Publications by authors named "Rami I Aqeilan"

100 Publications

DAZAP2 acts as specifier of the p53 response to DNA damage.

Nucleic Acids Res 2021 Feb 16. Epub 2021 Feb 16.

Institute of Toxicology, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany.

The DNA damage-responsive tumor suppressors p53 and HIPK2 are well established regulators of cell fate decision-making and regulate the cellular sensitivity to DNA-damaging drugs. Here, we identify Deleted in Azoospermia-associated protein 2 (DAZAP2), a small adaptor protein, as a novel regulator of HIPK2 and specifier of the DNA damage-induced p53 response. Knock-down or genetic deletion of DAZAP2 strongly potentiates cancer cell chemosensitivity both in cells and in vivo using a mouse tumour xenograft model. In unstressed cells, DAZAP2 stimulates HIPK2 polyubiquitination and degradation through interplay with the ubiquitin ligase SIAH1. Upon DNA damage, HIPK2 site-specifically phosphorylates DAZAP2, which terminates its HIPK2-degrading function and triggers its re-localization to the cell nucleus. Interestingly, nuclear DAZAP2 interacts with p53 and specifies target gene expression through modulating a defined subset of p53 target genes. Furthermore, our results suggest that DAZAP2 co-occupies p53 response elements to specify target gene expression. Collectively, our findings propose DAZAP2 as novel regulator of the DNA damage-induced p53 response that controls cancer cell chemosensitivity.
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http://dx.doi.org/10.1093/nar/gkab084DOI Listing
February 2021

Engineering organoids: a promising platform to understand biology and treat diseases.

Authors:
Rami I Aqeilan

Cell Death Differ 2021 Jan 14;28(1):1-4. Epub 2020 Dec 14.

The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

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http://dx.doi.org/10.1038/s41418-020-00680-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734914PMC
January 2021

Programmed DNA Damage and Physiological DSBs: Mapping, Biological Significance and Perturbations in Disease States.

Cells 2020 08 10;9(8). Epub 2020 Aug 10.

The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 9112001, Israel.

DNA double strand breaks (DSBs) are known to be the most toxic and threatening of the various types of breaks that may occur to the DNA. However, growing evidence continuously sheds light on the regulatory roles of programmed DSBs. Emerging studies demonstrate the roles of DSBs in processes such as T and B cell development, meiosis, transcription and replication. A significant recent progress in the last few years has contributed to our advanced knowledge regarding the functions of DSBs is the development of many next generation sequencing (NGS) methods, which have considerably advanced our capabilities. Other studies have focused on the implications of programmed DSBs on chromosomal aberrations and tumorigenesis. This review aims to summarize what is known about DNA damage in its physiological context. In addition, we will examine the advancements of the past several years, which have made an impact on the study of genome landscape and its organization.
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http://dx.doi.org/10.3390/cells9081870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463922PMC
August 2020

Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-β pathway.

Signal Transduct Target Ther 2020 06 5;5(1):75. Epub 2020 Jun 5.

Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China.

The activation of hepatic stellate cells (HSCs) participates in liver fibrosis, and emerging evidences indicate that microRNAs (miRNAs) are abnormally expressed during HSC activation. However, the potential roles of miRNAs in liver fibrosis still remain elusive. Therefore, this study aimed to investigate the role of miR-199a-3p in liver fibrosis and its underlying mechanism. We found that miR-199a-3p expression was dramatically upregulated during HSC activation in vitro, and during liver fibrogenesis in CCl-treated rats, and its liver expression was increased in the patients with cirrhosis. By the luciferase assay and RT-qPCR, we revealed that the expression of miR-199a-3p in HSCs was driven by the transcription factor Twist1 which could be further induced by TGF-β treatment. Functional studies showed that inhibition of miR-199a-3p in both human LX2 cells and rat HSCs significantly decreased the expression of fibrotic markers, such as fibronectin and connective tissue growth factor (CTGF), whereas the forced expression of miR-199a-3p exhibited opposite effects, demonstrating the role of miR-199a-3p in promoting HSC activation. Mechanistically, miR-199a-3p plays an important role in TGF-β signalling pathway activation through targeting CAV2 that negatively regulates the expression of transforming growth factor-beta receptor type I (TGFβRI). Importantly, administration of antagomiR-199a-3p in the CCl-treated mice significantly ameliorated hepatic fibrosis. In conclusion, Twist1-induced miR-199a-3p mediates the activation of HSCs by suppressing CAV2 expression and subsequently increasing TGFβRI expression to promote TGF-β pathway. Our findings highlight the therapeutic potential of miR-199a-3p for hepatic fibrosis.
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http://dx.doi.org/10.1038/s41392-020-0169-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272438PMC
June 2020

Mapping the breakome reveals tight regulation on oncogenic super-enhancers.

