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Abstract
Mice are the most important animals to model tumor formation and malignant progression in humans. Chemical induction of skin tumors in mice by treatment with DMBA and TPA is a well-studied tumor induction model that is easy to use and directly applicable to genetically modified mice without any mandatory crossing with mice carrying mutations in oncogenes and tumorsuppressors. This article describes the basic protocol for DMBA/TPA induced skin tumor formation and discusses the advantages and limitations of this model, in particular the translatability of results obtained in this system to human cancer patients.
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Affiliation(s)
- Hui Li
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
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2
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Kuonen F, Huskey NE, Shankar G, Jaju P, Whitson RJ, Rieger KE, Atwood SX, Sarin KY, Oro AE. Loss of Primary Cilia Drives Switching from Hedgehog to Ras/MAPK Pathway in Resistant Basal Cell Carcinoma. J Invest Dermatol 2019; 139:1439-1448. [PMID: 30707899 DOI: 10.1016/j.jid.2018.11.035] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 11/08/2018] [Accepted: 11/09/2018] [Indexed: 12/20/2022]
Abstract
Basal cell carcinomas (BCCs) rely on Hedgehog (HH) pathway growth signal amplification by the microtubule-based organelle, the primary cilium. Despite naive tumor responsiveness to Smoothened inhibitors (Smoi), resistance in advanced tumors remains common. Although the resistant BCCs usually maintain HH pathway activation, squamous cell carcinomas with Ras/MAPK pathway activation also arise, and the molecular basis of tumor type and pathway selection are still obscure. Here, we identify the primary cilium as a critical determinant controlling tumor pathway switching. Strikingly, Smoothened inhibitor-resistant BCCs have an increased mutational load in ciliome genes, resulting in reduced primary cilia and HH pathway activation compared with naive or Gorlin syndrome patient BCCs. Gene set enrichment analysis of resistant BCCs with a low HH pathway signature showed increased Ras/MAPK pathway activation. Tissue analysis confirmed an inverse relationship between primary cilia presence and Ras/MAPK activation, and primary cilia removal in BCCs potentiated Ras/MAPK pathway activation. Moreover, activating Ras in HH-responsive cell lines conferred resistance to both canonical (vismodegib) and noncanonical (atypical protein kinase C and MRTF inhibitors) HH pathway inhibitors and conferred sensitivity to MAPK inhibitors. Our results provide insights into BCC treatment and identify the primary cilium as an important lineage gatekeeper, preventing HH-to-Ras/MAPK pathway switching.
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Affiliation(s)
- François Kuonen
- Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
| | - Noelle E Huskey
- Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
| | - Gautam Shankar
- Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA
| | - Prajakta Jaju
- Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA
| | - Ramon J Whitson
- Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA
| | - Kerri E Rieger
- Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA
| | - Scott X Atwood
- Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA
| | - Kavita Y Sarin
- Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA
| | - Anthony E Oro
- Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.
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3
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Lin F, de Gooijer MC, Hanekamp D, Brandsma D, Beijnen JH, van Tellingen O. Targeting core (mutated) pathways of high-grade gliomas: challenges of intrinsic resistance and drug efflux. CNS Oncol 2015; 2:271-88. [PMID: 25054467 DOI: 10.2217/cns.13.15] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
High-grade gliomas are the most common type of primary brain tumor and are among the most lethal types of human cancer. Most patients with a high-grade glioma have glioblastoma multiforme (GBM), the most malignant glioma subtype that is associated with a very aggressive disease course and short overall survival. Standard treatment of newly diagnosed GBM involves surgery followed by chemoradiation with temozolomide. However, despite this extensive treatment the mean overall survival is still only 14.6 months and more effective treatments are urgently needed. Although different types of GBMs are indistinguishable by histopathology, novel molecular pathological techniques allow discrimination between the four main GBM subtypes. Targeting the aberrations in the molecular pathways underlying these subtypes is a promising strategy to improve therapy. In this article, we will discuss the potential avenues and pitfalls of molecularly targeted therapies for the treatment of GBM.
