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Tian Y, Zhang M, Liu LX, Wang ZC, Liu B, Huang Y, Wang X, Ling YZ, Wang F, Feng X, Tu Y. Exploring non-coding RNA mechanisms in hepatocellular carcinoma: implications for therapy and prognosis. Front Immunol 2024; 15:1400744. [PMID: 38799446 PMCID: PMC11116607 DOI: 10.3389/fimmu.2024.1400744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 04/03/2024] [Indexed: 05/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.
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Affiliation(s)
- Yu Tian
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
- School of Public Health, Benedictine University, Lisle, IL, United States
| | - Meng Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, China
| | - Li-xia Liu
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Zi-chao Wang
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Bin Liu
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Youcai Huang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoling Wang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Yun-zhi Ling
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Furong Wang
- Department of Pathology, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People’s Hospital, Gaozhou, Guangdong, China
| | - Yanyang Tu
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
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Creff J, Besson A. Functional Versatility of the CDK Inhibitor p57 Kip2. Front Cell Dev Biol 2020; 8:584590. [PMID: 33117811 PMCID: PMC7575724 DOI: 10.3389/fcell.2020.584590] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/17/2020] [Indexed: 12/19/2022] Open
Abstract
The cyclin/CDK inhibitor p57Kip2 belongs to the Cip/Kip family, with p21Cip1 and p27Kip1, and is the least studied member of the family. Unlike the other family members, p57Kip2 has a unique role during embryogenesis and is the only CDK inhibitor required for embryonic development. p57Kip2 is encoded by the imprinted gene CDKN1C, which is the gene most frequently silenced or mutated in the genetic disorder Beckwith-Wiedemann syndrome (BWS), characterized by multiple developmental anomalies. Although initially identified as a cell cycle inhibitor based on its homology to other Cip/Kip family proteins, multiple novel functions have been ascribed to p57Kip2 in recent years that participate in the control of various cellular processes, including apoptosis, migration and transcription. Here, we will review our current knowledge on p57Kip2 structure, regulation, and its diverse functions during development and homeostasis, as well as its potential implication in the development of various pathologies, including cancer.
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Affiliation(s)
- Justine Creff
- Centre National de la Recherche Scientifique, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Centre de Biologie Intégrative, Université de Toulouse, Toulouse, France
| | - Arnaud Besson
- Centre National de la Recherche Scientifique, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Centre de Biologie Intégrative, Université de Toulouse, Toulouse, France
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Rafiee A, Riazi-Rad F, Havaskary M, Nuri F. Long noncoding RNAs: regulation, function and cancer. Biotechnol Genet Eng Rev 2018; 34:153-180. [PMID: 30071765 DOI: 10.1080/02648725.2018.1471566] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Long noncoding RNAs (lncRNAs) are non-protein-coding RNA transcripts that exert a key role in many cellular processes and have potential toward addressing disease etiology. Here, we review existing noncoding RNA classes and then describe a variety of mechanisms and functions by which lncRNAs regulate gene expression such as chromatin remodeling, genomic imprinting, gene transcription and post-transcriptional processing. We also examine several lncRNAs that contribute significantly to pathogenesis, oncogenesis, tumor suppression and cell cycle arrest of diverse cancer types and also give a summary of the pathways that lncRNAs might be involved in.
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Affiliation(s)
- Aras Rafiee
- a Department of Biology , Central Tehran Branch, Islamic Azad University , Tehran , Iran
| | - Farhad Riazi-Rad
- b Immunology Department , Pasteur institute of Iran , Tehran , Iran
| | - Mohammad Havaskary
- c Young Researchers Club, Central Tehran Branch, Islamic Azad University , Tehran , Iran
| | - Fatemeh Nuri
- d Department of Biology , Central Tehran Branch, Islamic Azad University , Tehran , Iran
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Ramalho LN, Porta LD, Rosim RE, Petta T, Augusto MJ, Silva DM, Ramalho FS, Oliveira CA. Aflatoxin B 1 residues in human livers and their relationship with markers of hepatic carcinogenesis in São Paulo, Brazil. Toxicol Rep 2018; 5:777-784. [PMID: 30101081 PMCID: PMC6082919 DOI: 10.1016/j.toxrep.2018.07.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 05/10/2018] [Accepted: 07/25/2018] [Indexed: 01/15/2023] Open
Abstract
In this study, hepatic biopsies from autopsy cases in São Paulo, Brazil, showing hepatocellular carcinoma (HCC, n = 8), cirrhosis associated with viral hepatitis (VC, n = 20), cirrhosis associated with alcoholism (AC, n = 20), and normal livers (NL or controls, n = 10) were subjected to determination of aflatoxin B1 (AFB1) and its main metabolites, and of markers of hepatic carcinogenesis Only non-metabolized AFB1 was detected in 13 samples (27.1%, N = 48) of liver disorders (HCC, VC and AC), at levels between 10.0 and 418.0 pg/g (mean: 76.6 ± 107.7 pg/g). Immuno-labeling of p53, cyclin D1, p21, β-catenin, and Prohibitin (PB) increased mainly in HCC patients, in relation to the controls. AFB1+ samples of HCC presented higher expressions of p53, cyclin D1, p21, and β-catenin compared with AFB1-livers. In contrast, p27, p16, and Rb immuno-labeling decreased in HCC, VC, and AC samples, compared with NL, with lowest values in AFB1+ samples for all liver disorders. Compared with NL, gene expression of cyclin D1 and PB in AFB1+ samples of HCC and AC were also higher, along with higher gene expression of p21 in VC and AC AFB1+ livers. Results indicated that patients with liver disorders were exposed to dietary aflatoxins, and that residual AFB1 in liver negatively affected the p53 and protein Rb pathways in HCC. Moreover, the presence of AFB1 in cirrhotic livers warrants concern about the potential contribution of dietary aflatoxin to disease progression during VC and AC.
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Affiliation(s)
- Leandra N.Z. Ramalho
- Department of Pathology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Livia D. Porta
- Department of Pathology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Roice E. Rosim
- Department of Food Engineering, School of Animal Science and Food Engineering, University of São Paulo, Av. Duque de Caxias – Norte, 225, CEP 13635-900, Pirassununga, SP, Brazil
| | - Tânia Petta
- Department of Biochemistry and Immunology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Marlei J. Augusto
- Department of Pathology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Deisy M. Silva
- Department of Pathology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Fernando S. Ramalho
- Department of Pathology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Carlos A.F. Oliveira
- Department of Food Engineering, School of Animal Science and Food Engineering, University of São Paulo, Av. Duque de Caxias – Norte, 225, CEP 13635-900, Pirassununga, SP, Brazil
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Berretta M, Cavaliere C, Alessandrini L, Stanzione B, Facchini G, Balestreri L, Perin T, Canzonieri V. Serum and tissue markers in hepatocellular carcinoma and cholangiocarcinoma: clinical and prognostic implications. Oncotarget 2017; 8:14192-14220. [PMID: 28077782 PMCID: PMC5355172 DOI: 10.18632/oncotarget.13929] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 10/28/2016] [Indexed: 12/12/2022] Open
Abstract
HCC represents the sixth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options for advanced HCC remain limited and unsuccessful, resulting in a poor prognosis. Despite the major advances achieved in the diagnostic management of HCC, only one third of the newly diagnosed patients are presently eligible for curative treatments. Advances in technology and an increased understanding of HCC biology have led to the discovery of novel biomarkers. Improving our knowledge about serum and tissutal markers could ultimately lead to an early diagnosis and better and early treatment strategies for this deadly disease. Serum biomarkers are striking potential tools for surveillance and early diagnosis of HCC thanks to the non-invasive, objective, and reproducible assessments they potentially enable. To date, many biomarkers have been proposed in the diagnosis of HCC. Cholangiocarcinoma (CCA) is an aggressive malignancy, characterized by early lymph node involvement and distant metastasis, with 5-year survival rates of 5%-10%. The identification of new biomarkers with diagnostic, prognostic or predictive value is especially important as resection (by surgery or combined with a liver transplant) has shown promising results and novel therapies are emerging. However, the relatively low incidence of CCA, high frequency of co-existing cholestasis or cholangitis (primary sclerosing cholangitis –PSC- above all), and difficulties with obtaining adequate samples, despite advances in sampling techniques and in endoscopic visualization of the bile ducts, have complicated the search for accurate biomarkers. In this review, we attempt to analyze the existing literature on this argument.
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Affiliation(s)
| | - Carla Cavaliere
- Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto Taranto, Italy
| | - Lara Alessandrini
- Division of Pathology, National Cancer Institute, Aviano (PN), Italy
| | - Brigida Stanzione
- Department of Medical Oncology, National Cancer Institute, Aviano (PN), Italy
| | - Gaetano Facchini
- Department of Medical Oncology, National Cancer Institute, "G. Pascale" Foundation, Naples, Italy
| | - Luca Balestreri
- Department of Radiology, National Cancer Institute, Aviano (PN), Italy
| | - Tiziana Perin
- Division of Pathology, National Cancer Institute, Aviano (PN), Italy
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Cellular Response upon Stress: p57 Contribution to the Final Outcome. Mediators Inflamm 2015; 2015:259325. [PMID: 26491224 PMCID: PMC4600511 DOI: 10.1155/2015/259325] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 04/17/2015] [Accepted: 05/05/2015] [Indexed: 02/06/2023] Open
Abstract
Progression through the cell cycle is one of the most important decisions during the life of a cell and several kinds of stress are able to influence this choice. p57 is a cyclin-dependent kinase inhibitor belonging to the CIP/KIP family and is a well-known regulator of the cell cycle during embryogenesis and tissue differentiation. p57 loss has been reported in a variety of cancers and great effort has been spent during the past years studying the mechanisms of p57 regulation and the effects of p57 reexpression on tumor growth. Recently, growing amount of evidence points out that p57 has a specific function in cell cycle regulation upon cellular stress that is only partially shared by the other CIP/KIP inhibitors p21 and p27. Furthermore, it is nowadays emerging that p57 plays a role in the induction of apoptosis and senescence after cellular stress independently of its cell cycle related functions. This review focuses on the contribution that p57 holds in regulating cell cycle arrest, apoptosis, and senescence after cellular stress with particular attention to the response of cancer cells.
