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Szafron LA, Iwanicka-Nowicka R, Podgorska A, Bonna AM, Sobiczewski P, Kupryjanczyk J, Szafron LM. The Clinical Significance of CRNDE Gene Methylation, Polymorphisms, and CRNDEP Micropeptide Expression in Ovarian Tumors. Int J Mol Sci 2024; 25:7531. [PMID: 39062774 PMCID: PMC11277161 DOI: 10.3390/ijms25147531] [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: 04/28/2024] [Revised: 06/30/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
CRNDE is an oncogene expressed as a long non-coding RNA. However, our team previously reported that the CRNDE gene also encodes a micropeptide, CRNDEP. The amino acid sequence of CRNDEP has recently been revealed by other researchers, too. This study aimed to investigate genetic alterations within the CRNDEP-coding region of the CRNDE gene, methylation profiling of this gene, and CRNDEP expression analysis. All investigations were performed on clinical material from patients with ovarian tumors of diverse aggressiveness. We found that CRNDEP levels were significantly elevated in highly aggressive tumors compared to benign neoplasms. Consistently, a high level of this micropeptide was a negative, independent, prognostic, and predictive factor in high-grade ovarian cancer (hgOvCa) patients. The cancer-promoting role of CRNDE(P), shown in our recent study, was also supported by genetic and epigenetic results obtained herein, revealing no CRNDEP-disrupting mutations in any clinical sample. Moreover, in borderline ovarian tumors (BOTS), but not in ovarian cancers, the presence of a single nucleotide polymorphism in CRNDE, rs115515594, significantly increased the risk of recurrence. Consistently, in BOTS only, the same genetic variant was highly overrepresented compared to healthy individuals. We also discovered that hypomethylation of CRNDE is associated with increased aggressiveness of ovarian tumors. Accordingly, hypomethylation of this gene's promoter/first exon correlated with hgOvCa resistance to chemotherapy, but only in specimens with accumulation of the TP53 tumor suppressor protein. Taken together, these results contribute to a better understanding of the role of CRNDE(P) in tumorigenesis and potentially may lead to improvements in screening, diagnosis, and treatment of ovarian neoplasms.
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Affiliation(s)
| | - Roksana Iwanicka-Nowicka
- Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland
- Laboratory for Microarray Analysis, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Agnieszka Podgorska
- Cancer Molecular and Genetic Diagnostics Department, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
| | | | - Piotr Sobiczewski
- Department of Gynecological Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
| | - Jolanta Kupryjanczyk
- Department of Cancer Pathomorphology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland;
| | - Lukasz Michal Szafron
- Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
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2
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Csergeová L, Krbušek D, Janoštiak R. CIP/KIP and INK4 families as hostages of oncogenic signaling. Cell Div 2024; 19:11. [PMID: 38561743 PMCID: PMC10985988 DOI: 10.1186/s13008-024-00115-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 03/25/2024] [Indexed: 04/04/2024] Open
Abstract
CIP/KIP and INK4 families of Cyclin-dependent kinase inhibitors (CKIs) are well-established cell cycle regulatory proteins whose canonical function is binding to Cyclin-CDK complexes and altering their function. Initial experiments showed that these proteins negatively regulate cell cycle progression and thus are tumor suppressors in the context of molecular oncology. However, expanded research into the functions of these proteins showed that most of them have non-canonical functions, both cell cycle-dependent and independent, and can even act as tumor enhancers depending on their posttranslational modifications, subcellular localization, and cell state context. This review aims to provide an overview of canonical as well as non-canonical functions of CIP/KIP and INK4 families of CKIs, discuss the potential avenues to promote their tumor suppressor functions instead of tumor enhancing ones, and how they could be utilized to design improved treatment regimens for cancer patients.