Mol Cell Oncol 2020 11;7(3):1698933. Epub 2020 Feb 11.

The Lautenberg Center for General and Tumor Immunology; Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

DNA double-strand breaks (DSBs) could be deleterious and lead to age-related diseases, such as cancer. Recent evidence, however, associates DSBs with vital cellular processes. As discussed here, genome-wide mapping of DSBs revealed an unforeseen coupling mechanism between transcription and DNA repair at super-enhancers, as means of hypertranscription of oncogenic drivers.
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http://dx.doi.org/10.1080/23723556.2019.1698933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199745PMC
February 2020

Pleiotropic tumor suppressor functions of WWOX antagonize metastasis.

Signal Transduct Target Ther 2020 04 17;5(1):43. Epub 2020 Apr 17.

Lautenberg Center for Immunology and Cancer Research, Hebrew University-Hadassah Medical School, IMRIC, Jerusalem, Israel.

Tumor progression and metastasis are the major causes of death among cancer associated mortality. Metastatic cells acquire features of migration and invasion and usually undergo epithelia-mesenchymal transition (EMT). Acquirement of these various hallmarks rely on different cellular pathways, including TGF-β and Wnt signaling. Recently, we reported that WW domain-containing oxidoreductase (WWOX) acts as a tumor suppressor and has anti-metastatic activities involving regulation of several key microRNAs (miRNAs) in triple-negative breast cancer (TNBC). Here, we report that WWOX restoration in highly metastatic MDA-MB435S cancer cells alters mRNA expression profiles; further, WWOX interacts with various proteins to exert its tumor suppressor function. Careful alignment and analysis of gene and miRNA expression in these cells revealed profound changes in cellular pathways mediating adhesion, invasion and motility. We further demonstrate that WWOX, through regulation of miR-146a levels, regulates SMAD3, which is a member of the TGF-β signaling pathway. Moreover, proteomic analysis of WWOX partners revealed regulation of the Wnt-signaling activation through physical interaction with Disheveled. Altogether, these findings underscore a significant role for WWOX in antagonizing metastasis, further highlighting its role and therapeutic potential in suppressing tumor progression.
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http://dx.doi.org/10.1038/s41392-020-0136-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162874PMC
April 2020

Activation of Oncogenic Super-Enhancers Is Coupled with DNA Repair by RAD51.

Cell Rep 2019 10;29(3):560-572.e4

Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel; Department of Cancer Biology and Genetics, Wexner Medical Center, Ohio State University, Columbus, Ohio, USA. Electronic address:

DNA double-strand breaks (DSBs) are deleterious and tumorigenic but could also be essential for DNA-based processes. Yet the landscape of physiological DSBs and their role and repair are still elusive. Here, we mapped DSBs at high resolution in cancer and non-tumorigenic cells and found a transcription-coupled repair mechanism at oncogenic super-enhancers. At these super-enhancers the transcription factor TEAD4, together with various transcription factors and co-factors, co-localizes with the repair factor RAD51 of the homologous recombination pathway. Depletion of TEAD4 or RAD51 increases DSBs at RAD51/TEAD4 common binding sites within super-enhancers and decreases expression of related genes, which are mostly oncogenes. Co-localization of RAD51 with transcription factors at super-enhancers occurs in various cell types, suggesting a broad phenomenon. Together, our findings uncover a coupling between transcription and repair mechanisms at oncogenic super-enhancers, to control the hyper-transcription of multiple cancer drivers.
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http://dx.doi.org/10.1016/j.celrep.2019.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899447PMC
October 2019

AntimiR-155 Cyclic Peptide-PNA Conjugate: Synthesis, Cellular Uptake, and Biological Activity.

ACS Omega 2019 Aug 12;4(9):13954-13961. Epub 2019 Aug 12.

The Institute for Drug Research, The School of Pharmacy, and Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Hadassah Ein-Kerem, Jerusalem 9112102, Israel.