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Eggermann T, Binder G, Brioude F, Maher ER, Lapunzina P, Cubellis MV, Bergadá I, Prawitt D, Begemann M. CDKN1C mutations: two sides of the same coin. Trends Mol Med 2014; 20:614-22. [PMID: 25262539 DOI: 10.1016/j.molmed.2014.09.001] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 08/13/2014] [Accepted: 09/02/2014] [Indexed: 01/03/2023]
Abstract
Cyclin-dependent kinase (CDK)-inhibitor 1C (CDKN1C) negatively regulates cellular proliferation and it has been shown that loss-of-function mutations in the imprinted CDKN1C gene (11p15.5) are associated with the overgrowth disorder Beckwith-Wiedemann syndrome (BWS). With recent reports of gain-of-function mutations of the PCNA domain of CDKN1C in growth-retarded patients with IMAGe syndrome or Silver-Russell syndrome (SRS), its key role for growth has been confirmed. Thereby, the last gap in the spectrum of molecular alterations in 11p15.5 in growth-retardation and overgrowth syndromes could be closed. Recent functional studies explain the strict association of CDKN1C mutations with clinically opposite phenotypes and thereby contribute to our understanding of the function and regulation of the gene in particular and epigenetic regulation in general.
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Affiliation(s)
- Thomas Eggermann
- Institute of Human Genetics, University Hospital, Technical University Aachen, Aachen, Germany.
| | - Gerhard Binder
- University Children's Hospital, Paediatric Endocrinology, University of Tübingen, Tübingen, Germany
| | - Frédéric Brioude
- AP-HP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, Paris, France
| | - Eamonn R Maher
- Department of Medical Genetics, University of Cambridge, Cambridge, UK; NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Pablo Lapunzina
- INGEMM, Instituto de Genética Médica y Molecular, Hospital Universitario La Paz, IdiPAZ, CIBERER-ISCIII, Madrid, Spain
| | | | - Ignacio Bergadá
- Centro de Investigaciones Endocrinológicas 'Dr César Bergadá' (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Dirk Prawitt
- Molekulare Pädiatrie, Zentrum für Kinder- und Jugendmedizin, Universitätsmedizin Mainz, Mainz, Germany
| | - Matthias Begemann
- Institute of Human Genetics, University Hospital, Technical University Aachen, Aachen, Germany
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MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches. Cell Death Differ 2014; 22:46-57. [PMID: 25190143 DOI: 10.1038/cdd.2014.136] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 07/02/2014] [Accepted: 07/24/2014] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) constitute a large class of short RNAs (e.g., 20-24 nucleotides in length), whose main function is to posttranscriptionally regulate the expression of protein-coding genes. Their importance in tumorigenesis has been demonstrated over the past decade, and correspondingly, they have emerged as potential therapeutic molecules and targets. Liver cancer is one of the most common neoplastic diseases worldwide, and it currently has a poor prognosis owing to largely ineffective therapeutic options. Liver cancer is also an excellent model for testing miRNA-based therapy approaches as it can be easily targeted with the systemic delivery of oligonucleotides. In recent years, the role of miRNAs in hepatocellular carcinoma (HCC) has been established with molecular studies and the development of animal models. These studies have also provided the basis for evaluating the therapeutic potential of miRNAs, or anti-miRNAs. In general, the safety of miRNAs has been proven and antitumor activity has been observed. Moreover, because of the absence or presence of mild side effects, the prophylactic use of miRNA-based approaches may be foreseen.
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Nguyen NMP, Zhang L, Reddy R, Déry C, Arseneau J, Cheung A, Surti U, Hoffner L, Seoud M, Zaatari G, Bagga R, Srinivasan R, Coullin P, Ao A, Slim R. Comprehensive genotype-phenotype correlations between NLRP7 mutations and the balance between embryonic tissue differentiation and trophoblastic proliferation. J Med Genet 2014; 51:623-34. [PMID: 25097207 DOI: 10.1136/jmedgenet-2014-102546] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND Hydatidiform mole (HM) is a human pregnancy with excessive trophoblastic proliferation and abnormal embryonic development that may be sporadic or recurrent. In the sporadic form, the HM phenotype is driven by an abnormal ratio of paternal to maternal genomes, whereas in the recurrent form, the HM phenotype is caused by maternal-recessive mutations, mostly in NLRP7, despite the diploid biparental origin of the HM tissues. In this study, we characterised the expression of the imprinted, maternally expressed gene, CDKN1C (p57(KIP2)), the genotype, and the histopathology of 36 products of conception (POC) from patients with two defective alleles in NLRP7 and looked for potential correlations between the nature of the mutations in the patients and the various HM features. METHODS/RESULTS We found that all the 36 POCs are diploid biparental and have the same parental contribution to their genomes. However, some of them expressed variable levels of p57(KIP2) and this expression was strongly associated with the presence of embryonic tissues of inner cell mass origin and mild trophoblastic proliferation, which are features of triploid partial HMs, and were associated with missense mutations. Negative p57(KIP2) expression was associated with the absence of embryonic tissues and excessive trophoblastic proliferation, which are features of androgenetic complete HMs and were associated with protein-truncating mutations. CONCLUSIONS Our data suggest that NLRP7, depending on the severity of its mutations, regulates the imprinted expression of p57(KIP2) and consequently the balance between tissue differentiation and proliferation during early human development. This role is novel and could not have been revealed by any other approach on somatic cells.
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Affiliation(s)
- Ngoc Minh Phuong Nguyen
- Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Li Zhang
- Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Ramesh Reddy
- Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Christine Déry
- Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Jocelyne Arseneau
- Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Annie Cheung
- Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Urvashi Surti
- Department of Pathology, University of Pittsburgh, Magee-Womens Hospital, Pittsburgh, Pennsylvania, USA
| | - Lori Hoffner
- Department of Pathology, University of Pittsburgh, Magee-Womens Hospital, Pittsburgh, Pennsylvania, USA
| | - Muhieddine Seoud
- Department of Obstetrics and Gynecology, American University of Beirut, Beirut, Lebanon
| | - Ghazi Zaatari
- Department of Pathology, American University of Beirut, Beirut, Lebanon
| | - Rashmi Bagga
- Department of Obstetrics & Gynecology, Post Graduate Institute of Medical Education and Research, PGIMER, Chandigarh, India
| | - Radhika Srinivasan
- Cytology & Gynecological Pathology, Post Graduate Institute of Medical Education and Research, PGIMER, Chandigarh, India
| | - Philippe Coullin
- INSERM U782, Endocrinologie et Génétique de la Reproduction et du Développement, Clamart, France
| | - Asangla Ao
- Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Rima Slim
- Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada
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Hamid AS, Li J, Wang Y, Wu X, Ali HAA, Du Z, Bo L, Zhang Y, Zhang G. Recombinant human decorin upregulates p57KIP² expression in HepG2 hepatoma cell lines. Mol Med Rep 2013; 8:511-6. [PMID: 23754492 DOI: 10.3892/mmr.2013.1510] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 04/24/2013] [Indexed: 12/15/2022] Open
Abstract
Increasing the expression of cyclin-cyclin-dependent kinase inhibitors (cyclin-CDK) using small molecule inhibitors is a therapeutic strategy used to suppress cancer cell growth. Decorin (DCN), a functional component of the extracellular matrix, has been implicated in the suppression of cell proliferation by upregulating p21, a cyclin-CDK inhibitor. The purpose of this study was to examine the effect of recombinant decorin on the reactivation of p57KIP2, whose expression is silenced in hepatocellular carcinoma (HCC). Cell viability assay, cell cycle analysis, apoptosis assay and quantitative real time-PCR experiments were performed in three groups of HepG2 human cells: Uninfected HepG2 cells (control group), pcDNA3.1 vector-infected HepG2 cells (pcDNA3.1 group) and pcDNA3.1-DCN-infected HepG2 cells (pcDNA3.1‑DCN group). Our results revealed that recombinant human decorin inhibited cell proliferation, induced G0/G1 phase arrest and induced apoptosis by increasing the expression of caspase-3 in the pcDNA3.1-DCN group. The expression of p57KIP2 mRNA in the pcDNA3.1-DCN group was higher than in the pcDNA3.1 and control groups (P<0.05); however, there was no statistically significant difference between the control and pcDNA3.1 groups (P>0.05). In conclusion, recombinant human decorin reactivated p57KIP2 expression in HepG2 cells. As the expression level of p57KIP2 is downregulated in HCC, our finding may serve as a basis for the therapy and prognosis of HCC, although further studies are required.
