation assay (Illumina infinium450, 450 K) of normal (N = 20) and pre-colorectal cancer samples including 18 low-grade adenoma (LGA) and 22 high-grade adenoma (HGA), integrated with GEO and ArrayExpress datasets (N = 833). Results We identified 209 and 8692 CpG sites that were significantly hyper-methylated in LGA and HGA, respectively. Pathway analysis identified nervous system-related methylation changes that are significantly associated with early adenoma development. Integration analysis revealed that DNA methylation in the promoter region of ADHFE1 has the most potential for being an early diagnostic biomarker for colorectal adenoma and cancer (sensitivity = 0.96, specificity = 0.95, area under the curve = 0.97). Conclusions Overall, we demonstrated that DNA methylation have been shown significant changes in the stage of LGA and HGA in the development of colon cancer. Genome-wide DNA methylation to LGA and HGA provided an important proxy to identify promising early diagnosis biomarkers for colorectal cancer.
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Affiliation(s)
- Jian Fan
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jun Li
- Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, China
| | - Shicheng Guo
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53726, USA.,Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI, 54449, USA
| | - Chengcheng Tao
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Haikun Zhang
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wenjing Wang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, China
| | - Ying Zhang
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Dake Zhang
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. .,Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China.
| | - Shigang Ding
- Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, China.
| | - Changqing Zeng
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
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van Schie EH, van Amerongen R. Aberrant WNT/CTNNB1 Signaling as a Therapeutic Target in Human Breast Cancer: Weighing the Evidence. Front Cell Dev Biol 2020; 8:25. [PMID: 32083079 PMCID: PMC7005411 DOI: 10.3389/fcell.2020.00025] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 01/14/2020] [Indexed: 12/22/2022] Open
Abstract
WNT signaling is crucial for tissue morphogenesis during development in all multicellular animals. After birth, WNT/CTNNB1 responsive stem cells are responsible for tissue homeostasis in various organs and hyperactive WNT/CTNNB1 signaling is observed in many different human cancers. The first link between WNT signaling and breast cancer was established almost 40 years ago, when Wnt1 was identified as a proto-oncogene capable of driving mammary tumor formation in mice. Since that discovery, there has been a dedicated search for aberrant WNT signaling in human breast cancer. However, much debate and controversy persist regarding the importance of WNT signaling for the initiation, progression or maintenance of different breast cancer subtypes. As the first drugs designed to block functional WNT signaling have entered clinical trials, many questions about the role of aberrant WNT signaling in human breast cancer remain. Here, we discuss three major research gaps in this area. First, we still lack a basic understanding of the function of WNT signaling in normal human breast development and physiology. Second, the overall extent and precise effect of (epi)genetic changes affecting the WNT pathway in different breast cancer subtypes are still unknown. Which underlying molecular and cell biological mechanisms are disrupted as a result also awaits further scrutiny. Third, we survey the current status of targeted therapeutics that are aimed at interfering with the WNT pathway in breast cancer patients and highlight the importance and complexity of selecting the subset of patients that may benefit from treatment.
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Affiliation(s)
| | - Renée van Amerongen
- Section of Molecular Cytology and van Leeuwenhoek Centre for Advanced Microscopy, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
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Sehovic E, Hadrovic A, Dogan S. Detection and analysis of stable and flexible genes towards a genome signature framework in cancer. Bioinformation 2019; 15:772-779. [PMID: 31831960 PMCID: PMC6900328 DOI: 10.6026/97320630015772] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/05/2019] [Accepted: 11/09/2019] [Indexed: 01/11/2023] Open
Abstract
Comparison and detection of stable cancer genes across cancer types is of interest. The gene expression data of 6 different cancer types (colon, breast, lung, ovarian, brain
and renal) and a control group from The Cancer Genome Atlas (TCGA) database were used in this study. The comparison of gene expression data together with the calculation standard
deviations of such data was completed using a statistical model for the detection of stable genes. Genes having similar expression (referred as flexible genes) pattern to the
control group in four out of six cancer types are PATE, NEUROD4 and TRAFD1. Moreover, 13 genes showed low difference compared to the control group with low standard deviation
across cancer types (referred as stable genes). Among them, genes GDF2, KCNT1 and RNF151 showed consistent low expression while ODF4, OR5I1, MYOG and OR2B11 showed consistent high
expression. Thus, the detection and analysis of stable and flexible cancer genes help towards the design and development of a framework (outline) for specific genome signature
(biomarker) in cancer.