Efficient delivery of nucleic acids into cells still remains a great challenge. Peptide nucleic acids (PNAs) are DNA analogues with a neutral backbone and are synthesized by solid phase peptide chemistry. This allows a straightforward synthetic route to introduce a linear short peptide (a.k.a. cell-penetrating peptide) to the PNA molecule as a means of facilitating cellular uptake of PNAs. Herein, we have devised a synthetic route in which a cyclic peptide is prepared on a solid support and is extended with the PNA molecule, where all syntheses are accomplished on the solid phase. This allows the conjugation of the cyclic peptide to the PNA molecule with the need of only one purification step after the cyclic peptide-PNA conjugate (C-PNA) is cleaved from the solid support. The PNA sequence chosen is an antimiR-155 molecule that is complementary to mature miR-155, a well-established oncogenic miRNA. By labeling C-PNA with fluorescein isothiocyanate, we observe efficient cellular uptake into glioblastoma cells (U87MG) at a low concentration (0.5 μM), as corroborated by fluorescence-activated cell sorting (FACS) analysis and confocal microscopy. FACS analysis also suggests an uptake mechanism that is energy-dependent. Finally, the antimiR activity of C-PNA was shown by analyzing miR155 levels by quantitative reverse transcription polymerase chain reaction and by observing a reduction in cell viability and proliferation in U87MG cells, as corroborated by XTT and colony formation assays. Given the added biological stability of cyclic versus linear peptides, this synthetic approach may be a useful and straightforward approach to synthesize cyclic peptide-PNA conjugates.
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http://dx.doi.org/10.1021/acsomega.9b01697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714607PMC
August 2019

Editorial: WW Domain Proteins in Signaling, Cancer Growth, Neural Diseases, and Metabolic Disorders.

Front Oncol 2019 2;9:719. Epub 2019 Aug 2.

Faculty of Medicine, The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research, Israel-Canada (IMRIC), Hebrew University of Jerusalem, Jerusalem, Israel.

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http://dx.doi.org/10.3389/fonc.2019.00719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688159PMC
August 2019

Decoding the link between WWOX and p53 in aggressive breast cancer.

Cell Cycle 2019 06 16;18(11):1177-1186. Epub 2019 May 16.

a Lautenberg Center for Immunology and Cancer Research, IMRIC , Hebrew University-Hadassah Medical School, IMRIC , Jerusalem , Israel.

Basal-like breast cancer (BLBC) and triple-negative breast cancer (TNBC) are aggressive forms of human breast cancer with poor prognosis and limited treatment response. Molecular understanding of BLBC and TNBC biology is instrumental to improve detection and management of these deadly diseases. Tumor suppressors WW domain-containing oxidoreductase (WWOX) and TP53 are altered in BLBC and in TNBC. Nevertheless, the functional interplay between WWOX and p53 is poorly understood. In a recent study by Abdeen and colleagues, it has been demonstrated that WWOX loss drives BLBC formation via deregulating p53 functions. In this review, we highlight important signaling pathways regulated by WWOX and p53 that are related to estrogen receptor signaling, epithelial-to-mesenchymal transition, and genomic instability and how they impact BLBC and TNBC development.
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http://dx.doi.org/10.1080/15384101.2019.1616998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592247PMC
June 2019

MiR-16-1-3p and miR-16-2-3p possess strong tumor suppressive and antimetastatic properties in osteosarcoma.

Int J Cancer 2019 12 9;145(11):3052-3063. Epub 2019 May 9.

The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-IMRIC, The Hebrew University-Hadassah Medical School at Ein-Kerem, Jerusalem, Israel.

Osteosarcoma (OS) is an aggressive malignancy affecting mostly children and adolescents. MicroRNAs (miRNAs) play important roles in OS development and progression. Here we found that miR-16-1-3p and miR-16-2-3p "passenger" strands, as well as the "lead" miR-16-5p strand, are frequently downregulated and possess strong tumor suppressive functions in human OS. Furthermore, we report different although strongly overlapping functions for miR-16-1-3p and miR-16-2-3p in OS cells. Ectopic expression of these miRNAs affected primary tumor growth, metastasis seeding and chemoresistance and invasiveness of human OS cells. Loss-of-function experiments verified tumor suppressive functions of these miRNAs at endogenous levels of expression. Using RNA immunoprecipitation (RIP) assays, we identify direct targets of miR-16-1-3p and miR-16-2-3p in OS cells. Moreover, validation experiments identified FGFR2 as a direct target for miR-16-1-3p and miR-16-2-3p. Overall, our findings underscore the importance of passenger strand miRNAs, at least some, in osteosarcomagenesis.
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http://dx.doi.org/10.1002/ijc.32368DOI Listing
December 2019

Fhit-Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells.

Cell Death Dis 2019 02 15;10(3):147. Epub 2019 Feb 15.

Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA.

Fhit protein is lost in cancers of most, perhaps all, cancer types; when restored, it can induce apoptosis and suppress tumorigenicity, as shown in vitro and in mouse tumor models in vivo. Following protein cross-linking and proteomics analyses, we characterized a Fhit protein complex involved in triggering Fhit-mediated apoptosis. The complex includes the heat-shock chaperonin pair, HSP60/10, which is likely involved in importing Fhit into the mitochondria, where it interacts with ferredoxin reductase, responsible for transferring electrons from NADPH to cytochrome P450 via ferredoxin, in electron transport chain complex III. Overexpression of Fhit protein in Fhit-deficient cancer cells modulates the production of intracellular reactive oxygen species, causing increased ROS, following peroxide treatment, with subsequent increased apoptosis of lung cancer cells under oxidative stress conditions; conversely, Fhit-negative cells escape ROS overproduction and ROS-induced apoptosis, likely carrying oxidative damage. Thus, characterization of Fhit-interacting proteins has identified direct effectors of a Fhit-mediated apoptotic signal pathway that is lost in many cancers. This is of translational interest considering the very recent emphasis in a number of high-profile publications, concerning the role of oxidative phosphorylation in the treatment of human cancers, and especially cancer stem cells that rely upon oxidative phosphorylation for survival. Additionally, we have shown that cells from a Fhit-deficient lung cancer cell line, are sensitive to killing by exposure to atovaquone, thought to act as a selective oxidative phosphorylation inhibitor by targeting the CoQ10 dependence of the mitochondrial complex III, while the Fhit-expressing sister clone is resistant to this treatment.
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http://dx.doi.org/10.1038/s41419-019-1414-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377664PMC
February 2019

WWOX somatic ablation in skeletal muscles alters glucose metabolism.

Mol Metab 2019 04 31;22:132-140. Epub 2019 Jan 31.

The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel; Department of Cancer Biology and Genetics, Wexner Medical Center, The Ohio State University, Columbus, OH, USA. Electronic address:

Objective: WWOX, a well-established tumor suppressor, is frequently lost in cancer and plays important roles in DNA damage response and cellular metabolism.

Methods: We re-analyzed several genome-wide association studies (GWAS) using the Type 2 Diabetes Knowledge Portal website to uncover WWOX's association with metabolic syndrome (MetS). Using several engineered mouse models, we studied the effect of somatic WWOX loss on glucose homeostasis.

Results: Several WWOX variants were found to be strongly associated with MetS disorders. In mouse models, somatic ablation of Wwox in skeletal muscle (Wwox) results in weight gain, glucose intolerance, and insulin resistance. Furthermore, Wwox mice display reduced amounts of slow-twitch fibers, decreased mitochondrial quantity and activity, and lower glucose oxidation levels. Mechanistically, we found that WWOX physically interacts with the cellular energy sensor AMP-activated protein kinase (AMPK) and that its loss is associated with impaired activation of AMPK, and with significant accumulation of the hypoxia inducible factor 1 alpha (HIF1α) in SKM.

Conclusions: Our studies uncover an unforeseen role of the tumor suppressor WWOX in whole-body glucose homeostasis and highlight the intimate relationship between cancer progression and metabolic disorders, particularly obesity and type-2 diabetes.

Subject Areas: Genetics, Metabolic Syndrome, Diabetes.
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http://dx.doi.org/10.1016/j.molmet.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437662PMC
April 2019

WWOX Inhibits Metastasis of Triple-Negative Breast Cancer Cells via Modulation of miRNAs.

Cancer Res 2019 Apr 8;79(8):1784-1798. Epub 2019 Jan 8.

Lautenberg Center for Immunology and Cancer Research, Hebrew University-Hadassah Medical School, IMRIC, Jerusalem, Israel.

Triple-negative breast cancer (TNBC) is a heterogeneous, highly aggressive, and difficult to treat tumor type. The tumor suppressor spans FRA16D, a common fragile site that is commonly altered in breast cancer. Despite recent progress, the role of WWOX in TNBC metastasis is unknown. Here we report that WWOX inactivation correlates with advanced stages of TNBC and that its levels are frequently altered in TNBC cells. Ectopic restoration of WWOX in WWOX-negative TNBC cells inhibited metastasis while its depletion in WWOX-positive TNBC cells promoted metastasis. WWOX was a negative regulator of c-MYC, which regulated miR-146a expression and consequently fibronectin levels, contributing to an epithelial status of the cell. Treatment of TNBC cells with anti-miR-146a rescued the WWOX antimetastatic phenotype. Moreover, overexpression of MYC in WWOX-expressing TNBC cells overrode WWOX effects on miR-146a and fibronectin levels. Altogether, our data uncover an essential role for WWOX in antagonizing TNBC progression and highlight its potential use as a biomarker for metastasis. SIGNIFICANCE: These findings highlight the mechanism by which the tumor suppressor WWOX regulates metastasis of triple-negative breast cancer..
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0614DOI Listing
April 2019

Author Correction: WWOX controls hepatic HIF1α to suppress hepatocyte proliferation and neoplasia.