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Affiliation(s)
- Abdu Selim Hamid
- Central Laboratory, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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Holm R, Førsund M, Nguyen MT, Nesland JM, Trope CG. Expression of p15INK⁴b and p57KIP² and relationship with clinicopathological features and prognosis in patients with vulvar squamous cell carcinoma. PLoS One 2013; 8:e61273. [PMID: 23580324 PMCID: PMC3620337 DOI: 10.1371/journal.pone.0061273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Accepted: 03/09/2013] [Indexed: 12/03/2022] Open
Abstract
Background The cyclin-dependent kinase inhibitors p15INK4b and p57KIP2 are important regulators of the cell cycle, and their abnormal expression has been detected in various tumors. However, little is known about the role of p15INK4b and p57KIP2 in the pathogenesis of vulvar carcinoma, and the prognostic impact is still unknown. In our current study, we examined the expression of p15INK4b and p57KIP2 in a large series of vulvar squamous cell carcinomas to elucidate the prognostic impact. Methods Expression of p15INK4b and p57KIP2 were examined in 297 vulvar squamous cell carcinomas using immunohistochemistry. Both uni- and multivariate analysis of prognostic factors were performed, and correlations with clinicopathologic parameters were examined. Results Compared to the high levels of p15INK4b and p57KIP2 in normal vulvar squamous epithelium, low levels of p15INK4b and p57KIP2 were found in 82% and 44% of vulvar carcinomas, respectively. Low levels of p15INK4b and p57KIP2 correlated significantly with malignant features, including large tumor diameter (p = 0.03 and p = 0.001, respectively) and increased invasiveness (p = 0.003 and p = 0.04, respectively). Although p15INK4b and p57KIP2 levels could not be identified as prognostic markers, combined analysis of p14ARF/p15INK4b/p16INK4a showed that patients whose tumors expressed low levels of two or three of these INK4 proteins had a worse prognosis than those with only low levels of one or no protein (univariate analysis p = 0.02). The independent prognostic significance of these INK4 proteins was confirmed by multivariate analysis (p = 0.008). Conclusions We show for the first time that p15INK4b and p57KIP2 may be involved in the progression of vulvar carcinomas and the combined p14ARF/p15INK4b/p16INK4a status was a statistically independent prognostic factor.
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Affiliation(s)
- Ruth Holm
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
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12
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Critelli RM, Cariani E, Villa E. Expression Profiling of Hepatocellular Carcinoma. CANCER GENOMICS 2013:163-184. [DOI: 10.1007/978-94-007-5842-1_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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13
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Giovannini C, Gramantieri L, Minguzzi M, Fornari F, Chieco P, Grazi GL, Bolondi L. CDKN1C/P57 Is Regulated by the Notch Target Gene Hes1 and Induces Senescence in Human Hepatocellular Carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:413-22. [DOI: 10.1016/j.ajpath.2012.04.019] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2011] [Revised: 04/03/2012] [Accepted: 04/24/2012] [Indexed: 11/16/2022]
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Kavanagh E, Vlachos P, Emourgeon V, Rodhe J, Joseph B. p57(KIP2) control of actin cytoskeleton dynamics is responsible for its mitochondrial pro-apoptotic effect. Cell Death Dis 2012; 3:e311. [PMID: 22592318 PMCID: PMC3366085 DOI: 10.1038/cddis.2012.51] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
p57 (Kip2, cyclin-dependent kinase inhibitor 1C), often found downregulated in cancer, is reported to hold tumor suppressor properties. Originally described as a cyclin-dependent kinase (cdk) inhibitor, p57(KIP2) has since been shown to influence other cellular processes, beyond cell cycle regulation, including cell death and cell migration. Inhibition of cell migration by p57(KIP2) is attributed to the stabilization of the actin cytoskeleton through the activation of LIM domain kinase-1 (LIMK-1). Furthermore, p57(KIP2) is able to enhance mitochondrial-mediated apoptosis. Here, we report that the cell death promoting effect of p57(KIP2) is linked to its effect on the actin cytoskeleton. Indeed, whereas Jasplakinolide, an actin cytoskeleton-stabilizing agent, mimicked p57(KIP2)'s pro-apoptotic effect, destabilizing the actin cytoskeleton with cytochalsin D reversed p57(KIP2)'s pro-apoptotic function. Conversely, LIMK-1, the enzyme mediating p57(KIP2)'s effect on the actin cytoskeleton, was required for p57(KIP2)'s death promoting effect. Finally, p57(KIP2-)mediated stabilization of the actin cytoskeleton was associated with the displacement of hexokinase-1, an inhibitor of the mitochondrial voltage-dependent anion channel, from the mitochondria, providing a possible mechanism for the promotion of the mitochondrial apoptotic cell death pathway. Altogether, our findings link together two tumor suppressor properties of p57(KIP2), by showing that the promotion of cell death by p57(KIP2) requires its actin cytoskeleton stabilization function.
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Affiliation(s)
- E Kavanagh
- Department of Oncology-Pathology, Cancer Centrum Karolinska, R8:03, Karolinska Institutet, SE-171 76 Stockholm, Sweden
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15
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Chow SE, Wang JS, Lin MR, Lee CL. Downregulation of p57kip² promotes cell invasion via LIMK/cofilin pathway in human nasopharyngeal carcinoma cells. J Cell Biochem 2012; 112:3459-68. [PMID: 21769918 DOI: 10.1002/jcb.23277] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The members of Rho family are well known for their regulation of actin cytoskeleton to control cell migration. The Cip/kip members of cyclin-dependent (CDK) inhibitors have shown to implicate in cell migration and cytoskeletal dynamics. p57(kip2) , a CDK inhibitor, is frequently down-regulated in several malignancy tumors. However, its biological roles in human nasopharyngeal carcinoma (NPC) cells remained to be investigated. Here, we found p57(kip2) has nuclear and cytoplasm distributions and depletion of endogenous p57(kip2) did not change the cell-cycle progression. Inhibition of cell proliferation by mitomycin C promoted FBS-mediated cell migration and accompanied with the downregulation of ΔNp63α and p57(kip2), but did not change the level of p27(kip1) , another CDK inhibitor. By using siRNA transfection and cell migration/invasion assays, we found that knockdown of p57(kip2) , but not ΔNp63α, involved in promotion of NPC cell migration and invasion via decrease of phospho-cofilin (p-cofilin). Treatment with Y-27632, a specific ROCK inhibitor, we found that dysregulation of ROCK/cofilin pathway decreased p-cofilin expression and induced cell migration. This change of p-cofilin induced actin remodeling and pronounced increase of membrane protrusions. Further, silence of p57(kip2) not only decreased the interaction between p57(kip2) and LIMK-1 assayed by immunoprecipitation but also reduced the level of phospho-LIMK1/2. Therefore, this study indicated that dysregulation of p57(kip2) promoted cell migration and invasion through modulation of LIMK/cofilin signaling and suggested this induction of inappropriate cell motility might contribute to promoting tumor cell for metastasis.
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Affiliation(s)
- Shu-Er Chow
- Center for General Studies, Chang Gung University, Taoyuan, Taiwan.
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16
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Wang H, Wen W. Biomarkers of Hepatocellular Carcinoma. PRIMARY LIVER CANCER 2012:79-154. [DOI: 10.1007/978-3-642-28702-2_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Guo H, Lv Y, Tian T, Hu TH, Wang WJ, Sui X, Jiang L, Ruan ZP, Nan KJ. Downregulation of p57 accelerates the growth and invasion of hepatocellular carcinoma. Carcinogenesis 2011; 32:1897-904. [PMID: 22002319 DOI: 10.1093/carcin/bgr220] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
p57 is a multifunctional protein involved in the regulation of tumor formation and development; however, the biological role of p57 in the pathogenesis of hepatocellular carcinoma (HCC) is poorly understood. To explore the role of p57 in the development of HCC, we examined p57 messenger RNA (mRNA) and protein levels in HCC tissues and adjacent non-cancerous tissues by immunohistochemistry, real-time polymerase chain reaction and western blot analysis. Moreover, we generated stable p57 knockdown HCC cell lines to investigate the impact of p57 downregulation on the growth and invasion of HCC in vitro and in vivo. Our results showed that p57 mRNA and protein levels were significantly decreased in human HCC tissues. In addition, this reduction in p57 expression was associated with increased tumor size, more advanced TNM stages, the presence of capsule invasion and extrahepatic metastasis and decreased overall survival time. In human HCC cell lines, p57 downregulation increased the expression of cyclin D1 and CDK2 and enhanced the activities of CDK4/cyclin D1 and CDK2/cyclin E complexes, resulting in increased cellular proliferation and growth of xenografts. Furthermore, p57 downregulation accelerated the invasion of HCC cells in vitro and in vivo by controlling the activity of LIMK1. In conclusion, the downregulation of p57 accelerates the growth and invasion of HCC, indicating that p57 is an important tumor suppressor in HCC. Based on these findings, p57 may be a potential target for HCC prevention and therapy.
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Affiliation(s)
- Hui Guo
- Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, People's Republic of China
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18
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Stem cell associated genes working with one miRNA cluster have different clinic pathologic values in gastric cancer. Pathol Oncol Res 2011; 17:939-46. [PMID: 21553350 DOI: 10.1007/s12253-011-9407-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Accepted: 04/26/2011] [Indexed: 10/18/2022]
Abstract
Cancer stem cells are nowadays considered to be the origin of cancer. Also, stem cell associated genes are emerging as predictors of cancer malignancy. We investigated the association of several stemness genes (c-Myc, PTEN, p57 and p21) with clinic pathological parameters and survival in stomach cancer by performing immunohistochemistry on paraffin sections of gastric cancer patients who underwent surgical staging with following-up statistics. We discovered that expression of c-Myc was significantly related to distant metastasis, the combined expression of PTEN and p21 correlated positively to overall survival, while p57 was less useful in overall survival prediction in gastric cancer. Additionally, there is a positive correlation between expressions of p57 and p21. In conclusion, our present study indicated that expression of stemness genes (c-Myc, PTEN, p57 and p21) performed different predictive potential in the evaluation of clinical malignancy levels in gastric cancer.