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Affiliation(s)
- Emir Sehovic
- International Burch University Sarajevo, Francuske Revolucije BB, 71210 Sarajevo
| | - Adem Hadrovic
- Sarajevo School of Science and Technology, Hrasnicka Cesta 3a, 71210 Sarajevo
| | - Senol Dogan
- The University of Leipzig, Faculty of Physics and Earth Science, Peter Debye Institute for Soft Matter Physics, LinnestraBe 5, 04103 Leipzig, Germany
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Hu YT, Li BF, Zhang PJ, Wu D, Li YY, Li ZW, Shen L, Dong B, Gao J, Zhu X. Dbx2 exhibits a tumor-promoting function in hepatocellular carcinoma cell lines via regulating Shh-Gli1 signaling. World J Gastroenterol 2019; 25:923-940. [PMID: 30833799 PMCID: PMC6397724 DOI: 10.3748/wjg.v25.i8.923] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/25/2018] [Accepted: 12/27/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. HCC patients suffer from a high mortality-to-incidence ratio and low cure rate since we still have no specific and effective treatment. Although tremendous advances have been made in the investigation of HCC, the specific mechanisms of the progression of this disease are still only partially established. Hence, more research is needed to elucidate the underlying potential mechanisms to develop effective strategies for HCC. AIM To determine the role of developing brain homeobox 2 (Dbx2) gene in promoting the development of HCC. METHODS Dbx2 expression in clinical specimens and HCC cell lines was detected by Western blot (WB) and immunohistochemistry. Gain and loss of Dbx2 function assays were performed in vitro and in vivo. Cell viability assays were used to investigate cell growth, flow cytometry was employed to assess cell cycle and apoptosis, and trans-well assays were conducted to evaluate cell migration, invasion, and metastasis. The expression of key molecules in the sonic hedgehog (Shh) signaling was determined by WB. RESULTS Compared to matched adjacent non-tumorous tissues, Dbx2 was overexpressed in 5 HCC cell lines and 76 surgically resected HCC tissues. Dbx2 overexpression was correlated with large tumor size. Both gain and loss of function assays indicated that Dbx2 promoted HCC cell proliferation by facilitating the transition from G1 to S phase, attenuating apoptosis and promoted HCC proliferation, migration, and invasion in vitro and in vivo. Mechanistically, Dbx2 modulated Shh signaling by enhancing FTCH1 and GLi1 expression in HCC cells that overexpressed Dbx2, which was reversed in HCC cells with Dbx2 knockdown. CONCLUSION Our results indicate that Dbx2 is significantly upregulated in HCC tissues and plays significant roles in proliferation and metastasis of HCC cells by activating the Shh pathway.
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Affiliation(s)
- Yan-Ting Hu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Bei-Fang Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Peng-Jun Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Di Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yan-Yan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | | | - Lin Shen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Bin Dong
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Jing Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xu Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital and Institute, Beijing 100142, China
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Lang L, Chemmalakuzhy R, Shay C, Teng Y. PFKP Signaling at a Glance: An Emerging Mediator of Cancer Cell Metabolism. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1134:243-258. [PMID: 30919341 DOI: 10.1007/978-3-030-12668-1_13] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Phosphofructokinase-1 (PFK-1), a rate-determining enzyme of glycolysis, is an allosteric enzyme that regulates the oxidation of glucose in cellular respiration. Glycolysis phosphofructokinase platelet (PFKP) is the platelet isoform and works as an important mediator of cell metabolism. Considering that PFKP is a crucial player in many steps of cancer initiation and metastasis, we reviewed the specificities and complexities of PFKP and its biological roles in human diseases, especially malignant tumors. The possible use of PFKP as a diagnostic marker or a drug target in the prevention or treatment of cancer is also discussed.
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Affiliation(s)
- Liwei Lang
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Ron Chemmalakuzhy
- Department of Biology, College of Science and Mathematics, Augusta University, Augusta, GA, USA
| | - Chloe Shay
- The Robinson College of Business, Georgia State University, Atlanta, GA, USA
- Division of Endocrinology and Diabetes, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA
| | - Yong Teng
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA.
- Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
- Department of Medical Laboratory, Imaging and Radiologic Sciences, College of Allied Health, Augusta University, Augusta, GA, USA.
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Tan W, Zhong Z, Carney RP, Men Y, Li J, Pan T, Wang Y. Deciphering the metabolic role of AMPK in cancer multi-drug resistance. Semin Cancer Biol 2018; 56:56-71. [PMID: 30261277 DOI: 10.1016/j.semcancer.2018.09.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 09/02/2018] [Accepted: 09/18/2018] [Indexed: 02/07/2023]
Abstract
Multi-drug resistance (MDR) is a curious bottleneck in cancer research and chemotherapy, whereby some cells rapidly adapt to the tumor microenvironment via a myriad of heterogeneous metabolic activities. Despite being a major impediment to treatment, there is a silver lining: control over metabolic regulation could be an effective approach to overcome or correct resistance pathways. In this critical review, we comprehensively and carefully curated and analyzed large networks of previously identified proteins associated with metabolic adaptation in MDR. We employed data and text mining to study and categorize more than 600 studies in PubMed, with particular focus on AMPK, a central and fundamental modulator in the energy metabolism network that has been specifically implicated in cancer MDR pathways. We have identified one protein set of metabolic adaptations with 137 members closely related to cancer MDR processes, and a second protein set with 165 members derived from AMPK-based networks, with 28 proteins found at the intersection between the two sets. Furthermore, according to genomics analysis of the cancer genome atlas (TCGA) provisional data, the highest alteration frequency (80.0%) of the genes encoding the intersected proteins (28 proteins), ranked three cancer types with quite remarkable significance across 166 studies. The hierarchical relationships of the entire identified gene and protein networks indicate broad correlations in AMPK-mediated metabolic regulation pathways, which we use decipher and depict the metabolic roles of AMPK and demonstrate the potential of metabolic control for therapeutic intervention in MDR.
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Affiliation(s)
- Wen Tan
- School of Pharmacy, Lanzhou University, Lanzhou, Gansu province 730000, China; Micro-Nano Innovations (MiNI) Laboratory, Biomedical Engineering, University of California, Davis, CA 95616, United States
| | - Zhangfeng Zhong
- Center for Developmental Therapeutics, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60202, United States; Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR, 999078, China
| | - Randy P Carney
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States
| | - Yongfan Men
- Micro-Nano Innovations (MiNI) Laboratory, Biomedical Engineering, University of California, Davis, CA 95616, United States
| | - Jiannan Li
- Micro-Nano Innovations (MiNI) Laboratory, Biomedical Engineering, University of California, Davis, CA 95616, United States
| | - Tingrui Pan
- Micro-Nano Innovations (MiNI) Laboratory, Biomedical Engineering, University of California, Davis, CA 95616, United States.
| | - Yitao Wang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR, 999078, China.