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Affiliation(s)
- Fan Lin
- Department of Clinical Chemistry/Preclinical Pharmacology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Manzo-Merino J, Contreras-Paredes A, Vázquez-Ulloa E, Rocha-Zavaleta L, Fuentes-Gonzalez AM, Lizano M. The Role of Signaling Pathways in Cervical Cancer and Molecular Therapeutic Targets. Arch Med Res 2014; 45:525-39. [DOI: 10.1016/j.arcmed.2014.10.008] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 10/29/2014] [Indexed: 12/24/2022]
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Liu Y, Sánchez-Tilló E, Lu X, Huang L, Clem B, Telang S, Jenson AB, Cuatrecasas M, Chesney J, Postigo A, Dean DC. The ZEB1 transcription factor acts in a negative feedback loop with miR200 downstream of Ras and Rb1 to regulate Bmi1 expression. J Biol Chem 2013; 289:4116-25. [PMID: 24371144 DOI: 10.1074/jbc.m113.533505] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Ras mutations are frequent in cancer cells where they drive proliferation and resistance to apoptosis. However in primary cells, mutant Ras instead can cause oncogene-induced senescence, a tumor suppressor function linked to repression of the polycomb factor Bmi1, which normally regulates cell cycle inhibitory cyclin-dependent kinase inhibitors (cdki). It is unclear how Ras causes repression of Bmi1 in primary cells to suppress tumor formation while inducing the gene in cancer cells to drive tumor progression. Ras also induces the EMT transcription factor ZEB1 to trigger tumor invasion and metastasis. Beyond its well-documented role in EMT, ZEB1 is important for maintaining repression of cdki. Indeed, heterozygous mutation of ZEB1 is sufficient for elevated cdki expression, leading to premature senescence of primary cells. A similar phenotype is evident with Bmi1 mutation. We show that activation of Rb1 in response to mutant Ras causes dominant repression of ZEB1 in primary cells, but loss of the Rb1 pathway is a hallmark of cancer cells and in the absence of such Rb1 repression Ras induces ZEB1 in cancer cells. ZEB1 represses miR-200 in the context of a mutual repression loop. Because miR-200 represses Bmi1, induction of ZEB1 leads to induction of Bmi1. Rb1 pathway status then dictates the opposing effects of mutant Ras on the ZEB1-miR-200 loop in primary versus cancer cells. This loop not only triggers EMT, surprisingly we show it acts downstream of Ras to regulate Bmi1 expression and thus the critical decision between oncogene-induced senescence and tumor initiation.
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Affiliation(s)
- Yongqing Liu
- From the Molecular Targets Program, James Brown Cancer Center
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6
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Shin JW, Chung YH. Molecular targeted therapy for hepatocellular carcinoma: current and future. World J Gastroenterol 2013; 19:6144-55. [PMID: 24115810 PMCID: PMC3787343 DOI: 10.3748/wjg.v19.i37.6144] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 07/18/2013] [Accepted: 08/04/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide. The majority of HCC cases occur in patients with chronic liver disease. Despite regular surveillance to detect small HCC in these patients, HCC is often diagnosed at an advanced stage. Because HCC is highly resistant to conventional systemic therapies, the prognosis for advanced HCC patients remains poor. The introduction of sorafenib as the standard systemic therapy has unveiled a new direction for future research regarding HCC treatment. However, given the limited efficacy of the drug, a need exists to look beyond sorafenib. Many molecular targeted agents that inhibit different pathways involved in hepatocarcinogenesis are under various phases of clinical development, and novel targets are being assessed in HCC. This review aims to summarize the efforts to target molecular components of the signaling pathways that are responsible for the development and progression of HCC and to discuss perspectives on the future direction of research.