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Affiliation(s)
- Lucia Csergeová
- BIOCEV-First Faculty of Medicine, Charles University, Prague, Czechia
| | - David Krbušek
- BIOCEV-First Faculty of Medicine, Charles University, Prague, Czechia
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3
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Gabryelska MM, Conn SJ. The RNA interactome in the Hallmarks of Cancer. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1786. [PMID: 37042179 PMCID: PMC10909452 DOI: 10.1002/wrna.1786] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/12/2023] [Accepted: 03/20/2023] [Indexed: 04/13/2023]
Abstract
Ribonucleic acid (RNA) molecules are indispensable for cellular homeostasis in healthy and malignant cells. However, the functions of RNA extend well beyond that of a protein-coding template. Rather, both coding and non-coding RNA molecules function through critical interactions with a plethora of cellular molecules, including other RNAs, DNA, and proteins. Deconvoluting this RNA interactome, including the interacting partners, the nature of the interaction, and dynamic changes of these interactions in malignancies has yielded fundamental advances in knowledge and are emerging as a novel therapeutic strategy in cancer. Here, we present an RNA-centric review of recent advances in the field of RNA-RNA, RNA-protein, and RNA-DNA interactomic network analysis and their impact across the Hallmarks of Cancer. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.
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Affiliation(s)
- Marta M Gabryelska
- Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
| | - Simon J Conn
- Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
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Yamashita N, Kawahara M, Imai T, Tatsumi G, Asai-Nishishita A, Andoh A. Loss of Nudt15 thiopurine detoxification increases direct DNA damage in hematopoietic stem cells. Sci Rep 2023; 13:11908. [PMID: 37488179 PMCID: PMC10366091 DOI: 10.1038/s41598-023-38952-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 07/18/2023] [Indexed: 07/26/2023] Open
Abstract
Thiopurines, such as 6-mercaptopurine (6-MP), are widely used as cytotoxic agents and immunosuppressants for leukemia and autoimmune or inflammatory diseases. A nonsynonymous single nucleotide polymorphism (p.Arg139Cys; R139C) of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene causes the loss of thiopurine detoxification, inducing myelosuppression. To understand such hematotoxicity, we investigate the effects of NUDT15 R139C on hematopoietic stem cells (HSCs) upon thiopurine administration. Using previously established Nudt15R138C knock-in mice, which mimic myelosuppression in NUDT15R139C homozygous or heterozygous patients following thiopurine administration, we investigated the numerical changes of HSCs and hematopoietic progenitor cells following 6-MP administration using in vivo flowcytometry and ex vivo HSC expansion. Genes differentially expressed between Nudt15+/+ HSCs and Nudt15R138C/R138C HSCs were identified using RNA-sequencing before the emergence of 6-MP-induced HSC-damage. Gene Ontology (GO) and Transcriptional Regulatory Relationships Unraveled by Sentence-based Text Mining (TRRUST) analyses were performed to elucidate the molecular effects of 6-MP on HSCs. In Nudt15R138C/R138C mice, 6-MP induced exhaustion of HSCs faster than that of multipotent progenitors and as fast as that of myeloid-committed progenitors. Ex vivo-expanded Nudt15R138C/R138C HSCs were dose- and time-dependently damaged by 6-MP. GO analysis identified the DNA damage response and cell cycle process as the most strongly influenced processes in Nudt15R138C/R138C HSCs. TRRUST analysis revealed that the Trp53-regulated transcriptional regulatory network is influenced prior to HSC exhaustion in Nudt15R138C/R138C HSCs. The loss of NUDT15 thiopurine detoxification enhances thiopurine-mediated DNA damage via the Trp53 networks in HSCs. Therefore, caution is required in long-term thiopurine use in patients with NUDT15 R139C in view of its adverse effects on HSCs in the form of DNA damage.
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Affiliation(s)
- Noriaki Yamashita
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Masahiro Kawahara
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan.