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37
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Kumar A, Bandapalli OR, Paramasivam N, Giangiobbe S, Diquigiovanni C, Bonora E, Eils R, Schlesner M, Hemminki K, Försti A. Familial Cancer Variant Prioritization Pipeline version 2 (FCVPPv2) applied to a papillary thyroid cancer family. Sci Rep 2018; 8:11635. [PMID: 30072699 PMCID: PMC6072708 DOI: 10.1038/s41598-018-29952-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 07/19/2018] [Indexed: 12/20/2022] Open
Abstract
Whole-genome sequencing methods in familial cancer are useful to unravel rare clinically important cancer predisposing variants. Here, we present improvements in our pedigree-based familial cancer variant prioritization pipeline referred as FCVPPv2, including 12 tools for evaluating deleteriousness and 5 intolerance scores for missense variants. This pipeline is also capable of assessing non-coding regions by combining FANTOM5 data with sets of tools like Bedtools, ChromHMM, Miranda, SNPnexus and Targetscan. We tested this pipeline in a family with history of a papillary thyroid cancer. Only one variant causing an amino acid change G573R (dbSNP ID rs145736623, NM_019609.4:exon11:c.G1717A:p.G573R) in the carboxypeptidase gene CPXM1 survived our pipeline. This variant is located in a highly conserved region across vertebrates in the peptidase_M14 domain (Pfam ID PF00246). The CPXM1 gene may be involved in adipogenesis and extracellular matrix remodelling and it has been suggested to be a tumour suppressor in breast cancer. However, the presence of the variant in the ExAC database suggests it to be a rare polymorphism or a low-penetrance risk allele. Overall, our pipeline is a comprehensive approach for prediction of predisposing variants for high-risk cancer families, for which a functional characterization is a crucial step to confirm their role in cancer predisposition.
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Affiliation(s)
- Abhishek Kumar
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D69120, Heidelberg, Germany.
| | - Obul Reddy Bandapalli
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D69120, Heidelberg, Germany.
| | - Nagarajan Paramasivam
- Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), D69120, Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, D69120, Heidelberg, Germany
| | - Sara Giangiobbe
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D69120, Heidelberg, Germany
| | | | - Elena Bonora
- Unit of Medical Genetics, S.Orsola-Malpighi Hospital, 40138, Bologna, Italy
| | - Roland Eils
- Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), D69120, Heidelberg, Germany
- Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, D69120, Heidelberg, Germany
| | - Matthias Schlesner
- Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), D69120, Heidelberg, Germany
- Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), D69120, Heidelberg, Germany
| | - Kari Hemminki
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D69120, Heidelberg, Germany
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
| | - Asta Försti
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D69120, Heidelberg, Germany
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
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DiNardo AR, Nishiguchi T, Mace EM, Rajapakshe K, Mtetwa G, Kay A, Maphalala G, Secor WE, Mejia R, Orange JS, Coarfa C, Bhalla KN, Graviss EA, Mandalakas AM, Makedonas G. Schistosomiasis Induces Persistent DNA Methylation and Tuberculosis-Specific Immune Changes. THE JOURNAL OF IMMUNOLOGY 2018; 201:124-133. [PMID: 29752313 DOI: 10.4049/jimmunol.1800101] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 04/09/2018] [Indexed: 12/29/2022]
Abstract
Epigenetic mechanisms, such as DNA methylation, determine immune cell phenotype. To understand the epigenetic alterations induced by helminth coinfections, we evaluated the longitudinal effect of ascariasis and schistosomiasis infection on CD4+ T cell DNA methylation and the downstream tuberculosis (TB)-specific and bacillus Calmette-Guérin-induced immune phenotype. All experiments were performed on human primary immune cells from a longitudinal cohort of recently TB-exposed children. Compared with age-matched uninfected controls, children with active Schistosoma haematobium and Ascaris lumbricoides infection had 751 differentially DNA-methylated genes, with 72% hypermethylated. Gene ontology pathway analysis identified inhibition of IFN-γ signaling, cellular proliferation, and the Th1 pathway. Targeted real-time quantitative PCR after methyl-specific endonuclease digestion confirmed DNA hypermethylation of the transcription factors BATF3, ID2, STAT5A, IRF5, PPARg, RUNX2, IRF4, and NFATC1 and cytokines or cytokine receptors IFNGR1, TNFS11, RELT (TNF receptor), IL12RB2, and IL12B (p < 0.001; Sidak-Bonferroni). Functional blockage of the IFN-γ signaling pathway was confirmed, with helminth-infected individuals having decreased upregulation of IFN-γ-inducible genes (Mann-Whitney p < 0.05). Hypomethylation of the IL-4 pathway and DNA hypermethylation of the Th1 pathway was confirmed by Ag-specific multidimensional flow cytometry demonstrating decreased TB-specific IFN-γ and TNF and increased IL-4 production by CD4+ T cells (Wilcoxon signed-rank p < 0.05). In S. haematobium-infected individuals, these DNA methylation and immune phenotypic changes persisted at least 6 mo after successful deworming. This work demonstrates that helminth infection induces DNA methylation and immune perturbations that inhibit TB-specific immune control and that the duration of these changes are helminth specific.