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Zhang R, Sun J, Zhang Y, Cheng S, Zhang X. Signal transduction disturbance related to hepatocarcinogenesis in mouse by prolonged exposure to Nanjing drinking water. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2013; 20:6468-6481. [PMID: 23591932 DOI: 10.1007/s11356-013-1695-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Accepted: 03/28/2013] [Indexed: 06/02/2023]
Abstract
Toxicogenomic approaches were used to investigate the potential hepatocarcinogenic effects on mice by oral exposure to Nanjing drinking water (NJDW). Changes in the hepatic transcriptome of 3 weeks male mice (Mus musculus) were monitored and dissected after oral exposure to NJDW for 90 days. No preneoplastic and neoplastic lesions were observed in the hepatic tissue by the end of NJDW exposure. However, total of 746 genes were changed transcriptionally. Thirty-one percent of differentially expressed genes (DEGs) were associated with the functional categories of cell cycle regulation, adhesion, growth, apoptosis, and signal transduction, which are closely implicated in tumorigenesis and progression. Interrogation of Kyoto Encyclopedia of Genes and Genomes revealed that 43 DEGs were mapped to several crucial signaling pathways implicated in the pathogenesis of hepatocellular carcinoma (HCC). In signal transduction network constructed via Genes2Networks software, Egfr, Akt1, Atf2, Ctnnb1, Hras, Mapk1, Smad2, and Ccnd1 were hubs. Direct gene-disease relationships obtained from Comparative Toxicogenomics Database and scientific literatures revealed that the hubs have direct mechanism or biomarker relationships with hepatocellular preneoplastic lesions or hepatocarcinogenesis. Therefore, prolonged intake of NJDW without employing any indoor water treatment strategy might predispose mouse to HCC. Furthermore, Egfr, Akt1, Ctnnb1, Hras, Mapk1, Smad2, and Ccnd1 were identified as promising biomarkers of the potential combined hepatocarcinogenicity.
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Affiliation(s)
- Rui Zhang
- State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, 163 Xianlin Road, Nanjing, 210046, People's Republic of China
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Gu L, Song G, Chen L, Nie Z, He B, Pan Y, Xu Y, Li R, Gao T, Cho WC, Wang S. Inhibition of miR-21 induces biological and behavioral alterations in diffuse large B-cell lymphoma. Acta Haematol 2013; 130:87-94. [PMID: 23548551 DOI: 10.1159/000346441] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 11/30/2012] [Indexed: 12/21/2022]
Abstract
MicroRNA-21 (miR-21) has been ascribed a key role in many cellular processes, e.g. tumorigenesis via inhibition of target gene expression. However, its role in diffuse large B-cell lymphoma (DLBCL) is still unclear, and there are no in-depth studies on the relationship between miR-21 and the cellular phenotype of DLBCL. In this study, we investigated the expression and role of miR-21 in the regulation of cell biological processes in DLBCL. Firstly, miR-21 expression was evaluated in three DLBCL cell lines by real-time quantitative reverse-transcription (qRT) polymerase chain reaction (PCR). Then, to determine the possible role of miR-21 in the biological and behavioral characteristics of DLBCL, we performed miR-21 knockdown by transfection with anti-miR-21. In addition, PDCD4 and PTEN were assessed by luciferase reporter assay, qRT-PCR, and Western blot. Our study revealed that miR-21 was significantly upregulated in activated B-cell-like DLBCL cells compared to germinal center-like DLBCL cells. We demonstrated that inhibition of miR-21 induced suppression of proliferation and invasion, as well as increased apoptosis in DLBCL. Moreover, knockdown of miR-21 increased PDCD4 and PTEN expression at the protein level but not at the mRNA level. In conclusion, miR-21 can regulate proliferation, invasion, and apoptosis, and thus it has a potential therapeutic application in DLBCL.