| | - Takayuki Imai
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Goichi Tatsumi
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Ai Asai-Nishishita
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
| | - Akira Andoh
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan
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Zhang K, Ni X, Ma X, Sun R, Qiu J, Luo C. LINC01012 upregulation promotes cervical cancer proliferation and migration via downregulation of CDKN2D. Oncol Lett 2023; 25:124. [PMID: 36844616 PMCID: PMC9950337 DOI: 10.3892/ol.2023.13710] [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: 08/21/2022] [Accepted: 01/12/2023] [Indexed: 02/10/2023] Open
Abstract
The incidence and mortality of cervical cancer (CC) rank fourth among those of all gynecological malignancies. Long noncoding RNAs (lncRNAs) serve important roles in the development of various types of cancer. The aim of the present study was to explore the role of lncRNAs in the pathogenesis of CC and to identify novel therapeutic targets. LINC01012 was identified to be associated with an unfavorable prognosis in patients with CC based on bioinformatics analyses. Upregulated LINC01012 expression was further verified in CC samples and in cervical intraepithelial neoplasia grade 3 tissues compared with healthy tissues using reverse transcription-quantitative PCR. Functionally, following transfection with LINC01012 short hairpin RNA (sh-LINC01012), the proliferation and migration of CC cell lines were examined using 5-ethynyl-2'-deoxyuridine staining, colony formation and Transwell assays, which demonstrated that knockdown of LINC01012 in CC cells suppressed cell proliferation and migration in vitro and tumor growth in an in vivo xenograft model. The potential mechanisms of LINC01012 were further explored. A negative association between LINC01012 and cyclin dependent kinase inhibitor 2D (CDKN2D) was also identified based on The Cancer Genome Atlas data and this was confirmed using western blotting and rescue experiments. Consistently, knockdown of LINC01012 in CC cells upregulated CDKN2D expression. The inhibition of proliferation and migration of CC cells following transfection with sh-LINC01012 was reversed following co-transfection of sh-LINC01012 and CDKN2D short hairpin RNA. These findings suggested that upregulated LINC01012 expression in CC may stimulate the proliferation and migration of cancer cells, thus promoting CC progression via downregulation of CDKN2D.
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Affiliation(s)
- Keyi Zhang
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210036, P.R. China
| | - Xiao Ni
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210036, P.R. China
| | - Xiaoling Ma
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210036, P.R. China
| | - Rui Sun
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210036, P.R. China
| | - Jiangnan Qiu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210036, P.R. China
| | - Chengyan Luo
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210036, P.R. China,Correspondence to: Professor Chengyan Luo, Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, 368 North Jiangdong Road, Nanjing, Jiangsu 210036, P.R. China, E-mail:
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6
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D'costa M, Bothe A, Das S, Udhaya Kumar S, Gnanasambandan R, George Priya Doss C. CDK regulators—Cell cycle progression or apoptosis—Scenarios in normal cells and cancerous cells. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 135:125-177. [PMID: 37061330 DOI: 10.1016/bs.apcsb.2022.11.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Serine/threonine kinases called cyclin-dependent kinases (CDKs) interact with cyclins and CDK inhibitors (CKIs) to control the catalytic activity. CDKs are essential controllers of RNA transcription and cell cycle advancement. The ubiquitous overactivity of the cell cycle CDKs is caused by a number of genetic and epigenetic processes in human cancer, and their suppression can result in both cell cycle arrest and apoptosis. This review focused on CDKs, describing their kinase activity, their role in phosphorylation inhibition, and CDK inhibitory proteins (CIP/KIP, INK 4, RPIC). We next compared the role of different CDKs, mainly p21, p27, p57, p16, p15, p18, and p19, in the cell cycle and apoptosis in cancer cells with respect to normal cells. The current work also draws attention to the use of CDKIs as therapeutics, overcoming the pharmacokinetic barriers of pan-CDK inhibitors, analyze new chemical classes that are effective at attacking the CDKs that control the cell cycle (cdk4/6 or cdk2). It also discusses CDKI's drawbacks and its combination therapy against cancer patients. These findings collectively demonstrate the complexity of cancer cell cycles and the need for targeted therapeutic intervention. In order to slow the progression of the disease or enhance clinical outcomes, new medicines may be discovered by researching the relationship between cell death and cell proliferation.