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Affiliation(s)
- Andrew R DiNardo
- The Global Tuberculosis Program, Immigrant and Global Health, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030;
| | - Tomoki Nishiguchi
- The Global Tuberculosis Program, Immigrant and Global Health, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030
| | - Emily M Mace
- Department of Pathology, Baylor College of Medicine, Houston, TX 77030.,Texas Children's Hospital Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital Center for Human Immunobiology, Baylor College of Medicine, Houston, TX 77030
| | - Kimal Rajapakshe
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030
| | - Godwin Mtetwa
- Baylor-Swaziland Children's Foundation, Mbabane H100, Swaziland
| | - Alexander Kay
- Baylor-Swaziland Children's Foundation, Mbabane H100, Swaziland
| | | | - W Evan Secor
- Parasitic Diseases Branch, Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, GA 30333
| | - Rojelio Mejia
- Department of Pediatrics, National School of Tropical Medicine, Texas Children's Hospital Center for Human Immunobiology, Houston, TX 77030
| | - Jordan S Orange
- Department of Pathology, Baylor College of Medicine, Houston, TX 77030.,Texas Children's Hospital Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital Center for Human Immunobiology, Baylor College of Medicine, Houston, TX 77030
| | - Cristian Coarfa
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030
| | - Kapil N Bhalla
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX 77030; and
| | - Edward A Graviss
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital Research Institute, Houston, TX 77030
| | - Anna M Mandalakas
- The Global Tuberculosis Program, Immigrant and Global Health, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030
| | - George Makedonas
- Department of Pathology, Baylor College of Medicine, Houston, TX 77030.,Texas Children's Hospital Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital Center for Human Immunobiology, Baylor College of Medicine, Houston, TX 77030
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Sanford T, Meng MV, Railkar R, Agarwal PK, Porten SP. Integrative analysis of the epigenetic basis of muscle-invasive urothelial carcinoma. Clin Epigenetics 2018; 10:19. [PMID: 29456764 PMCID: PMC5809922 DOI: 10.1186/s13148-018-0451-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 01/30/2018] [Indexed: 12/20/2022] Open
Abstract
Background Elucidation of epigenetic alterations in bladder cancer will lead to further understanding of the biology of the disease and hopefully improved therapies. Our aim was to perform an integrative epigenetic analysis of invasive urothelial carcinoma of the bladder to identify the epigenetic abnormalities involved in the development and progression of this cancer. Methods Pre-processed methylation data and RNA-seq data were downloaded from The Cancer Genome Atlas (TCGA) and processed using the R package TCGA-Assembler. An R package MethylMix was used to perform an analysis incorporating both methylation and gene expression data on all samples, as well as a subset analysis comparing patients surviving less than 2 years and patients surviving more than 2 years. Genes associated with poor prognosis were individually queried. Pathway analysis was performed on statistically significant genes identified by MethylMix criteria using ConsensusPathDB. Validation was performed using flow cytometry on bladder cancer cell lines. Results A total of 408 patients met all inclusion criteria. There were a total of 240 genes differentially methylated by MethylMix criteria. Review of individual genes specific to poor-prognosis patients revealed the majority to be candidate tumor suppressors in other cancer types. Pathway analysis showed increase in methylation of genes involved in antioxidant pathways including glutathione and NRF2. Genes involved in estrogen metabolism were also hypermethylated while genes involved in the EGFR pathway were found to be hypomethylated. EGFR expression was confirmed to be elevated in six bladder cancer cell lines. Conclusions In patients with invasive urothelial carcinoma, we found differential methylation in patients with better and worse prognosis after cystectomy. Differentially methylated genes are involved in many relevant oncologic pathways, including EGFR and antioxidant pathways, that may be a target for therapy or chemoprevention.
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Affiliation(s)
- Thomas Sanford
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10—Hatfield CRC, Room 2-5952, Bethesda, MD 20892-1210 USA
| | - Maxwell V. Meng
- Department of Urology, University of California, Mail code 1695, 550 16th Street, 6th Floor, San Francisco, CA 94143 USA
| | - Reema Railkar
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10—Hatfield CRC, Room 2-5952, Bethesda, MD 20892-1210 USA
| | - Piyush K. Agarwal
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10—Hatfield CRC, Room 2-5952, Bethesda, MD 20892-1210 USA
| | - Sima P. Porten
- Department of Urology, University of California, Mail code 1695, 550 16th Street, 6th Floor, San Francisco, CA 94143 USA
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Yi R, Yang S, Wen E, Hu Z, Long H, Zeng Y, Wang X, Huang X, Liao Y, Luo M, Wang J, Zhou M, Wang W, Xu A, Lin J, Wu Z, Song Y. Negative nuclear expression of CDKL2 correlates with disease progression and poor prognosis of glioma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:712-719. [PMID: 31938157 PMCID: PMC6958001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Accepted: 01/09/2018] [Indexed: 06/10/2023]
Abstract
AIMS This study aimed to investigate the nuclear expression status of cyclin dependent kinase like 2 (CDKL2) in glioma and its correlation with the characteristics of clinical pathology, including patient survival. METHODS AND RESULTS In the present study, the expression of CDKL2 mRNA was detected by real-time QPCR in freshly collected glioma and para-carcinoma tissues. Moreover, immunohistochemistry was used to identified nuclear expression of CDKL2, and the characteristics of clinical pathology from glioma cases (n = 144) and non-cancerous brain tissues (n = 32) were counted. Low mRNA and nuclear protein expression of CDKL2 was observed in glioma tissues compared to non-cancerous tissues. Glioma patients with negative nuclear expression of CDKL2 were correlated with histologic type, clinical World Health Organization (WHO) grade, tumor location, and KI-67 expression status. Negative nuclear expression of CDKL2 in glioma patients predicted an observably shorter overall survival time than did positive expression. However, as demonstrated by multivariate analysis, nuclear expression of CDKL2 was not an independent prognostic biomarker for the survival of patients with glioma. CONCLUSIONS Our study indicated that negative nuclear expression of CDKL2 may represent a potential unfavorable marker for progression and poor prognostic in glioma.