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Affiliation(s)
- Ling Gu
- Department of Life Sciences, Nanjing Normal University, Nanjing, China
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Tam B, Salamon A, Bajtai A, Németh A, Kiss J, Simon L, Molnár T. The real face of juvenile polyposis syndrome. J Gastrointest Oncol 2012. [PMID: 23205314 DOI: 10.3978/j.issn.2078-6891.2012.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Colorectal cancers are mostly sporadic; some cases of familial clustering and autosomal dominant conditions are also known to occur. Juvenile polyposis syndrome (JPS) is an autosomal dominant condition caused by the mutation of the SMAD4 or the BMPR1A genes. JPS is characterized by hamartomatous polyps developing in the upper and lower intestine. Contradicting previous studies, many of these polyps can go through malignant transformation.This paper reports the case of a male patient who was continuously treated for juvenile polyposis. During the eighteen years of treatment, more than hundred polyps were endoscopically removed from his gastrointestinal tract. The patient's care was interrupted for eight years due to insufficient compliance. He was subsequently referred to our Department of Gastroenterology in severe clinical condition caused by metastatic colorectal cancer. He died after a short palliative therapy at the age of 31. His first-degree accessible relatives were further examined for juvenile polyposis syndrome. Several gastrointestinal polyps of different histological origin were observed in the deceased patient's brother, who subsequently had to undergo a left lateral hemicolectomy. Genetic analyses revealed mutations of the BMPR1A gene in the clinically affected brother, the brother's daughter, and in the deceased proband's daughter.Indebt genetic analyses helped customize and deliver care to a very specific group of individuals. We were able to identify potential family members on whom preventive care and treatment could be focused and simultaneously prevented unnecessary clinical and invasive procedures on those who were healthy. Furthermore, these analyses helped prevent future unnecessary trauma or distress on the analyzed family.
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Affiliation(s)
- Beatrix Tam
- Department of Gastroenterology, Tolna County Teaching Hospital, Szekszárd, Hungary
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Zhang BG, Li JF, Yu BQ, Zhu ZG, Liu BY, Yan M. microRNA-21 promotes tumor proliferation and invasion in gastric cancer by targeting PTEN. Oncol Rep 2012; 27:1019-26. [PMID: 22267008 PMCID: PMC3583594 DOI: 10.3892/or.2012.1645] [Citation(s) in RCA: 229] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Accepted: 12/01/2011] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer is one of the most common carcinomas in China. microRNAs, a type of non-coding RNA, are important specific regulators and are involved in numerous bioprocesses of an organism. microRNA-21 (miR-21) has been identified as the most suitable choice for further investigation because it is overexpressed in nearly all solid tumors; furthermore, it has been demonstrated that miR-21 is involved in the genesis and progression of human cancer. It has been reported that PTEN, an important tumour suppressor, is regulated by multiple miRNAs. Thus, in this study we focused on the expression and significance of miR-21 in gastric cancer tissues, and the role of miR-21 in the biological behaviour and the expression of PTEN in gastric cancer cells. Real-time PCR was used to detect miR-21 expression in gastric cancer tissues, the adjacent normal tissues, and the gastric cell lines. The gastric cancer cell line BGC-823 was transfected with pre-miR-21/miR-21 inhibitor to overexpress/downregulate miR-21. The influence of miR-21 on the biological behaviour of gastric cancer cells was evaluated using the CCK-8 kit, FCMs, the scratch healing assay and the transwell test. Western blotting and the Luciferase Reporter Assay were used to evaluate the change of PTEN expression after lowered expression of miR-21 in gastric cancer cell lines. Real-time PCR analysis indicated that miR-21 exhibited higher expression in gastric cancer tissues compared to the adjacent non-tumor tissues. miR-21 expression was significantly associated with the degree of differentiation of the tumour tissues (P=0.004), as well as local invasion and lymph node metastasis (P<0.01). After transfection, pre-miR21 BGC-823 cells grew faster than the negative and control groups (P<0.01). The reduction in miR-21 expression demonstrated a remarkable effect on the biological behaviour of gastric cancer cells (P<0.05); the pre-miR-21-transfected cells healed more quickly compared to the control cells in the scratch healing assay, whereas the transwell test indicated that cell migration in vitro was notably inhibited with the downregulation of miR-21 (P<0.05). The western blot results and Luciferase Reporter Assay demonstrated that PTEN expression was remarkably increased after miR-21 inhibition (P<0.05). microRNA-21 expression was upregulated in gastric carcinoma tissues and was significantly associated with the degree of differentiation of tumour tissues, local invasion and lymph node metastasis. Overexpression of miR-21 promoted BGC-823 cell growth, invasion and cell migration in vitro, whereas downregulation of miR-21 exhibited a stronger inhibitory effect on the biological behaviour of gastric cancer cells; additionally, miR-21 inhibition may upregulate the PTEN expression level, which indicates that PTEN may be a target gene for gastric cancer initiation and development.