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The hallmarks of CDKN1C (p57, KIP2) in cancer. Biochim Biophys Acta Rev Cancer 2011; 1816:50-6. [PMID: 21447370 DOI: 10.1016/j.bbcan.2011.03.002] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Revised: 03/18/2011] [Accepted: 03/22/2011] [Indexed: 12/18/2022]
Abstract
Cyclin-dependent kinase inhibitor 1C CDKN1C (p57(KIP2)) regulates several hallmarks of cancer, including apoptosis, cell invasion and metastasis, tumor differentiation and angiogenesis. p57(KIP2) is generally not mutated in cancer, but its expression is downregulated through epigenetic changes such as DNA methylation and repressive histone marks at the promoter. This opens up possibilities for therapeutic intervention through reactivation of p57(KIP2) gene expression. Furthermore, p57(KIP2) has been tested as a prognostic factor for many types of cancer, even differentiating between early and late stage cancer. In this review, the multifunctional tumor suppressor capabilities of p57(KIP2), the mechanisms of p57(KIP2) transcriptional repression in cancer, and the therapeutic potential of reactivation of p57(KIP2) protein expression will be discussed.
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20
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PELLEGRINI M, ARGIBAY P, GOMEZ D. Dietary factors, genetic and epigenetic influences in colorectal cancer. Exp Ther Med 2010; 1:241-250. [PMID: 22993535 PMCID: PMC3445943 DOI: 10.3892/etm_00000038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 11/10/2009] [Indexed: 01/05/2023] Open
Abstract
Genetic influences, together with epigenetic components and dietary factors, play a fundamental role in the initiation and progression of cancer by causing a number of deregulations. Colorectal cancer (CRC) is a disease influenced by dietary factors, for which established genetic and epigenetic alterations have been identified. Within CRC, there are hereditary syndromes that present mutations in the germ-line hMLH1, and also alterations in the methylation of the promoters. Epigenetics has also been established as a pathway of carcinogenesis. In the present review, we analyzed studies conducted to discern the different pathways leading to established CRC, stressing the importance of identifying factors that may predict CRC at an early stage, since it is mostly a silent disease observed at the clinical level in advanced stages.
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Affiliation(s)
- M.L. PELLEGRINI
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires
| | - P. ARGIBAY
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires
| | - D.E. GOMEZ
- Laboratorio de Oncología Molecular, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Buenos Aires,
Argentina
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Akaishi K, Nakayama J, Sakai K, Kobayashi T, Rutka JT. Antigen p57/Kip2 as a potential negative regulator of human astrocytoma growth. J Clin Neurosci 2009; 16:1615-8. [DOI: 10.1016/j.jocn.2009.05.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2009] [Revised: 05/01/2009] [Accepted: 05/06/2009] [Indexed: 12/01/2022]
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Pateras IS, Apostolopoulou K, Niforou K, Kotsinas A, Gorgoulis VG. p57KIP2: "Kip"ing the cell under control. Mol Cancer Res 2009; 7:1902-19. [PMID: 19934273 DOI: 10.1158/1541-7786.mcr-09-0317] [Citation(s) in RCA: 117] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
p57(KIP2) is an imprinted gene located at the chromosomal locus 11p15.5. It is a cyclin-dependent kinase inhibitor belonging to the CIP/KIP family, which includes additionally p21(CIP1/WAF1) and p27(KIP1). It is the least studied CIP/KIP member and has a unique role in embryogenesis. p57(KIP2) regulates the cell cycle, although novel functions have been attributed to this protein including cytoskeletal organization. Molecular analysis of animal models and patients with Beckwith-Wiedemann Syndrome have shown its nodal implication in the pathogenesis of this syndrome. p57(KIP2) is frequently down-regulated in many common human malignancies through several mechanisms, denoting its anti-oncogenic function. This review is a thorough analysis of data available on p57(KIP2), in relation to p21(CIP1/WAF1) and p27(KIP1), on gene and protein structure, its transcriptional and translational regulation, and its role in human physiology and pathology, focusing on cancer development.
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Affiliation(s)
- Ioannis S Pateras
- Molecular Carcinogenesis Group, Laboratory of Histology-Embryology, Medical School, University of Athens, Greece
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23
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Gramantieri L, Fornari F, Callegari E, Sabbioni S, Lanza G, Croce CM, Bolondi L, Negrini M. MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med 2009; 12:2189-204. [PMID: 19120703 PMCID: PMC4514099 DOI: 10.1111/j.1582-4934.2008.00533.x] [Citation(s) in RCA: 211] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. Curative options for HCC are limited and exclusively available for patients carrying an early stage HCC. In advanced stages, traditional chemotherapy proved to be only marginally effective or even toxic. Thus, the identification of new treatment options is needed. New targets for non-conventional treatment will necessarily take advantage of progresses on the molecular pathogenesis of HCC. MicroRNAs (miRNAs) are a group of tiny RNAs with a fundamental role in the regulation of gene expression. Aberrant expression of several miRNAs was found to be involved in human hepatocarcinogenesis. miRNA expression signatures were correlated with bio-pathological and clinical features of HCC. In some cases, aberrantly expressed miRNAs could be linked to cancer-associated pathways, indicating a direct role in liver tumourigenesis. For example, up-regulation of mir-221 and mir-21 could promote cell cycle progression, reduce cell death and favour angiogenesis and invasion. These findings suggest that miRNAs could become novel molecular targets for HCC treatment. The demonstration of in vivo efficacy and safety of anti-miRNA compounds has opened the way to their use in clinical trials.
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Affiliation(s)
- Laura Gramantieri
- Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy
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24
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Jin RJ, Lho Y, Wang Y, Ao M, Revelo MP, Hayward SW, Wills ML, Logan SK, Zhang P, Matusik RJ. Down-regulation of p57Kip2 induces prostate cancer in the mouse. Cancer Res 2008; 68:3601-8. [PMID: 18483241 DOI: 10.1158/0008-5472.can-08-0073] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
p57(Kip2) has been considered a candidate tumor suppressor gene because of its location in the genome, biochemical activities, and imprinting status. However, little is known about the role of p57(Kip2) in tumorigenesis and cancer progression. Here, we show that the expression of p57(Kip2) is significantly decreased in human prostate cancer, and the overexpression of p57(Kip2) in prostate cancer cells significantly suppressed cell proliferation and reduced invasive ability. In addition, overexpression of p57(Kip2) in LNCaP cells inhibited tumor formation in nude mice, resulting in well-differentiated squamous tumors rather than adenocarcinoma. Furthermore, the prostates of p57(Kip2) knockout mice developed prostatic intraepithelial neoplasia and adenocarcinoma. Remarkably, this mouse prostate cancer is pathologically identical to human prostate adenocarcinoma. Therefore, these results strongly suggest that p57(Kip2) is an important gene in prostate cancer tumorigenesis, and the p57(Kip2) pathway may be a potential target for prostate cancer prevention and therapy.
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Affiliation(s)
- Ren Jie Jin
- Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tenessee, USA
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25
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MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 2008; 27:5651-61. [PMID: 18521080 DOI: 10.1038/onc.2008.178] [Citation(s) in RCA: 476] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The identification of target mRNAs is a key step for assessing the role of aberrantly expressed microRNAs in human cancer. MiR-221 is upregulated in human hepatocellular carcinoma (HCC) as well as in other malignancies. One proven target of miR-221 is CDKN1B/p27, whose downregulation affects HCC prognosis. Here, we proved that the cyclin-dependent kinase inhibitor (CDKI) CDKN1C/p57 is also a direct target of miR-221. Indeed, downregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to miR-221 transfection into HCC-derived cells and a significant upregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to antimiR-221 transfection. A direct interaction of miR-221 with a target site on the 3' UTR of CDKN1C/p57 mRNA was also demonstrated. By controlling these two CDKIs, upregulation of miR-221 can promote growth of HCC cells by increasing the number of cells in S-phase. To assess the relevance of these studies in primary tumors, matched HCC and cirrhosis samples were assayed for miR-221, for CDKN1B/p27 and CDKN1C/p57 expression. MiR-221 was upregulated in 71% of HCCs, whereas CDKN1B/p27 and CDKN1C/p57 proteins were downregulated in 77% of cases. A significant inverse correlation between miR-221 and both CDKN1B/p27 and CDKN1C/p57 was found in HCCs. In conclusion, we suggest that miR-221 has an oncogenic function in hepatocarcinogenesis by targeting CDKN1B/p27 and CDKN1C/p57, hence promoting proliferation by controlling cell-cycle inhibitors. These findings establish a basis toward the development of therapeutic strategies aimed at blocking miR-221 in HCC.