Cell Death Dis 2018 Nov 23;9(12):1159. Epub 2018 Nov 23.

The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Since the publication of their article, the authors reported that duplication had mistakenly occurred in Fig 3A and D - H&E panels.
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http://dx.doi.org/10.1038/s41419-018-1158-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251905PMC
November 2018

Modeling WWOX Loss of Function : What Have We Learned?

Front Oncol 2018 10;8:420. Epub 2018 Oct 10.

Faculty of Medicine, The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research, Israel-Canada (IMRIC), Hebrew University of Jerusalem, Jerusalem, Israel.

The WW domain-containing oxidoreductase ( gene encompasses a common fragile sites (CFS) known as , and is implicated in cancer. encodes a 46kDa adaptor protein, which contains two N-terminal WW-domains and a catalytic domain at its C-terminus homologous to short-chain dehydrogenase/reductase (SDR) family proteins. A high sequence conservation of orthologues from insects to rodents and ultimately humans suggest its significant role in physiology and homeostasis. Indeed, data obtained from several animal models including flies, fish, and rodents demonstrate WWOX requirement and that its deregulation results in severe pathological consequences including growth retardation, post-natal lethality, neuropathy, metabolic disorders, and tumorigenesis. Altogether, these findings set WWOX as an essential protein that is necessary to maintain normal cellular/physiological homeostasis. Here, we review and discuss lessons and outcomes learned from modeling loss of WWOX expression .
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http://dx.doi.org/10.3389/fonc.2018.00420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194312PMC
October 2018

Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer.

Cell Death Dis 2018 08 6;9(8):832. Epub 2018 Aug 6.

Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, IMRIC, Jerusalem, Israel.

Inactivation of WW domain-containing oxidoreductase (WWOX), the gene product of the common fragile site FRA16D, is a common event in breast cancer and is associated with worse prognosis of triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC). Despite recent progress, the role of WWOX in driving breast carcinogenesis remains unknown. Here we report that ablation of Wwox in mammary tumor-susceptible mice results in increased tumorigenesis, and that the resultant tumors resemble human BLBC. Interestingly, copy number loss of Trp53 and downregulation of its transcript levels were observed in the Wwox knockout tumors. Moreover, tumors isolated from Wwox and Trp53 mutant mice were indistinguishable histologically and transcriptionally. Finally, we find that deletion of TP53 and WWOX co-occurred and is associated with poor survival of breast cancer patients. Altogether, our data uncover an essential role for WWOX as a bona fide breast cancer tumor suppressor through the maintenance of p53 stability.
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http://dx.doi.org/10.1038/s41419-018-0896-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079009PMC
August 2018

Microenvironmental Cues Determine Tumor Cell Susceptibility to Neutrophil Cytotoxicity.

Cancer Res 2018 09 2;78(17):5050-5059. Epub 2018 Jul 2.

Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.

We have recently shown that neutrophil antitumor cytotoxicity is Ca dependent and is mediated by TRPM2, an HO-dependent Ca channel. However, neutrophil antitumor activity is dependent on context and is manifested in the premetastatic niche, but not at the primary site. We therefore hypothesized that expression of TRPM2 and the consequent susceptibility to neutrophil cytotoxicity may be associated with the epithelial/mesenchymal cellular state. We found that TRPM2 expression was upregulated during epithelial-to-mesenchymal transition (EMT), and mesenchymal cells were more susceptible to neutrophil cytotoxicity. Conversely, cells undergoing mesenchymal-to-epithelial transition (MET) expressed reduced levels of TRPM2, rendering them resistant to neutrophil cytotoxicity. Cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung. These data identify TRPM2 as the link between environmental cues at the primary tumor site, tumor cell susceptibility to neutrophil cytotoxicity, and disease progression. Furthermore, these data identify EMT as a process enhancing tumor-cell immune susceptibility and, by contrast, MET as a novel mode of immune evasion. EMT is required for metastatic spread and concomitantly enhances tumor cell susceptibility to neutrophil cytotoxicity. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0540DOI Listing
September 2018

MicroRNA-214 promotes hepatic stellate cell activation and liver fibrosis by suppressing Sufu expression.