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Affiliation(s)
- Renhui Yi
- Gannan Medical UniversityGanzhou, Jiangxi, P. R. China
- Department of Neurosurgery, First Affiliated Hospital of Gannan Medical UniversityGanzhou, Jiangxi, P. R. China
| | - Shaochun Yang
- Department of Neurosurgery, First Affiliated Hospital of Gannan Medical UniversityGanzhou, Jiangxi, P. R. China
| | - Ersheng Wen
- Gannan Medical UniversityGanzhou, Jiangxi, P. R. China
| | - Zheng Hu
- Department of Neurosurgery, First Affiliated Hospital of Gannan Medical UniversityGanzhou, Jiangxi, P. R. China
| | - Hao Long
- Department of Neurosurgery, Nanfang Hospital, Southern Medical UniversityGuangzhou, Guangdong, P. R. China
| | - Yu Zeng
- Department of Neurosurgery, Nanfang Hospital, Southern Medical UniversityGuangzhou, Guangdong, P. R. China
| | - Xizhao Wang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical UniversityGuangzhou, Guangdong, P. R. China
| | - Xiaoyu Huang
- Gannan Medical UniversityGanzhou, Jiangxi, P. R. China
| | - Yuanyuan Liao
- Department of Ultrasonography, First Affiliated Hospital of Gannan Medical UniversityGanzhou, Jiangxi, P. R. China
| | - Muyun Luo
- Department of Neurosurgery, First Affiliated Hospital of Gannan Medical UniversityGanzhou, Jiangxi, P. R. China
| | - Jizhou Wang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical UniversityGuangzhou, Guangdong, P. R. China
| | - Mingfeng Zhou
- Department of Neurosurgery, Nanfang Hospital, Southern Medical UniversityGuangzhou, Guangdong, P. R. China
| | - Wen Wang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical UniversityGuangzhou, Guangdong, P. R. China
| | - Anqi Xu
- Department of Neurosurgery, Nanfang Hospital, Southern Medical UniversityGuangzhou, Guangdong, P. R. China
| | - Jie Lin
- Department of Neurosurgery, Nanfang Hospital, Southern Medical UniversityGuangzhou, Guangdong, P. R. China
| | - Zhiyong Wu
- Department of Neurosurgery, Nanfang Hospital, Southern Medical UniversityGuangzhou, Guangdong, P. R. China
| | - Ye Song
- Department of Neurosurgery, Nanfang Hospital, Southern Medical UniversityGuangzhou, Guangdong, P. R. China
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Fang J, Zhang JG, Deng HW, Wang YP. Joint Detection of Associations between DNA Methylation and Gene Expression from Multiple Cancers. IEEE J Biomed Health Inform 2017; 22:1960-1969. [PMID: 29990049 DOI: 10.1109/jbhi.2017.2784621] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
DNA methylation plays an important role in the development of various cancers mainly through the regulation on gene expression. Hence, the study on the relation between DNA methylation and gene expression is of particular interest to understand cancers. Recently, an increasing number of datasets are available from multiple cancers, which makes it possible to study both the similarity and difference of genomic alterations across multiple tumor types. However, most of the existing pan-cancer analysis methods perform simple aggregations, which may overlook the heterogeneity of the interactions. In this paper, we propose a novel method to jointly detect complex associations between DNA methylation and gene expression levels from multiple cancers. The main idea is to apply joint sparse canonical correlation analysis to detect a small set of methylated sites, which are associated with another set of genes either shared across cancers or specific to a particular group (group-specific) of cancers. These methylated sites and genes form a complex module with strong multivariate correlations. We further introduced a joint sparse precision matrix estimation method to identify driver methylation-gene pairs in the module. These pairs are characterized by significant partial correlations, which may imply high functional impacts and contribute to complementary information to the main step. We apply our method to The Cancer Genome Atlas(TCGA) datasets with 1166 samples from four cancers. The results reveal significant shared and groupspecific interactions between DNA methylation and gene expression levels. To promote reproducible research, the Matlab code is available at https://sites.google.com/site/jianfang86/jointTCGA.