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26
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Larson PS, Schlechter BL, King CL, Yang Q, Glass CN, Mack C, Pistey R, de Las Morenas A, Rosenberg CL. CDKN1C/p57kip2 is a candidate tumor suppressor gene in human breast cancer. BMC Cancer 2008; 8:68. [PMID: 18325103 PMCID: PMC2323395 DOI: 10.1186/1471-2407-8-68] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2007] [Accepted: 03/06/2008] [Indexed: 12/03/2022] Open
Abstract
Background CDKN1C (also known as p57KIP2) is a cyclin-dependent kinase inhibitor previously implicated in several types of human cancer. Its family members (CDKN1A/p21CIP1 and B/p27KIP1) have been implicated in breast cancer, but information about CDKN1C's role is limited. We hypothesized that decreased CDKN1C may be involved in human breast carcinogenesis in vivo. Methods We determined rates of allele imbalance or loss of heterozygosity (AI/LOH) in CDKN1C, using an intronic polymorphism, and in the surrounding 11p15.5 region in 82 breast cancers. We examined the CDKN1C mRNA level in 10 cancers using quantitative real-time PCR (qPCR), and the CDKN1C protein level in 20 cancers using immunohistochemistry (IHC). All samples were obtained using laser microdissection. Data were analyzed using standard statistical tests. Results AI/LOH at 11p15.5 occurred in 28/73 (38%) informative cancers, but CDKN1C itself underwent AI/LOH in only 3/16 (19%) cancers (p = ns). In contrast, CDKN1C mRNA levels were reduced in 9/10 (90%) cancers (p < 0.0001), ranging from 2–60% of paired normal epithelium. Similarly, CDKN1C protein staining was seen in 19/20 (95%) cases' normal epithelium but in only 7/14 (50%) cases' CIS (p < 0.004) and 5/18 (28%) cases' IC (p < 0.00003). The reduction appears primarily due to loss of CDKN1C expression from myoepithelial layer cells, which stained intensely in 17/20 (85%) normal lobules, but in 0/14 (0%) CIS (p < 0.00001). In contrast, luminal cells displayed less intense, focal staining fairly consistently across histologies. Decreased CDKN1C was not clearly associated with tumor grade, histology, ER, PR or HER2 status. Conclusion CDKN1C is expressed in normal epithelium of most breast cancer cases, mainly in the myothepithelial layer. This expression decreases, at both the mRNA and protein level, in the large majority of breast cancers, and does not appear to be mediated by AI/LOH at the gene. Thus, CDKN1C may be a breast cancer tumor suppressor.
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Affiliation(s)
- Pamela S Larson
- Department of Pathology and Laboratory Medicine, Boston University Medical Center, Boston, MA, USA.
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27
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Matarasso N, Bar-Shira A, Rozovski U, Rosner S, Orr-Urtreger A. Functional analysis of the Aurora Kinase A Ile31 allelic variant in human prostate. Neoplasia 2007; 9:707-15. [PMID: 17898866 PMCID: PMC1993855 DOI: 10.1593/neo.07322] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2007] [Revised: 07/03/2007] [Accepted: 07/05/2007] [Indexed: 11/18/2022] Open
Abstract
Overexpression of the centrosome-associated serine/threonine kinase Aurora Kinase A (AURKA) has been demonstrated in both advanced prostate cancer and high-grade prostatic intraepithelial neoplasia lesions. The single-nucleotide polymorphism T91A (Phe31Ile) has been implicated in AURKA overexpression and has been suggested as a low-penetrance susceptibility allele in multiple human cancers, including prostate cancer. We studied the transcriptional consequences of the AURKA Ile31 allele in 28 commercial normal prostate tissue RNA samples (median age, 27 years). Significant overexpression of AURKA was demonstrated in homozygous and heterozygous AURKA Ile31 prostate RNA (2.07-fold and 1.93-fold, respectively; P < .05). Expression levels of 1509 genes differentiated between samples homozygous for Phe31 alleles and samples homozygous for Ile31 alleles (P = .05). Gene Ontology classification revealed overrepresentation of cell cycle arrest, ubiquitin cycle, antiapoptosis, and angiogenesis-related genes. When these hypothesis-generating results were subjected to more stringent statistical criteria, overexpression of a novel transcript of the natural killer tumor recognition sequence (NKTR) gene was revealed and validated in homozygous Ile31 samples (2.6-fold; P < .05). In summary, our data suggest an association between the AURKA Ile31 allele and an altered transcriptome in normal non-neoplastic prostates.
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Affiliation(s)
- Noa Matarasso
- Genetic Institute, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Anat Bar-Shira
- Genetic Institute, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
| | - Uri Rozovski
- Genetic Institute, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
| | - Serena Rosner
- Genetic Institute, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
| | - Avi Orr-Urtreger
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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28
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Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, Galun E. The H19 non-coding RNA is essential for human tumor growth. PLoS One 2007; 2:e845. [PMID: 17786216 PMCID: PMC1959184 DOI: 10.1371/journal.pone.0000845] [Citation(s) in RCA: 539] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2007] [Accepted: 08/10/2007] [Indexed: 12/26/2022] Open
Abstract
Background Mutations and epigenetic aberrant signaling of growth factors pathways contribute to carcinogenesis. Recent studies reveal that non-coding RNAs are controllers of gene expression. H19 is an imprinted gene that demonstrates maternal monoallelic expression without a protein product; although its expression is shut off in most tissues postnatally, it is re-activated during adult tissue regeneration and tumorigenesis. Moreover, H19 is highly expressed in liver metastasis derived from a range of carcinomas. The objective of this study is to explore the role of H19 in carcinogenesis, and to determine its identification as an anti-tumor target. Methodology/ Principle Findings By controlling oxygen pressure during tumor cell growth and H19 expression levels, we investigated the role of H19 expression in vitro and in vivo in hepatocellular (HCC) and bladder carcinoma. Hypoxia upregulates the level of H19 RNA. Ablations of tumorigenicity of HCC and bladder carcinomas in vivo are seen by H19 knockdown which also significantly abrogates anchorage-independent growth after hypoxia recovery, while ectopic H19 expression enhances tumorigenic potential of carcinoma cells in vivo. Knocking-down H19 message in hypoxic stress severely diminishes p57kip2 induction. We identified a number of potential downstream targets of H19 RNA, including angiogenin and FGF18. Conclusions H19 RNA harbors pro-tumorigenic properties, thus the H19 gene behaves as an oncogene and may serve as a potential new target for anti-tumor therapy.
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Affiliation(s)
- Imad J. Matouk
- Department of Biological Chemistry, Institute of Life Sciences, Hebrew University, Jerusalem, Israel
| | - Nathan DeGroot
- Department of Biological Chemistry, Institute of Life Sciences, Hebrew University, Jerusalem, Israel
| | - Shaul Mezan
- Department of Biological Chemistry, Institute of Life Sciences, Hebrew University, Jerusalem, Israel
| | - Suhail Ayesh
- Department of Biological Chemistry, Institute of Life Sciences, Hebrew University, Jerusalem, Israel
| | - Rasha Abu-lail
- Department of Biological Chemistry, Institute of Life Sciences, Hebrew University, Jerusalem, Israel
| | - Abraham Hochberg
- Department of Biological Chemistry, Institute of Life Sciences, Hebrew University, Jerusalem, Israel
| | - Eithan Galun
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
- * To whom correspondence should be addressed. E-mail:
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Mann CD, Neal CP, Garcea G, Manson MM, Dennison AR, Berry DP. Prognostic molecular markers in hepatocellular carcinoma: a systematic review. Eur J Cancer 2007; 43:979-92. [PMID: 17291746 DOI: 10.1016/j.ejca.2007.01.004] [Citation(s) in RCA: 183] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2006] [Revised: 12/22/2006] [Accepted: 01/04/2007] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and its incidence is rising. Surgery, including transplantation, remains the only potentially curative modality for HCC, yet recurrence rates are high and long-term survival poor. The ability to predict individual recurrence risk and subsequently prognosis would help guide surgical and chemotherapeutic treatment. As understanding of hepatocarcinogenesis has increased, the myriad of genetic and molecular events that drive the hepatocarcinogenic disease process, including angiogenesis, invasion and metastasis, have been identified. This systematic review examines the evidence from published manuscripts reporting the prognostic potential of molecular biomarkers in hepatocellular carcinoma. In summary, a number of molecular biomarkers with prognostic significance have been identified in hepatocellular carcinoma. Not only might these molecules allow more accurate prediction of prognosis for patients with HCC, but they may also provide targets for potential therapeutic agents.
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Affiliation(s)
- Christopher D Mann
- Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, Biocentre, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom.
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Pateras IS, Apostolopoulou K, Koutsami M, Evangelou K, Tsantoulis P, Liloglou T, Nikolaidis G, Sigala F, Kittas C, Field JK, Kotsinas A, Gorgoulis VG. Downregulation of the KIP family members p27(KIP1) and p57(KIP2) by SKP2 and the role of methylation in p57(KIP2) inactivation in nonsmall cell lung cancer. Int J Cancer 2006; 119:2546-56. [PMID: 16988944 DOI: 10.1002/ijc.22214] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Knowing the status of molecules involved in cell cycle control in cancer is vital for therapeutic approaches aiming at their restoration. The p27(KIP1) and p57(KIP2) cyclin-dependent kinase inhibitors are nodal factors controlling normal cell cycle. Their expression in normal lung raises the question whether they have a mutual exclusive or redundant role in nonsmall cell lung cancer (NSCLC). A comparative comprehensive analysis was performed in a series of 70 NSCLCs. The majority of cases showed significantly reduced expression of both members compared to normal counterparts. Low KIP protein levels correlated with increased proliferation, which seems to be histological subtype preponderant. At mechanistic level, degradation by SKP2 was demonstrated, in vivo and in vitro, by siRNA-methodology, to be the most important downregulating mechanism of both KIPs in NSCLC. Decreased p57(KIP) (2)-transcription complements the above procedure in lowering p57(KIP2)-protein levels. Methylation was the main cause of decreased p57(KIP) (2)-mRNA levels. Allelic loss and imprinting from LIT1 mRNA contribute also to decreased p57(KIP2) transcription. In vitro recapitulation of the in vivo findings, in A549 lung cells (INK4A-B((-/-))), suggested that inhibition of the SKP2-degradation mechanism restores p27(KIP1) and p57(KIP2) expression. Double siRNA treatments demonstrated that each KIP is independently capable of restraining cell growth. An additional demethylation step is required for complete reconstitution of p57(KIP2) expression in NSCLC.