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Affiliation(s)
- Maria D'costa
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Anusha Bothe
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Soumik Das
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - S Udhaya Kumar
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - R Gnanasambandan
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
| | - C George Priya Doss
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
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7
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Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives. Cancers (Basel) 2021; 13:cancers13123035. [PMID: 34204543 PMCID: PMC8235237 DOI: 10.3390/cancers13123035] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/14/2021] [Accepted: 06/14/2021] [Indexed: 02/02/2023] Open
Abstract
Simple Summary Altered regulation of the cell cycle is a hallmark of cancer. The recent clinical success of the inhibitors of CDK4 and CDK6 has convincingly demonstrated that targeting cell cycle components may represent an effective anti-cancer strategy, at least in some cancer types. However, possible applications of CDK4/6 inhibitors in patients with ovarian cancer is still under evaluation. Here, we describe the possible biological role of CDK4 and CDK6 complexes in ovarian cancer and provide the rationale for the use of CDK4/6 inhibitors in this pathology, alone or in combination with other drugs. This review, coupling basic, preclinical and clinical research studies, could be of great translational value for investigators attempting to design new clinical trials for the better management of ovarian cancer patients. Abstract Alterations in components of the cell-cycle machinery are present in essentially all tumor types. In particular, molecular alterations resulting in dysregulation of the G1 to S phase transition have been observed in almost all human tumors, including ovarian cancer. These alterations have been identified as potential therapeutic targets in several cancer types, thereby stimulating the development of small molecule inhibitors of the cyclin dependent kinases. Among these, CDK4 and CDK6 inhibitors confirmed in clinical trials that CDKs might indeed represent valid therapeutic targets in, at least some, types of cancer. CDK4 and CDK6 inhibitors are now used in clinic for the treatment of patients with estrogen receptor positive metastatic breast cancer and their clinical use is being tested in many other cancer types, alone or in combination with other agents. Here, we review the role of CDK4 and CDK6 complexes in ovarian cancer and propose the possible use of their inhibitors in the treatment of ovarian cancer patients with different types and stages of disease.
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8
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Han X, Kuang Y, Chen H, Liu T, Zhang J, Liu J. p19INK4d: More than Just a Cyclin-Dependent Kinase Inhibitor. Curr Drug Targets 2021; 21:96-102. [PMID: 31400265 DOI: 10.2174/1389450120666190809161901] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 07/11/2019] [Accepted: 07/17/2019] [Indexed: 12/28/2022]
Abstract
Cyclin-dependent kinase inhibitors (CDKIs) are important cell cycle regulators. The CDKI family is composed of the INK4 family and the CIP/KIP family. p19INK4d belongs to the INK4 gene family and is involved in a series of normal physiological activities and the pathogenesis of diseases. Many factors play regulatory roles in the p19INK4d gene expression at the transcriptional and posttranscriptional levels. p19INK4d not only regulates the cell cycle but also plays regulatory roles in apoptosis, DNA damage repair, cell differentiation of hematopoietic cells, and cellular senescence. In this review, the regulatory network of the p19INK4d gene expression and its biological functions are summarized, which provides a basis for further study of p19INK4d as a drug target for disease treatment.
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Affiliation(s)
- Xu Han
- Molecular Biology Research Center and the Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Yijin Kuang
- Molecular Biology Research Center and the Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Huiyong Chen
- Molecular Biology Research Center and the Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Ting Liu
- Department of Rheumatology, the First Affiliated Hospital of South China University, Hengyang, Hunan, China
| | - Ji Zhang
- Department of Rheumatology, the First Affiliated Hospital of South China University, Hengyang, Hunan, China
| | - Jing Liu
- Molecular Biology Research Center and the Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
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Kumar S, Suman S, Fornace AJ, Datta K. Intestinal stem cells acquire premature senescence and senescence associated secretory phenotype concurrent with persistent DNA damage after heavy ion radiation in mice. Aging (Albany NY) 2020; 11:4145-4158. [PMID: 31239406 PMCID: PMC6629005 DOI: 10.18632/aging.102043] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 06/17/2019] [Indexed: 12/19/2022]
Abstract
Heavy ion radiation, prevalent in outer space and relevant for radiotherapy, is densely ionizing and poses risk to stem cells that are key to intestinal homeostasis. Currently, the molecular spectrum of heavy ion radiation-induced perturbations in intestinal stem cells (ISCs), that could trigger intestinal pathologies, remains largely unexplored. The Lgr5-EGFP-IRES-creERT mice were exposed to 50 cGy of iron radiation. Mice were euthanized 60 d after exposure and ISCs were sorted using fluorescence activated cell sorting. Reactive oxygen species (ROS) and mitochondrial superoxide were measured using fluorescent probes. Since DNA damage is linked to senescence and senescent cells acquire senescence-associated secretory phenotype (SASP), we stained ISCs for both senescence markers p16, p21, and p19 as well as SASP markers IL6, IL8, and VEGF. Due to potential positive effects of SASP on proliferation, we also stained for PCNA. Data show increased ROS and ongoing DNA damage, by staining for γH2AX, and 53BP1, along with accumulation of senescence markers. Results also showed increased SASP markers in senescent cells. Collectively, our data suggest that heavy-ion-induced chronic stress and ongoing DNA damage is promoting SASP in a fraction of the ISCs, which has implications for gastrointestinal function, inflammation, and carcinogenesis in astronauts and patients.