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Singla H, Ludhiadch A, Kaur RP, Chander H, Kumar V, Munshi A. Recent advances in HER2 positive breast cancer epigenetics: Susceptibility and therapeutic strategies. Eur J Med Chem 2017; 142:316-327. [DOI: 10.1016/j.ejmech.2017.07.075] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 07/27/2017] [Accepted: 07/31/2017] [Indexed: 12/31/2022]
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Lin RK, Hung WY, Huang YF, Chang YJ, Lin CH, Chen WY, Chiu SF, Chang SC, Tsai SF. Hypermethylation of BEND5 contributes to cell proliferation and is a prognostic marker of colorectal cancer. Oncotarget 2017; 8:113431-113443. [PMID: 29371920 PMCID: PMC5768337 DOI: 10.18632/oncotarget.22266] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 05/10/2017] [Indexed: 01/05/2023] Open
Abstract
Aberrant hypermethylation of CpG islands in tumor suppressor genes (TSGs) contributes to colorectal tumorigenesis. To identify new colorectal cancer (CRC) screening marker, we investigated DNA methylation alterations in novel TSGs. Using HumanMethylation450 BeadChip arrays, CpG regions in BEND5 were the most highly methylated among all genomic regions in 26 colorectal tumors compared to paired non-neoplastic tissues from a Taiwan cohort. Therefore, BEND5 was selected for further analysis. Quantitative methylation-specific real-time PCR revealed that 86.7% (117/135) of CRC patients exhibited hypermethylated BEND5. Real-time reverse transcription PCR identified that BEND5 mRNA expression was downregulated in 68% (32/47) of the analyzed samples. BEND5 hypermethylation was associated with poor overall survival (OS) in Taiwan patients with early-stage CRC (P = 0.037). In a CRC tissue set from South Korea, OS was higher in patients with high BEND5 protein expression than in those with low BEND5 protein expression (P = 0.037) by using immunohistochemistry assays. Consistently, BEND5 hypermethylation was associated with poor OS in patients with early-stage CRC in The Cancer Genome Atlas (TCGA) data set (P = 0.003). Multivariate Cox proportional hazards regression analysis further supported that hypermethylation of BEND5 genes was significantly associated with OS in Taiwan and TCGA CRC patients (P = 0.023 and 0.033, respectively). Finally, the cell model assay with transient transfection of BEND5 or si-BEND5 knockdown indicated that BEND5 inhibited cancer cell proliferation. In conclusion, epigenetic alteration in the candidate TSG BEND5 contributes to colorectal cancer development and is a prognostic marker of CRC.
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Affiliation(s)
- Ruo-Kai Lin
- Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan, R.O.C.,Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University, Taipei, Taiwan, R.O.C.,PH.D Program for Clinical Drug Development of Chinese Herbal Medicine, Ph.D Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan, R.O.C
| | - Wan-Yu Hung
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University, Taipei, Taiwan, R.O.C
| | - Yu-Fang Huang
- Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan, R.O.C
| | - Yu-Jia Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, R.O.C
| | - Chien-Hsing Lin
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
| | - Wei-Yu Chen
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, R.O.C.,Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, R.O.C
| | - Shih-Feng Chiu
- Professional Master Program in Pharmaceutics and Biotechnology, Taipei Medical University, Taipei, Taiwan, R.O.C
| | - Shih-Ching Chang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C
| | - Shih-Feng Tsai
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
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Hasegawa T, Adachi R, Iwakata H, Takeno T, Sato K, Sakamaki T. ErbB2 signaling epigenetically suppresses microRNA-205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer. FEBS Open Bio 2017; 7:1154-1165. [PMID: 28781955 PMCID: PMC5537069 DOI: 10.1002/2211-5463.12256] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 05/05/2017] [Accepted: 05/25/2017] [Indexed: 01/28/2023] Open
Abstract
We previously reported that microRNA-205 (miR-205) is downregulated by overexpression of the receptor tyrosine kinase ErbB2 and that ectopic transfection of miR-205 precursor decreases ErbB2 tumorigenicity in soft agar. In this study, we further analyzed the regulatory mechanisms linking ErbB2 overexpression and miR-205 downregulation. In ErbB2-overexpressing breast epithelial cells, miR-205 expression was significantly increased by treatment with MEK inhibitor U0126 or PD98059, Raf-1 inhibitor ZM-336372, and ERK inhibitor SCH772984, but PI3K inhibitor LY294002 and p38 MAPK inhibitor SB203580 had no effect. We established breast epithelial cells overexpressing RafCAAX, a constitutively active form of Raf-1, and showed that overexpression of RafCAAX dramatically reduced miR-205 expression. In RafCAAX-overexpressing cells, miR-205 expression was also significantly increased by SCH772984. Moreover, miR-205 expression was significantly increased by treatment with DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine and expression of several DNMT family members was increased in both ErbB2- and RafCAAX-overexpressing cells. DNA methylation analysis by bisulfite sequencing revealed that the putative miR-205 promoters were predominantly hypermethylated in both ErbB2- and RafCAAX-overexpressing cells. Reporter activity of the putative miR-205 promoters was reduced in both ErbB2-overexpressing and RafCAAX-overexpressing cells. Together, these findings indicate that ErbB2 signaling epigenetically suppresses miR-205 transcription via the Ras/Raf/MEK/ERK pathway.
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Affiliation(s)
- Takuya Hasegawa
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Ryohei Adachi
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Hitoshi Iwakata
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Takayoshi Takeno
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Koji Sato
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Toshiyuki Sakamaki
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
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Liu Y, Sun L, Fong P, Yang J, Zhang Z, Yin S, Jiang S, Liu X, Ju H, Huang L, Bai J, Gong K, Yan S, Zhang C, Shao G. An association between overexpression of DNA methyltransferase 3B4 and clear cell renal cell carcinoma. Oncotarget 2017; 8:19712-19722. [PMID: 28160561 PMCID: PMC5386716 DOI: 10.18632/oncotarget.14966] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 01/03/2017] [Indexed: 12/20/2022] Open
Abstract
It is well known that abnormal DNA methylations occur frequently in kidney cancer. However, it remains unclear exactly which types of DNA methyltransferases (DNMT) contribute to the pathologies of kidney cancers. In order to determine the functions of DNA methyltransferase in kidney tumorigenesis on the molecular level, we examined the mRNA expression levels of DNMT1, DNMT3A, DNMT3B, and DNMT3B variants in renal cell carcinoma tissue. Both mRNA and protein levels of DNMT3B4, a splice variant of DNMT3B, were increased in renal cell carcinoma tissue compared with adjacent control tissues. Additionally, Alu elements and long interspersed nuclear elements (LINE-1) were hypomethylated in renal cell carcinoma tissue. Meanwhile, methylation of the promoter for RASSF1A, a tumor suppressor gene, was moderately increased in renal cell carcinoma tissue, while RASSF1A expression was decreased. Thus, our data suggest that the overexpression of DNMT3B4 may play an important role in human kidney tumorigenesis through chromosomal instability and methylation of RASSF1A.