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Affiliation(s)
- Ioannis S Pateras
- Molecular Carcinogenesis Group, Laboratory of Histology-Embryology, Medical School, University of Athens, Athens, Greece
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31
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Taieb J, Barbare JC, Rougier P. Medical treatments for hepatocellular carcinoma (HCC): what’s next? Ann Oncol 2006; 17 Suppl 10:x308-14. [PMID: 17018744 DOI: 10.1093/annonc/mdl279] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- J Taieb
- Service d'Hépato-gastroentérologie, Groupe Hospitalier Pitié Salpétrière, Paris, France
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32
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Thomas MB, Abbruzzese JL. Opportunities for targeted therapies in hepatocellular carcinoma. J Clin Oncol 2005; 23:8093-108. [PMID: 16258107 DOI: 10.1200/jco.2004.00.1537] [Citation(s) in RCA: 126] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular cancer (HCC) is the fifth most common solid tumor worldwide, accounting for 500,000 new cases annually. Although less common in the United States, HCC is expected to increase in incidence over the next two decades largely because of the prevalence of hepatitis C virus infection. A majority of patients present with advanced disease and are not candidates for liver transplantation, surgical resection, or regional therapy. In 60% to 80% of patients with HCC, treatment is complicated by underlying liver cirrhosis and hepatic dysfunction. Systemic treatments are minimally effective, can have significant toxicity, and have not been shown to improve patient survival. New approaches targeting molecular abnormalities specific to HCC are needed to improve patient outcome. This review summarizes the state of knowledge of those key aspects of the molecular pathogenesis of HCC that may represent rational therapeutic targets in this disease. Relevant preclinical and clinical information on novel compounds directed toward abnormalities in HCC is reviewed.
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Affiliation(s)
- Melanie B Thomas
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA.
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33
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Umemoto T, Yamato M, Nishida K, Yang J, Tano Y, Okano T. p57Kip2 is expressed in quiescent mouse bone marrow side population cells. Biochem Biophys Res Commun 2005; 337:14-21. [PMID: 16176803 DOI: 10.1016/j.bbrc.2005.09.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2005] [Accepted: 09/01/2005] [Indexed: 12/16/2022]
Abstract
Hematopoietic stem cells can be accurately identified by the side population (SP) phenotype. It has been previously shown that hematopoietic stem cells are cell cycle arrested, but the mechanisms involved are currently poorly understood. In the present study, results from quantitative real-time RT-PCR show that while SP cells have increased expression of various cyclins and cyclin-dependent kinases, the increased expression of cyclin-dependent kinase inhibitors, in particular p57(Kip2), is responsible for the observed cell cycle arrest. In addition, gene expression analysis of c-kit(+/)/Sca-1(+)/Lineage- SP (KSL-SP) cells demonstrates that only p57(Kip2) shows both higher expression compared to both SP and non-SP cells. Furthermore, immunostaining also demonstrates significantly higher protein expression in KSL-SP cells. These results demonstrate that the maintenance of bone marrow SP cells in G0/G1 may be carefully controlled by p57(Kip2).
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Affiliation(s)
- Terumasa Umemoto
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
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Yue H, Jiang HY. Expression of cell cycle regulator p57 kip2, cyclinE protein and proliferating cell nuclear antigen in human pancreatic cancer: An immunohistochemical study. World J Gastroenterol 2005; 11:5057-60. [PMID: 16124066 PMCID: PMC4321930 DOI: 10.3748/wjg.v11.i32.5057] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of p57kip2, cyclinE protein and proliferating cell nuclear antigen (PCNA) on occurrence and progression of human pancreatic cancer.
METHODS: The expression of p57kip2, cyclinE protein and PCNA in tumor tissues and adjacent tissues from 32 patients with pancreatic cancer was detected by SP immunohistochemical technique.
RESULTS: The positive expression rate of p57kip2 protein in tumor tissues was 46.9%, which was lower than that in adjacent pancreatic tissues (χ2 = 5.317, P<0.05). p57kip2 protein positive expression remarkably correlated with tumor cell differentiation (P<0.05), but not with lymph node metastasis (P>0.05). The positive expression rate of cyclinE protein in tumor tissues was 68.8%, which was higher than that in adjacent pancreatic tissues (χ2 = 4.063, P<0.05). CyclinE protein positive expression significantly correlated with tumor cell differentiation and lymph node metastasis (P<0.05). The positive expression rate of PCNA in the tumor tissues was 71.9%, which was higher than that in adjacent pancreatic tissues (χ2 = 5.189, P<0.05). PCNA positive expression remarkably correlated with tumor cell differentiation and lymph node metastasis (P<0.05).
CONCLUSION: The decreased expression of p57kip2 and/or overexpression of cyclinE protein and PCNA may contribute to the occurrence and progression of pancreatic cancer. p57kip2, cyclinE protein, and PCNA play an important role in occurrence and progression of pancreatic cancer.
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Affiliation(s)
- Hui Yue
- Institute for Digestive Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China.
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35
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Hagan JP, Kozlov SV, Chiang Y, Sewell L, Stewart CL. Intraspecific mating with CzechII/Ei mice rescue lethality associated with loss of function mutations of the imprinted genes, Igf2r and Cdkn1c. Genomics 2005; 84:836-43. [PMID: 15475262 DOI: 10.1016/j.ygeno.2004.07.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2004] [Revised: 07/09/2004] [Accepted: 07/13/2004] [Indexed: 02/04/2023]
Abstract
Maternal inheritance of targeted loss of function alleles encoding either the cyclin-dependent kinase inhibitor 1C (Cdkn1c) or the insulin-like growth factor 2 receptor (Igf2r) leads to fully penetrant perinatal lethality in C57BL/6J mice due to genomic imprinting. Here, we demonstrate that there is a marked enhancement in postnatal viability of F(1) mice carrying either the ablated Igf2r ( approximately 32%) or Cdkn1c ( approximately 83%) when the paternal genome was derived from the inbred Mus musculus musculus CzechII/Ei strain. Genetic and molecular analyses indicated that the increased viability was not caused by relaxation of imprinted gene expression, but is the consequence of unidentified polygenic modifiers that are not imprinted. In the course of this study, restriction-site polymorphisms between 129S1 and CzechII/Ei in 21 imprinted and 14 biallelically expressed genes were identified. These polymorphisms may prove useful in determining the effects of different mutant backgrounds on genomic imprinting.
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Affiliation(s)
- John P Hagan
- Cancer and Developmental Biology Laboratory, Center for Cancer Research, NCI-FCRDC, National Institutes of Health, P.O. Box B, Frederick, MD 21702, USA
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36
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Hsu S, Yamamoto T, Borke J, Walsh DS, Singh B, Rao S, Takaaki K, Nah-Do N, Lapp C, Lapp D, Foster E, Bollag WB, Lewis J, Wataha J, Osaki T, Schuster G. Green tea polyphenol-induced epidermal keratinocyte differentiation is associated with coordinated expression of p57/KIP2 and caspase 14. J Pharmacol Exp Ther 2005; 312:884-90. [PMID: 15537824 DOI: 10.1124/jpet.104.076075] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, exerts chemopreventive effects by selectively inducing apoptosis in tumor cells. In contrast, EGCG accelerates terminal differentiation in normal human epidermal keratinocytes (NHEK) mediated partially by up-regulation of p57/KIP2, a cyclin-dependent kinase inhibitor that confers growth arrest and differentiation. However, it is unclear if EGCG modulates caspase 14, a unique regulator of epithelial cell terminal differentiation associated with cornification. Here, we examined the effect of EGCG on caspase 14 expression in NHEK and correlated the protein and mRNA expression of p57/KIP2 with those of caspase 14 in either normal keratinocytes or p57/KIP2-expressing tumor cells (OSC2, an oral squamous cell carcinoma cell line). Additionally, paraffin-embedded normal and untreated psoriatic (aberrant keratinization) skin sections from humans were assessed for caspase 14 by immunohistochemistry. In NHEK, EGCG induced the expression of caspase 14 mRNA and protein levels within a 24-h period. The expression of p57/KIP2 in OSC2 cells was adequate to induce caspase 14 in the absence of EGCG; this induction of caspase 14 was down-regulated by transforming growth factor-beta1. In human psoriatic skin samples, caspase 14 staining in the upper epidermis was reduced, especially in nuclear areas. These results suggest that, in addition to p57/KIP2, EGCG-induced terminal differentiation of epidermal keratinocytes involves up-regulation of caspase 14. Further understanding of how EGCG modulates cellular differentiation may be useful in developing green tea preparations for selected clinical applications.
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Affiliation(s)
- Stephen Hsu
- Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, AD1443, Medical College of Georgia, Augusta, GA 30912-1126, USA.