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Affiliation(s)
- Santosh Kumar
- Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Shubhankar Suman
- Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Albert J Fornace
- Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Kamal Datta
- Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
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Distinct plasma lipids profiles of recurrent ovarian cancer by liquid chromatography-mass spectrometry. Oncotarget 2018; 8:46834-46845. [PMID: 27564116 PMCID: PMC5564526 DOI: 10.18632/oncotarget.11603] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 07/29/2016] [Indexed: 12/24/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the most deadly gynecologic malignancy worldwide due to its high recurrence rate after surgery and chemotherapy. There is a critical need for discovery of novel biomarkers for EOC recurrence providing higher prediction power than that of the present ones. Lipids have been reported to associate with development and progression of cancer. In the current study, we aim to identify and validate the lipids which were relevant to the ovarian cancer recurrence based on plasma lipidomics performed by ultra-performance liquid chromatography coupled with mass spectrometry. In order to fulfill this objective, plasma from 70 EOC patients with follow up information was obtained. The results revealed that patients with and without recurrence could be clearly distinguished based on their lipid profiles. Thirty-one lipid metabolites were identified as potential biomarkers for EOC recurrence. The AUC value of these metabolite combinations for predicting EOC recurrence was 0.897. In terms of clinical applicability, LysoPG(20:5) arose as a potential EOC recurrence predictive biomarker to increase the predictive power of clinical predictors from AUC value 0.739 to 0.875. Additionally, we still found that individuals with early relapses (< 6 months) had a distinctive metabolomic pattern compared with late EOC and non-EOC recurrence subjects. Interestingly, decreased levels of triglycerides (TGs) were found to be a specific metabolic feature foreshadowing an early relapse. In conclusion, plasma lipidomics study could be used for predicting EOC recurrences, as well as early and late recurrent cases. The lipid biomarker research improves the predictive power of clinical predictors and the identified biomarkers are of great prognostic and therapeutic potential.
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11
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Zang X, Chen M, Zhou Y, Xiao G, Xie Y, Wang X. Identifying CDKN3 Gene Expression as a Prognostic Biomarker in Lung Adenocarcinoma via Meta-analysis. Cancer Inform 2015; 14:183-91. [PMID: 26052221 PMCID: PMC4444140 DOI: 10.4137/cin.s17287] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 01/30/2015] [Accepted: 02/09/2015] [Indexed: 02/06/2023] Open
Abstract
Lung cancer is among the major causes of cancer deaths, and the survival rate of lung cancer patients is extremely low. Recent studies have demonstrated that the gene CDKN3 is related to neoplasia, but in the literature severe controversy exists over whether it is involved in cancer progression or, conversely, tumor inhibition. In this study, we investigated the expression of CDKN3 and its association with prognosis in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) using datasets in Lung Cancer Explorer (LCE; http://qbrc.swmed.edu/lce/). We found that CDKN3 was up-regulated in ADC and SCC compared to normal tissues. We also found that CDKN3 was expressed at a higher level in SCC than in ADC, which was further validated through meta-analysis (coefficient = 2.09, 95% CI = 1.50-2.67, P < 0.0001). In addition, based on meta-analysis for the prognostic value of CDKN3, we found that higher CDKN3 expression was associated with poorer survival outcomes in ADC (HR = 1.65, 95% CI = 1.39-1.96, P < 0.0001), but not in SCC (HR = 1.10, 95% CI = 0.84-1.44, P = 0.494). Our findings indicate that CDKN3 may be a prognostic marker in ADC, though the detailed mechanism is yet to be revealed.