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Affiliation(s)
- You Liu
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
| | - Liantao Sun
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
| | - Peter Fong
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Jie Yang
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
| | - Zhuxia Zhang
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
| | - Shuihui Yin
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
| | - Shuyuan Jiang
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
| | - Xiaolei Liu
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
| | - Hongge Ju
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
| | - Lihua Huang
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
| | - Jing Bai
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
| | - Kerui Gong
- Department of Oral and Maxillofacial Surgery, University of California San Francsico, San Francisco, CA, USA
| | - Shaochun Yan
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
| | - Chunyang Zhang
- Department of Neurology, First Affiliated Hospital of Baotou Medical College, Inner Mongolia, PRC
| | - Guo Shao
- Biomedicine Research Center and Basic Medical College, Baotou Medical College, Inner Mongolia, PRC
- Institute for Hypoxia Medicine, Capital Medical University, Beijing, PRC
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Galamb O, Kalmár A, Barták BK, Patai &AV, Leiszter K, Péterfia B, Wichmann B, Valcz G, Veres G, Tulassay Z, Molnár B. Aging related methylation influences the gene expression of key control genes in colorectal cancer and adenoma. World J Gastroenterol 2016; 22:10325-10340. [PMID: 28058013 PMCID: PMC5175245 DOI: 10.3748/wjg.v22.i47.10325] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 09/20/2016] [Accepted: 11/13/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To analyze colorectal carcinogenesis and age-related DNA methylation alterations of gene sequences associated with epigenetic clock CpG sites. METHODS In silico DNA methylation analysis of 353 epigenetic clock CpG sites published by Steve Horvath was performed using methylation array data for a set of 123 colonic tissue samples [64 colorectal cancer (CRC), 42 adenoma, 17 normal; GEO accession number: GSE48684]. Among the differentially methylated age-related genes, secreted frizzled related protein 1 (SFRP1) promoter methylation was further investigated in colonic tissue from 8 healthy adults, 19 normal children, 20 adenoma and 8 CRC patients using bisulfite-specific PCR followed by methylation-specific high resolution melting (MS-HRM) analysis. mRNA expression of age-related "epigenetic clock" genes was studied using Affymetrix HGU133 Plus2.0 whole transcriptome data of 153 colonic biopsy samples (49 healthy adult, 49 adenoma, 49 CRC, 6 healthy children) (GEO accession numbers: GSE37364, GSE10714, GSE4183, GSE37267). Whole promoter methylation analysis of genes showing inverse DNA methylation-gene expression data was performed on 30 colonic samples using methyl capture sequencing. RESULTS Fifty-seven age-related CpG sites including hypermethylated PPP1R16B, SFRP1, SYNE1 and hypomethylated MGP, PIPOX were differentially methylated between CRC and normal tissues (P < 0.05, Δβ ≥ 10%). In the adenoma vs normal comparison, 70 CpG sites differed significantly, including hypermethylated DKK3, SDC2, SFRP1, SYNE1 and hypomethylated CEMIP, SPATA18 (P < 0.05, Δβ ≥ 10%). In MS-HRM analysis, the SFRP1 promoter region was significantly hypermethylated in CRC (55.0% ± 8.4 %) and adenoma tissue samples (49.9% ± 18.1%) compared to normal adult (5.2% ± 2.7%) and young (2.2% ± 0.7%) colonic tissue (P < 0.0001). DNA methylation of SFRP1 promoter was slightly, but significantly increased in healthy adults compared to normal young samples (P < 0.02). This correlated with significantly increased SFRP1 mRNA levels in children compared to normal adult samples (P < 0.05). In CRC tissue the mRNA expression of 117 age-related genes were changed, while in adenoma samples 102 genes showed differential expression compared with normal colonic tissue (P < 0.05, logFC > 0.5). The change of expression for several genes including SYNE1, CLEC3B, LTBP3 and SFRP1, followed the same pattern in aging and carcinogenesis, though not for all genes (e.g., MGP). CONCLUSION Several age-related DNA methylation alterations can be observed during CRC development and progression affecting the mRNA expression of certain CRC- and adenoma-related key control genes.
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Vymetalkova V, Vodicka P, Pardini B, Rosa F, Levy M, Schneiderova M, Liska V, Vodickova L, Nilsson TK, Farkas SA. Epigenome-wide analysis of DNA methylation reveals a rectal cancer-specific epigenomic signature. Epigenomics 2016; 8:1193-207. [DOI: 10.2217/epi-2016-0044] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Aim: The aim of the present study is to address a genome-wide search for novel methylation biomarkers in the rectal cancer (RC), as only scarce information on methylation profile is available. Materials & methods: We analyzed methylation status in 25 pairs of RC and adjacent healthy mucosa using the Illumina Human Methylation 450 BeadChip. Results: We found significantly aberrant methylation in 33 genes. After validation of our results by pyrosequencing, we found a good agreement with our findings. The BPIL3 and HBBP1 genes resulted hypomethylated in RC, whereas TIFPI2, ADHFE1, FLI1 and TLX1 were hypermethylated. An external validation by TCGA datasets confirmed the results. Conclusion: Our study, with external validation, has demonstrated the feasibility of using specific methylated DNA signatures for developing biomarkers in RC.