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Affiliation(s)
- Bao Gui Zhang
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
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Deng MY, Lam S, Meyer U, Feldon J, Li Q, Wei R, Luk L, Chua SE, Sham P, Wang Y, McAlonan GM. Frontal-subcortical protein expression following prenatal exposure to maternal inflammation. PLoS One 2011; 6:e16638. [PMID: 21347362 PMCID: PMC3037372 DOI: 10.1371/journal.pone.0016638] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 12/30/2010] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Maternal immune activation (MIA) during prenatal life is a risk factor for neurodevelopmental disorders including schizophrenia and autism. Such conditions are associated with alterations in fronto-subcortical circuits, but their molecular basis is far from clear. METHODOLOGY/PRINCIPAL FINDINGS Using two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry, with targeted western blot analyses for confirmation, we investigated the impact of MIA on the prefrontal and striatal proteome from an established MIA mouse model generated in C57B6 mice, by administering the viral analogue PolyI:C or saline vehicle (control) intravenously on gestation day (GD) 9. In striatum, 11 proteins were up-regulated and 4 proteins were down-regulated in the PolyI:C mice, while 10 proteins were up-regulated and 7 proteins down-regulated in prefrontal cortex (PFC). These were proteins involved in the mitogen-activated protein kinase (MAPK) signaling pathway, oxidation and auto-immune targets, including dual specificity mitogen-activated protein kinase kinase 1 (MEK), eukaryotic initiation factor (eIF) 4A-II, creatine kinase (CK)-B, L-lactate dehydrogenase (LDH)-B, WD repeat-containing protein and NADH dehydrogenase in the striatum; and guanine nucleotide-binding protein (G-protein), 14-3-3 protein, alpha-enolase, olfactory maker protein and heat shock proteins (HSP) 60, and 90-beta in the PFC. CONCLUSIONS/SIGNIFICANCE This data fits with emerging evidence for disruption of critical converging intracellular pathways involving MAPK pathways in neurodevelopmental conditions and it shows considerable overlap with protein pathways identified by genetic modeling and clinical post-mortem studies. This has implications for understanding causality and may offer potential biomarkers and novel treatment targets for neurodevelopmental conditions.
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Affiliation(s)
- Michelle Y. Deng
- Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
| | - Sylvia Lam
- Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
| | - Urs Meyer
- Laboratory and Behavioral Neurobiology, Swiss Federal Institute of Technology Zurich (ETH), Schwerzenbach, Switzerland
| | - Joram Feldon
- Laboratory and Behavioral Neurobiology, Swiss Federal Institute of Technology Zurich (ETH), Schwerzenbach, Switzerland
| | - Qi Li
- Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
| | - Ran Wei
- Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
| | - Lawrence Luk
- Genome Research Centre, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
| | - Siew Eng Chua
- Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
- State Key Laboratory for Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
| | - Pak Sham
- Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
- State Key Laboratory for Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
| | - Yu Wang
- Department of Pharmacology, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
| | - Grainne Mary McAlonan
- Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
- State Key Laboratory for Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China
- * E-mail:
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Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs. Oncotarget 2010; 1:530-43. [PMID: 21317449 PMCID: PMC3248125 DOI: 10.18632/oncotarget.101012] [Citation(s) in RCA: 155] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2010] [Accepted: 10/21/2010] [Indexed: 11/25/2022] Open
Abstract
It is well established that the PI3K pathway plays a central role in various cellular processes that can contribute to the malignant phenotype. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, agents targeting upstream receptor tyrosine kinases are best studied and have achieved greatest clinical success. Further downstream, despite efficacy in certain tumor types, the rapalogs have been somewhat disappointing in the clinic. Novel inhibitors of PI3K, Akt, and mTORC1 and 2 are now passing through early phase clinical trials. It is hoped that these agents will circumvent some of the shortcomings of the rapalogs and lead to meaningful benefits for cancer patients.