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37
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Kimura S, Ito C, Jyoko N, Segawa H, Kuroda J, Okada M, Adachi S, Nakahata T, Yuasa T, Filho VC, Furukawa H, Maekawa T. Inhibition of leukemic cell growth by a novel anti-cancer drug (GUT-70) from calophyllum brasiliense that acts by induction of apoptosis. Int J Cancer 2004; 113:158-65. [PMID: 15386357 DOI: 10.1002/ijc.20505] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
During our search for cancer chemopreventing compounds derived from plant sources, we discovered that the natural product GUT-70, isolated from the stem bark of Calophyllum brasiliense collected in Brazil, significantly inhibits the growth of leukemic cells. GUT-70, characterized as a tricyclic coumarin, 5-methoxy-2,2-dimethyl-6-(2-methyl-1-oxo-2-butenyl) -10-propyl-2H,8H-benzo[1,2-b;3,4-b']dipyran-8-one (C(23)H(26)O(5)), inhibited all 6 human leukemic cell lines evaluated, including the P-glycoprotein overexpressing cell line, in a concentration and time-dependent manner with IC(50) values from 2-5 microM. Furthermore, GUT-70 did not inhibit colony formation by normal hematopoietic progenitors up to 30 microM and also did not inhibit the proliferation of normal human hepatocytes up to 30 microM. GUT-70 activated the caspase 2, 3, 8 and 9, and induced the apoptosis in leukemic cells, which was inhibited by caspase inhibitors. GUT-70 induced anti-leukemic effects independent of the p53-p2l(WAFl/CIP1) pathway and increased the overall expression of p27(KIP1) and p57(KIP2), to stop the cell cycle at the G(1)/S transition. Thus, a novel anti-cancer drug, GUT-70 isolated from the stem bark of C. brasiliense induces caspase-mediated and p53-independent apoptosis to overcome multidrug resistance and may become a potent leukemia therapeutics.
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Affiliation(s)
- Shinya Kimura
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan.
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38
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Sakai K, Peraud A, Mainprize T, Nakayama J, Tsugu A, Hongo K, Kobayashi S, Rutka JT. Inducible expression of p57KIP2 inhibits glioma cell motility and invasion. J Neurooncol 2004; 68:217-23. [PMID: 15332324 DOI: 10.1023/b:neon.0000033380.08940.c8] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
To examine the role of p57KIP2 in human malignant glioma cells, we studied its expression in a panel of human malignant glioma specimens by western blot and immunohistochemical analysis. To determine the effects of p57KIP2 expression on the phenotype of glioma cells, we analyzed two inducible stably transfected p57KIP2 expressing glioma cell lines. Expression of p57KIP2 was induced in U373 and U87 malignant glioma cells with doxycycline using the tetracycline repressor system. A phagokinetic track assay on gold particles was used to investigate differences in cell migration between p57KIP2 expressing and non-expressing control cells. The effects of the extracellular matrix (ECM) on U373 motility was determined in p57+ and p57-cells on surfaces coated with 5 microg/cm2 of fibronectin, laminin, type I and type IV collagens. The invasion of p57+ and p57- glioma cells across BD Biocoat Matrigel invasion chambers was then determined. p57KIP2 was weakly expressed in 4/6 glioblastoma (GBM) specimens by western blot. By immunohistochemistry, p57KIP2 immunoreactivity was positive in 8/40 GBMs, and was primarily nuclear in location. The motility of U373 glioma cells was significantly reduced after p57KIP2 induction. The presence of ECM proteins did not further alter the motility of p57+ and p57- glioma cells. The results of the invasion chamber assay showed that p57+ cells exhibited a 35% reduction in their invasive capacity as compared to p57- cells. These data suggest that p57KIP2 is expressed in at least some malignant gliomas. Inducible expression of 57KIP2 in cell lines deficient in this cyclin-dependent kinase inhibitor reduces their otility and invasiveness.
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Affiliation(s)
- K Sakai
- Department of Neurosurgery, Shinshu University School of Medicine
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39
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Sebire NJ, Rees HC, Peston D, Seckl MJ, Newlands ES, Fisher RA. p57KIP2 immunohistochemical staining of gestational trophoblastic tumours does not identify the type of the causative pregnancy. Histopathology 2004; 45:135-41. [PMID: 15279631 DOI: 10.1111/j.1365-2559.2004.01904.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AIM To determine whether immunohistochemical staining for p57(KIP2), the product of the maternally expressed gene CDKN1C, can be used to differentiate between gestational trophoblastic tumours arising from a complete hydatidiform mole and those originating from non-molar pregnancies. METHODS The immunohistochemical expression of p57(KIP2) was investigated in 23 cases of choriocarcinoma and 17 placental site trophoblastic tumours. Fourteen of the tumours examined were shown by DNA analysis to have arisen from complete hydatidiform moles and 26 from non-molar pregnancies. RESULTS Five of 11 (45%) post-complete hydatidiform mole choriocarcinomas and two of three (67%) post-complete hydatidiform mole placental site trophoblastic tumours were found to be p57(KIP2)+ and showed similar immunostaining characteristics to tumours that developed from non-molar pregnancies. Although there was a statistically significant reduction in the proportion of cases showing positive p57(KIP2) staining in post-complete hydatidiform mole tumours compared with those originating in non-molar pregnancies [proportion difference 0.35 [95% confidence interval (CI) 0.05, 0.61], P = 0.02], immunostaining did not provide diagnostically useful information to differentiate between these tumours in clinical practice. There was no significant difference between the extent of staining in choriocarcinoma versus placental site trophoblastic tumours [proportion difference 0.17 (95% CI - 12, 42), P = 0.19]. The majority of both types of gestational trophoblastic tumour were positive for the presence of the p57(KIP2) protein irrespective of their genetic origin. CONCLUSION Immunostaining for p57(KIP2) fails to discriminate between gestational trophoblastic tumours that have arisen from complete hydatidiform moles and those that have originated from other types of pregnancy.
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Affiliation(s)
- N J Sebire
- Department of Histopathology, Charing Cross Hospital, London, UK.
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40
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Ito Y, Yoshida H, Matsuzuka F, Matsuura N, Nakamura Y, Nakamine H, Kakudo K, Kuma K, Miyauchi A. Expression of the Components of the Cip/Kip Family in Malignant Lymphoma of the Thyroid. Pathobiology 2004; 71:164-70. [PMID: 15051930 DOI: 10.1159/000076472] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2003] [Accepted: 10/23/2003] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE For evaluating the characteristics of human neoplasms, investigation of regulators of cell cycle progression is important. We studied three components of the Cip/Kip family, p57, p27 and p21, in malignant lymphomas of the thyroid. METHODS We immunohistochemically investigated the expression of the three proteins for 49 cases of thyroid lymphomas, as well as 10 cases of chronic thyroiditis. RESULTS In infiltrating lymphocytes in chronic thyroiditis, p57 and p27 were diffusely expressed, whereas p21 immunoreactivity was only occasionally observed. In lymphoma, decreased expression of p57 (less than 50% of lymphoma cells were positive) was observed in 24 cases (49.0%). p57 expression was inversely linked to the MIB-1 labeling index, grade of malignancy and aberrant p53 expression. Decreased expression of p27 was observed in 25 cases (51.0%), which was also related to the MIB-1 labeling index and aberrant p53 expression. On the other hand, p21 expression was occasional, and when the cut-off value was set at 3%, 38 cases (77.6%) were regarded as negative. P21 expression was not linked to any clinicopathological parameters. CONCLUSION These findings suggest that, among the 3 components of the Cip/Kip family, p57 and p27 play a role in negatively regulating the cell proliferation of thyroid lymphoma cells and decreased expression of them contributes to the progression of this disease.
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Affiliation(s)
- Yasuhiro Ito
- Kuma Hospital, Shimoyamate-dori, Chuo-ku, Kobe, Japan.
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41
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Hsu S, Yu FXX, Huang Q, Lewis J, Singh B, Dickinson D, Borke J, Sharawy M, Wataha J, Yamamoto T, Osaki T, Schuster G. A Mechanism-Based In Vitro Anticancer Drug Screening Approach for Phenolic Phytochemicals. Assay Drug Dev Technol 2003; 1:611-8. [PMID: 15090233 DOI: 10.1089/154065803770380968] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Plant-derived phenolic compounds, including polyphenols (e.g., tannins), flavonoids, and phenolic acids, have been under investigation for their anticancer therapeutic and chemoprevention properties. Recently, certain mechanisms underlying the differential effects of green tea polyphenols (GTPPs) on tumor versus normal cells have been determined. These suggest that GTPPs may simultaneously activate multiple pathways. However, existing screening methods are insufficient for the identification of agents that possess both a cytotoxic effect on tumor cells and a protective effect on normal cells. The current study describes the establishment of an in vitro survival/apoptosis testing system based on detecting these mechanisms by a double-fluorescence method. This system is able to screen potential chemopreventive or therapeutic agents from (but not limited to) plant-derived compounds based on the pathways differentially activated by the agents. Tumor cell death and normal cell survival are detected simultaneously, in a device that co-cultures normal human cells adjacent to human tumor cells.
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Affiliation(s)
- Stephen Hsu
- Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, Medical College of Georgia, Augusta, GA 30912-1126, USA.
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Go JH. Expressions of the CIP/KIP family of CDK inhibitor proteins in primary intestinal large B-cell lymphomas: correlation with clinical outcomes. Pathol Res Pract 2003; 198:741-6. [PMID: 12530577 DOI: 10.1078/0344-0338-00330] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Immunohistochemistry was performed for p21, p27, p57 and p53 on paraffin-embedded tissue sections from 25 patients who had surgically resected intestinal lymphomas. It was then correlated with the patients' clinical course in an attempt to determine the expression patterns and clinical significance of the CIP/KIP family of cyclin-dependent kinase inhibitors in primary intestinal large B-cell lymphomas. p21 immunostaining was positive in 11 cases (44%) and p27 was positive in 8 cases (32%). All cases were p57-negative. p53 immunostaining was positive in 14 cases (56%) and negative in 11 cases (44%). With respect to the relationship between p21 and p53, seven cases were p53+/p21-, seven cases were p53+/p21+, seven cases were p53-/p2l-, and four cases were p53-/p21+. The expression patterns of p21 and p53 did not influence the patient's clinical outcome. However, p27-positive cases had a much higher percentage of patients sustaining a continuous complete remission state (8/8, 100%) as compared to p27-negative cases (10/17, 59%), although this difference was not statistically significant (p = 0.057). These results suggest that p27 immunoreactivity may be associated with a better clinical outcome. However, further study with larger series are planned to determine the clinical significance of p27 overexpression in primary intestinal large B-cell lymphomas.