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Affiliation(s)
- Veronika Vymetalkova
- Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
- Institute of Biology & Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic
| | - Pavel Vodicka
- Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
- Institute of Biology & Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Czech Republic
| | | | - Fabio Rosa
- Human Genetics Foundation, (HuGeF), Torino, Italy
| | - Miroslav Levy
- Department of Surgery, 1st Faculty of Medicine, Charles University & Thomayer Hospital, Prague, Czech Republic
| | | | - Vaclav Liska
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Czech Republic
- Department of Surgery, Teaching Hospital & Medical School in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ludmila Vodickova
- Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
- Institute of Biology & Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Czech Republic
| | | | - Sanja A Farkas
- Department of Laboratory Medicine, Örebro University; Örebro, Sweden
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48
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Longacre M, Snyder NA, Housman G, Leary M, Lapinska K, Heerboth S, Willbanks A, Sarkar S. A Comparative Analysis of Genetic and Epigenetic Events of Breast and Ovarian Cancer Related to Tumorigenesis. Int J Mol Sci 2016; 17:E759. [PMID: 27213343 PMCID: PMC4881580 DOI: 10.3390/ijms17050759] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 05/02/2016] [Accepted: 05/12/2016] [Indexed: 01/02/2023] Open
Abstract
Breast cancer persists as the most common cause of cancer death in women worldwide. Ovarian cancer is also a significant source of morbidity and mortality, as the fifth leading cause of cancer death among women. This reflects the continued need for further understanding and innovation in cancer treatment. Though breast and ovarian cancer usually present as distinct clinical entities, the recent explosion of large-scale -omics research has uncovered many overlaps, particularly with respect to genetic and epigenetic alterations. We compared genetic, microenvironmental, stromal, and epigenetic changes common between breast and ovarian cancer cells, as well as the clinical relevance of these changes. Some of the most striking commonalities include genetic alterations of BRCA1 and 2, TP53, RB1, NF1, FAT3, MYC, PTEN, and PIK3CA; down regulation of miRNAs 9, 100, 125a, 125b, and 214; and epigenetic alterations such as H3K27me3, H3K9me2, H3K9me3, H4K20me3, and H3K4me. These parallels suggest shared features of pathogenesis. Furthermore, preliminary evidence suggests a shared epigenetic mechanism of oncogenesis. These similarities, warrant further investigation in order to ultimately inform development of more effective chemotherapeutics, as well as strategies to circumvent drug resistance.
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Affiliation(s)
| | - Nicole A Snyder
- Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
| | - Genevieve Housman
- School of Human Evolution and Social Change, Arizona State University, Tempe, AZ 85281, USA.
| | - Meghan Leary
- Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
| | - Karolina Lapinska
- Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
| | - Sarah Heerboth
- School of Medicine, Vanderbilt University, Nashville, TN 37240, USA.
| | - Amber Willbanks
- Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
| | - Sibaji Sarkar
- Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
- Genome Science Institute, Boston University School of Medicine, Boston, MA 02118, USA.
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Abstract
Aberrant DNA methylation is considered to be one of the most common hallmarks of cancer. Several recent advances in assessing the DNA methylome provide great promise for deciphering the cancer-specific DNA methylation patterns. Herein, we present the current key technologies used to detect high-throughput genome-wide DNA methylation, and the available cancer-associated methylation databases. Additionally, we focus on the computational methods for preprocessing, analyzing and interpreting the cancer methylome data. It not only discusses the challenges of the differentially methylated region calling and the prediction model construction but also highlights the biomarker investigation for cancer diagnosis, prognosis and response to treatment. Finally, some emerging challenges in the computational analysis of cancer methylome data are summarized.
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50
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Kazanets A, Shorstova T, Hilmi K, Marques M, Witcher M. Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1865:275-88. [PMID: 27085853 DOI: 10.1016/j.bbcan.2016.04.001] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 04/08/2016] [Indexed: 12/20/2022]
Abstract
Cancer constitutes a set of diseases with heterogeneous molecular pathologies. However, there are a number of universal aberrations common to all cancers, one of these being the epigenetic silencing of tumor suppressor genes (TSGs). The silencing of TSGs is thought to be an early, driving event in the oncogenic process. With this in consideration, great efforts have been made to develop small molecules aimed at the restoration of TSGs in order to limit tumor cell proliferation and survival. However, the molecular forces that drive the broad epigenetic reprogramming and transcriptional repression of these genes remain ill-defined. Undoubtedly, understanding the molecular underpinnings of transcriptionally silenced TSGs will aid us in our ability to reactivate these key anti-cancer targets. Here, we describe what we consider to be the five most logical molecular mechanisms that may account for this widely observed phenomenon: 1) ablation of transcription factor binding, 2) overexpression of DNA methyltransferases, 3) disruption of CTCF binding, 4) elevation of EZH2 activity, 5) aberrant expression of long non-coding RNAs. The strengths and weaknesses of each proposed mechanism is highlighted, followed by an overview of clinical efforts to target these processes.
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Affiliation(s)
- Anna Kazanets
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Tatiana Shorstova
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Khalid Hilmi
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Maud Marques
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Michael Witcher
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
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