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Affiliation(s)
- Xiao Zang
- Quantitative Biomedical Research Center, Department of Clinical Sciences
| | - Min Chen
- Department of Mathematical Sciences, University of Texas at Dallas
| | - Yunyun Zhou
- Quantitative Biomedical Research Center, Department of Clinical Sciences
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center
| | - Guanghua Xiao
- Quantitative Biomedical Research Center, Department of Clinical Sciences
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center
| | - Yang Xie
- Quantitative Biomedical Research Center, Department of Clinical Sciences
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center
| | - Xinlei Wang
- Department of Statistics, Southern Methodist University
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Zang WQ, Yang X, Wang T, Wang YY, Du YW, Chen XN, Li M, Zhao GQ. MiR-451 inhibits proliferation of esophageal carcinoma cell line EC9706 by targeting CDKN2D and MAP3K1. World J Gastroenterol 2015; 21:5867-5876. [PMID: 26019450 PMCID: PMC4438020 DOI: 10.3748/wjg.v21.i19.5867] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 01/15/2015] [Accepted: 02/13/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the underlying molecular mechanisms of miR-451 to inhibit proliferation of esophageal carcinoma cell line EC9706.
METHODS: Assays for cell growth, apoptosis and invasion were used to evaluate the effects of miR-451 expression on EC cells. Luciferase reporter and Western blot assays were used to test whether cyclin-dependent kinase inhibitor 2D (CDKN2D) and MAP3K1 act as major targets of miR-451.
RESULTS: The results showed that CDKN2D and MAP3K1 are direct targets of miR-451. CDKN2D and MAP3K1 overexpression reversed the effect of miR-451. MiR-451 inhibited the proliferation of EC9706 by targeting CDKN2D and MAP3K1.
CONCLUSION: These findings suggest that miR-451 might be a novel prognostic biomarker and a potential target for the treatment of esophageal squamous cell carcinoma in the future.
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13
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Li T, Xue H, Guo Y, Guo K. CDKN3 is an independent prognostic factor and promotes ovarian carcinoma cell proliferation in ovarian cancer. Oncol Rep 2014; 31:1825-31. [PMID: 24573179 DOI: 10.3892/or.2014.3045] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 02/06/2014] [Indexed: 11/06/2022] Open
Abstract
Cyclin-dependent kinase inhibitor 3 (CDKN3) has been reported to promote tumor genesis. Since it is unclear whether CDKN3 participates in the development of epithelial ovarian cancer (EOC), this study assessed the association between CDKN3 expression and cell biological functions, and demonstrated the clinical significance and prognosis of CDKN3 in EOC. CDKN3 expression was evaluated in 97 cases of tumor tissue by immunohistochemistry and in 60 tissues by western blotting. The clinical correlation was analyzed by Kaplan-Meier method and Cox hazards model. The molecular functional roles of CDKN3 in ovarian cancer cell line OVCAR3 were examined by small interfering RNA-mediated depletion of the protein followed by analyses of cell proliferation and invasion. Twenty-three out of 30 (76.7%) human EOC tissues exhibited stronger levels of CDKN3 protein compared with 10 out of 30 (33.3%) human ovarian surface epithelial (HOSE) tissues. The mean level of CDKN3 expression in the EOC tissues was 3.35-fold that in the HOSE tissues. CDKN3 protein was found to be overexpressed in 68.0% of the EOC samples and was correlated with poor patient survival (P<0.05). Furthermore, expression of CDKN3 was significantly associated with FIGO stage, recurrence and residual tumor size (P<0.05), and the CDKN3 status was a significant prognostic factor for EOC patients (P=0.005). In addition, depletion of CDKN3 expression inhibited the growth and clonogenic potential of the OVCAR3 cell line. Our present research found that CDKN3 may play an important role in the development and proliferation of EOC. CDKN3 may be used as a novel tumor marker to predict the prognosis of EOC.
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Affiliation(s)
- Tianren Li
- Department of Gynecology, The First Hospital of China Medical University, Shenyang 110001, P.R. China
| | - Hui Xue
- Department of Gynecology, The First Hospital of China Medical University, Shenyang 110001, P.R. China
| | - Yi Guo
- Department of Gynecology, The First Hospital of China Medical University, Shenyang 110001, P.R. China
| | - Kejun Guo
- Department of Gynecology, The First Hospital of China Medical University, Shenyang 110001, P.R. China
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