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Affiliation(s)
- Ben Markman
- Centre for Cancer Research, Monash Institute of Medical Research, Southern Health, Melbourne, Victoria, Australia
| | - Rodrigo Dienstmann
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
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13
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Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs. Oncotarget 2010; 1:530-543. [PMID: 21317449 PMCID: PMC3248125 DOI: 10.18632/oncotarget.188] [Citation(s) in RCA: 243] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2010] [Accepted: 10/21/2010] [Indexed: 11/25/2022] Open
Abstract
It is well established that the PI3K pathway plays a central role in various cellular processes that can contribute to the malignant phenotype. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, agents targeting upstream receptor tyrosine kinases are best studied and have achieved greatest clinical success. Further downstream, despite efficacy in certain tumor types, the rapalogs have been somewhat disappointing in the clinic. Novel inhibitors of PI3K, Akt, and mTORC1 and 2 are now passing through early phase clinical trials. It is hoped that these agents will circumvent some of the shortcomings of the rapalogs and lead to meaningful benefits for cancer patients.
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Affiliation(s)
- Ben Markman
- Centre for Cancer Research, Monash Institute of Medical Research, Southern Health, Melbourne, Victoria, Australia
| | - Rodrigo Dienstmann
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
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14
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Whittaker S, Marais R, Zhu AX. The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 2010; 29:4989-5005. [PMID: 20639898 DOI: 10.1038/onc.2010.236] [Citation(s) in RCA: 671] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a highly prevalent, treatment-resistant malignancy with a multifaceted molecular pathogenesis. Current evidence indicates that during hepatocarcinogenesis, two main pathogenic mechanisms prevail: (1) cirrhosis associated with hepatic regeneration after tissue damage caused by hepatitis infection, toxins (for example, alcohol or aflatoxin) or metabolic influences, and (2) mutations occurring in single or multiple oncogenes or tumor suppressor genes. Both mechanisms have been linked with alterations in several important cellular signaling pathways. These pathways are of interest from a therapeutic perspective, because targeting them may help to reverse, delay or prevent tumorigenesis. In this review, we explore some of the major pathways implicated in HCC. These include the RAF/MEK/ERK pathway, phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, WNT/beta-catenin pathway, insulin-like growth factor pathway, hepatocyte growth factor/c-MET pathway and growth factor-regulated angiogenic signaling. We focus on the role of these pathways in hepatocarcinogenesis, how they are altered, and the consequences of these abnormalities. In addition, we also review the latest preclinical and clinical data on the rationally designed targeted agents that are now being directed against these pathways, with early evidence of success.
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Affiliation(s)
- S Whittaker
- Dana-Farber Cancer Institute, Boston, MA, USA
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15
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Liu C, Yu J, Yu S, Lavker RM, Cai L, Liu W, Yang K, He X, Chen S. MicroRNA-21 acts as an oncomir through multiple targets in human hepatocellular carcinoma. J Hepatol 2010; 53:98-107. [PMID: 20447717 DOI: 10.1016/j.jhep.2010.02.021] [Citation(s) in RCA: 131] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2009] [Revised: 01/28/2010] [Accepted: 02/15/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS MicroRNA-21 negatively regulates several targets, thereby affecting tumorigenesis. However, its mechanism of action in human hepatocellular carcinoma is poorly understood, and no direct evidence has shown a correlation between microRNA-21 function and phenotype. In this study, we investigate the function of microRNA-21 as a potent oncomir and probe the relationship between microRNA-21, its targets, and phenotypic alterations. METHODS We designed a set of rescue experiments using different combinations of anti-microRNA-21, siRNA, and a negative control to modulate the protein level of microRNA-21 targets and resulting phenotypic alterations. MicroRNA-21 was suppressed using anti-microRNA-21 to further uncover its effect on several critical signaling pathways. RESULTS We demonstrate that hepatocellular carcinoma is characterized by elevated levels of microRNA-21 and marked reductions of PTEN, PDCD4, and RECK expression. Silencing of PTEN and PDCD4 to prevent their induction by anti-microRNA-21 treatment led to decreased apoptosis and increased invasion, while silencing of RECK only led to increased invasion. Moreover, knockdown of microRNA-21 resulted in alterations of the Akt signaling pathway, the expression of p21 and MMP families, which are associated with apoptosis, and the cell cycle or invasiveness of cancer cells. CONCLUSIONS MicroRNA-21 simultaneously regulates multiple programs that enhance cell proliferation, apoptosis or tumor invasiveness by targeting PTEN, PDCD4, and RECK in hepatocellular carcinomas. Targeting of microRNA-21 is sufficient to limit tumor cell proliferation and invasion in a manner that is likely to involve associated changes in multiple targets, suggesting that suppression of microRNA-21 may be a novel approach for the treatment of hepatocellular carcinoma.