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MESH Headings
- Adolescent
- Adult
- Aged
- Biomarkers, Tumor/biosynthesis
- Cell Cycle Proteins/biosynthesis
- Child
- Cyclin-Dependent Kinase Inhibitor p21
- Cyclin-Dependent Kinase Inhibitor p27
- Cyclin-Dependent Kinase Inhibitor p57
- Cyclins/biosynthesis
- Female
- Humans
- Immunohistochemistry
- Intestinal Neoplasms/metabolism
- Intestinal Neoplasms/mortality
- Intestinal Neoplasms/pathology
- Lymphoma, B-Cell/metabolism
- Lymphoma, B-Cell/mortality
- Lymphoma, B-Cell/pathology
- Lymphoma, Large B-Cell, Diffuse/metabolism
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/pathology
- Male
- Middle Aged
- Nuclear Proteins/biosynthesis
- Prognosis
- Treatment Outcome
- Tumor Suppressor Proteins/biosynthesis
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Affiliation(s)
- Jai Hyang Go
- Department of Pathology, Dankook University College of Medicine, 16-5 Anseo-dong, Cheonan, Chungnam 330-715, Korea.
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Shen L, Toyota M, Kondo Y, Obata T, Daniel S, Pierce S, Imai K, Kantarjian HM, Issa JPJ, Garcia-Manero G. Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia. Blood 2003; 101:4131-6. [PMID: 12586619 DOI: 10.1182/blood-2002-08-2466] [Citation(s) in RCA: 107] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
P57KIP2 is a cyclin-dependent kinase inhibitor silenced in a variety of human malignancies. DNA methylation of a region surrounding the transcription start site of p57KIP2 was found in acute lymphocytic leukemia (ALL)-derived cell lines. Methylation of this region correlated with gene silencing, and treatment of methylated/silenced cell lines with 5-aza-2'-deoxycytidine resulted in gene re-expression. P57KIP2 was methylated in 31 (50%) of 63 patients with newly diagnosed ALL, and in 11 (52%) of 21 patients with relapsed ALL. In 5 of them (25%), methylation was acquired at relapse. No association was observed between methylation of p57KIP2 alone and clinical-biologic characteristics studied, including overall survival (OS) or disease-free survival. Methylation of multiple genes in a cell-cycle regulatory pathway composed of p73, p15, and p57KIP2 occurred in 22% of Philadelphia chromosome (Ph)-negative patients. Ph-negative patients with methylation of 2 or 3 genes of this pathway had a significantly worse median OS compared with those with methylation of 0 or 1 gene (50 vs 467 weeks, respectively; P =.02). Our results indicate that p57KIP2 is frequently methylated in adult patients with ALL, and that inactivation of a pathway composed of p73, p15, and p57KIP2 predicts for poor prognosis in Ph-negative patients.
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Affiliation(s)
- LanLan Shen
- Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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Yue H, Yu JP, Cao YH, Zhao X. Expression of p57 kip2 and p27 kip1 proteins and its relationship with clinicopathology in human pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2003; 11:318-320. [DOI: 10.11569/wcjd.v11.i3.318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of p57kip2 and p27kip1 proteins on the development and progression of pancreatic cancer.
METHODS: Expression of p57kip2 and p27kip1 proteins in tumor and adjacent tissues of 32 patients with pancreatic cancer were detected by SP immunohistochemical technique.
RESULTS: p57kip2 protein positive rate in tumor tissues of pancreatic cancer was 46.9%, which was lower than that in adjacent pancreatic tissues (75.0%)(x2 = 5.317, P < 0.05), p57kip2 protein expression correlated remarkably with tumor cell differentiation (x2 = 4.979, P < 0.05), but did not correlate with lymph node metastasis (x2 = 3.698, P < 0.05); p27kip1 protein positive rate in the tumor tissues was 56.3%, which was lower than that in adjacent pancreatic tissues (84.4%) (x2 = 6.063, P < 0.05). p27kip1 expression was correlated remarkably with tumor cell differentiation and lymph node metastasis (x2 = 5.776; x2 = 4.097, P < 0.05). p57kip2 protein positive rate (50.0%) in p27kip1 protein positive group was higher than that (42.9%) in p27kip1 protein negative group, and there was no significant correlation between the two groups (r = 0.19657, P > 0.05).
CONCLUSION: p57kip2 and p27kip1 proteins may play an important role in carcinogenesis and progression of human pancreatic cancer. Decreased expression of p57kip2 and p27kip1 proteins is subject to the development of pancreatic cancer and determination of cell differentiation degree, and helpful to evaluate prognosis of the diseases.
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Yue H, Na YL, Feng XL, Ma SR, Song FL, Yang B. Expression of p57 kip2, Rb protein and PCNA and their relationships with clinicopathology in human pancreatic cancer. World J Gastroenterol 2003; 9:377-80. [PMID: 12532471 PMCID: PMC4611351 DOI: 10.3748/wjg.v9.i2.377] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of inhibiting factor of cell cycle regulation p57kip2, retinoblastinoma protein (Rb protein) and proliferating cell nuclear antigen (PCNA) in the genesis and progression of human pancreatic cancer.
METHODS: The expression of p57kip2, Rb protein and PCNA in tumor tissues and adjacent tissues of 32 patients with pancreatic cancer was detected with SP immunohistochemical technique.
RESULTS: p57kip2 protein positive-expression rate in tumor tissues of pancreatic cancer was 46.9%, which was lower than that in adjacent pancreatic tissues (75.0%) (χ2 = 5.317, P < 0.05), p57kip2 protein positive-expression correlated significantly with tumor cell differentiation (well-differentiation versus moderate or low-differentiation, P < 0.05) but did not correlate significantly with lymph node metastasis (lymph node metastasis versus non-lymph node metastasis, P > 0.05); Rb gene protein positive-expression rate in tumor tissues was 50.0%, which was also lower than that in adjacent pancreatic tissues (78.1%) (χ2 = 5.497, P < 0.05); PCNA positive-expression rate was 71.9%, being higher than that in adjacent pancreatic tissues (43.8%) (χ2 = 5.189, P < 0.05), PCNA positive-expression also correlated significantly with tumor cell differentiation and lymph node metastasis (well-differentiation versus moderate or low- differentiation, lymph node metastasis versus non-lymph node metastasis, P < 0.05). Rb protein positive-expression rate in the tumor tissues of p57kip2 protein positive-expression group was 53.3%; and Rb protein positive-expression rate in the tumor tissues of p57kip2 protein negative-expression group was 47.1%. There was no significant relationship between the two groups (r = 0.16507, P > 0.05).
CONCLUSION: The decreased expression of p57kip2, Rb protein or over-expression of PCNA protein might contribute to the genesis or progression of pancreatic cancer, p57kip2, Rb protein and PCNA may play an important role in genesis and progression of pancreatic cancer.
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Affiliation(s)
- Hui Yue
- Department of Gastroenterology, General Hospital of Shenyang Military Region, Shenyang 110016, Liaoning Province, China.
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Ayesh S, Matouk I, Schneider T, Ohana P, Laster M, Al-Sharef W, De-Groot N, Hochberg A. Possible physiological role of H19 RNA. Mol Carcinog 2002; 35:63-74. [PMID: 12325036 DOI: 10.1002/mc.10075] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The product of the imprinted oncofetal H19 gene is an untranslated RNA of unknown function. With the human cDNA Atlas microarray, we detected differentially expressed genes modulated by the presence of H19 RNA. Many of the genes that are upregulated by H19 RNA are known to contribute to the invasive, migratory, and angiogenic capacities of cells. Moreover, we provided experimental data indicating that whereas H19 RNA did not have any growth advantage for the cells when cultured in 10% fetal calf serum, it did confer an advantage when cells were cultured in serum-poor medium. This observation can be explained in part by the inability of the H19-expressing cells to induce the cyclin-dependent kinase inhibitor p57(kip2) in response to serum stress. Our results favor the possible role of the H19 gene in promoting cancer progression, angiogenesis, and metastasis.
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Affiliation(s)
- Suhail Ayesh
- Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel
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Samuelsson MKR, Pazirandeh A, Okret S. A pro-apoptotic effect of the CDK inhibitor p57(Kip2) on staurosporine-induced apoptosis in HeLa cells. Biochem Biophys Res Commun 2002; 296:702-9. [PMID: 12176039 DOI: 10.1016/s0006-291x(02)00912-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Apoptosis, or programmed cell death, is involved in many biological events, including tumorigenesis. Recently, it has been reported that two members of the Cip/Kip family of CDK inhibitors, p21(Cip1) and p27(Kip1), are involved in the regulation of apoptosis. Here, we report that selective expression of the third member in this family, p57(Kip2), potentiated staurosporine-induced apoptosis in HeLa cells. This pro-apoptotic effect was associated with an increased caspase-3 activity. In contrast, glucocorticoid treatment, despite inducing p57(Kip2) expression in HeLa cells, was found to have an inhibitory effect on staurosporine-induced apoptosis. This anti-apoptotic effect of glucocorticoids could be explained by a concomitant increase in Bcl-x(L) expression. The results presented in this study show that p57(Kip2) has a stimulatory effect on apoptosis induced by staurosporine, suggesting a role for p57(Kip2) in the response of tumor cells to cytotoxic drugs.
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Affiliation(s)
- Magnus K R Samuelsson
- Department of Medical Nutrition, Karolinska Institutet, Huddinge University Hospital, Novum, Huddinge SE-141 86, Sweden.
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