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Affiliation(s)
- Changzheng Liu
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Department of Biochemistry, Beijing, PR China
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Markman B, Atzori F, Pérez-García J, Tabernero J, Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol 2009; 21:683-691. [PMID: 19713247 DOI: 10.1093/annonc/mdp347] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
The phosphatidylinositol 3-kinase (PI3K) signalling pathway is integral to diverse cellular functions, including cellular proliferation, differentiation and survival. The 'phosphate and tensin homologue deleted from chromosome 10' (PTEN) tumor suppressor gene plays a critical role as a negative regulator of this pathway. An array of genetic mutations and amplifications has been described affecting key components of this pathway, with implications not only for tumorigenesis but also for resistance to some classic cytotoxics and targeted agents. Emerging preclinical research has significantly advanced our understanding of the PI3K pathway and its complex machinations and interactions. This knowledge has enabled the evolution of rationally designed drugs targeting elements of this pathway. It is important that the development of suitable biomarkers continues in parallel to optimize use of these agents. A new generation of PI3K inhibitors is now entering early clinical trials, with much anticipation that they will add to the growing armamentarium of targeted cancer therapeutics.
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Affiliation(s)
- B Markman
- Medical Oncology Service, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - F Atzori
- Medical Oncology Service, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - J Pérez-García
- Medical Oncology Service, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - J Tabernero
- Medical Oncology Service, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - J Baselga
- Medical Oncology Service, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Universitat Autonoma de Barcelona, Barcelona, Spain.
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Holm S. ‘New Embryos’ – New Challenges for the Ethics of Stem Cell Research. Cells Tissues Organs 2008; 187:257-62. [DOI: 10.1159/000116763] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Chow LML, Baker SJ. PTEN function in normal and neoplastic growth. Cancer Lett 2006; 241:184-96. [PMID: 16412571 DOI: 10.1016/j.canlet.2005.11.042] [Citation(s) in RCA: 204] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2005] [Revised: 11/21/2005] [Accepted: 11/22/2005] [Indexed: 01/19/2023]
Abstract
The PTEN tumor suppressor is a central negative regulator of the PI3K/AKT signaling cascade that influences multiple cellular functions including cell growth, survival, proliferation and migration in a context-dependent manner. Dysregulation of this signaling pathway contributes to many cancers in man. PTEN is the most commonly altered component of the PI3K pathway in human malignancies. Mutations occur in both heritable and sporadic settings, with high frequency in sporadic glioblastoma, prostate and endometrial cancer. Data from human tumors and animal models support the concept that the effects of PTEN inactivation are tissue-specific. Elucidation of the mechanisms regulating activation of unique downstream effectors that mediate distinct outcomes of PTEN loss will augment our understanding of tumorigenesis and ultimately lead to novel therapeutic options.
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Affiliation(s)
- Lionel M L Chow
- Department of Developmental Neurobiology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA
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Abstract
All eukaryotic cells coordinate cell growth with the availability of nutrients in their environment. The mTOR protein kinase has emerged as a critical growth-control node, receiving stimulatory signals from Ras and phosphatidylinositol-3-OH kinase (PI(3)K) downstream from growth factors, as well as nutrient inputs in the form of amino-acid, glucose and oxygen availability. Notably, components of the Ras and PI(3)K signalling pathways are mutated in most human cancers. The preponderance of mutations in these interconnected pathways suggests that the loss of growth-control checkpoints and promotion of cell survival in nutrient-limited conditions may be an obligate event in tumorigenesis.
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Affiliation(s)
- Reuben J Shaw
- Dulbecco Laboratory for Cancer Research, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, California 9203, USA.
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