Cell Death Dis 2018 06 18;9(7):718. Epub 2018 Jun 18.

Department of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China.

MicroRNAs (miRNAs) have been demonstrated to modulate cellular processes in the liver. However, the role of miRNAs in liver fibrosis is poorly understood. Because the activation of hepatic stellate cells (HSCs) is a pivotal event in the initiation and progression of hepatic fibrosis, we investigate the differential expression of miRNAs in activated and quiescent rat HSCs by microarray analysis and find that miR-214 (miR-214-3p) is significantly upregulated during HSC activation. Moreover, the robust induction of miR-214 is correlated with liver fibrogenesis in carbon tetrachloride (CCl)-treated rats and mice, high-fat diet-induced non-alcoholic steatohepatitis in mice, and cirrhosis in humans. We identify that miR-214 expression is driven by the helix-loop-helix transcription factor Twist1 via the E-box element. The increased miR-214 inhibits the expression of suppressor-of-fused homolog (Sufu), a negative regulator of the Hedgehog signaling pathway, thereby contributing to HSC activation to promote the accumulation of fibrous extracellular matrix and the expression of profibrotic genes in HSCs and LX2 cells. Furthermore, miR-214 expression is inversely correlated with the expression of Sufu in clinical cirrhosis samples. To explore the clinical potential of miR-214, we inject antagomiR-214 oligos into mice to induce hepatic fibrosis. The knockdown of miR-214 in vivo enhances Sufu expression and reduces fibrosis marker expression, which ameliorates liver fibrosis in mice. In conclusions, the Twist1-regulated miR-214 promotes the activation of HSC cells through targeting Sufu involved in the Hedgehog pathway and participates in the development of hepatic fibrosis. Hence, the knockdown of miR-214 expression may be a promising therapeutic strategy for liver fibrosis.
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http://dx.doi.org/10.1038/s41419-018-0752-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006298PMC
June 2018

WWOX controls hepatic HIF1α to suppress hepatocyte proliferation and neoplasia.

Cell Death Dis 2018 05 1;9(5):511. Epub 2018 May 1.

The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Liver cancer is one of the most lethal malignancies with very poor prognosis once diagnosed. The most common form of liver cancer is hepatocellular carcinoma (HCC). The WW domain-containing oxidoreductase (WWOX) is a large gene that is often perturbed in a wide variety of tumors, including HCC. WWOX has been shown to act as a tumor suppressor modulating cellular metabolism via regulating hypoxia-inducible factor 1α (HIF-1α) levels and function. Given that WWOX is commonly inactivated in HCC, we set to determine whether specific targeted deletion of murine Wwox affects liver biology and HCC development. WWOX liver-specific knockout mice (Wwox ) showed more potent liver regeneration potential and enhanced proliferation as compared with their control littermates. Moreover, WWOX deficiency in hepatocytes combined with diethylnitrosamine treatment increased the tumor burden, which was associated with increased HIF1α levels and target gene transactivation. Inhibition of HIF1α by systemic treatment with digoxin significantly delayed HCC formation. Our work suggests that WWOX inactivation has a central role in promoting HCC through rewiring of cellular metabolism and modulating proliferation.
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http://dx.doi.org/10.1038/s41419-018-0510-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938702PMC
May 2018

TRPM2 Mediates Neutrophil Killing of Disseminated Tumor Cells.

Cancer Res 2018 05 28;78(10):2680-2690. Epub 2018 Feb 28.

Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.

Neutrophils play a critical role in cancer, with both protumor and antitumor neutrophil subpopulations reported. The antitumor neutrophil subpopulation has the capacity to kill tumor cells and limit metastatic spread, yet not all tumor cells are equally susceptible to neutrophil cytotoxicity. Because cells that evade neutrophils have greater chances of forming metastases, we explored the mechanism neutrophils use to kill tumor cells. Neutrophil cytotoxicity was previously shown to be mediated by secretion of HO We report here that neutrophil cytotoxicity is Ca dependent and is mediated by TRPM2, a ubiquitously expressed HO-dependent Ca channel. Perturbing TRPM2 expression limited tumor cell proliferation, leading to attenuated tumor growth. Concomitantly, cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung. These findings identify the mechanism utilized by neutrophils to kill disseminated tumor cells and to limit metastatic spread. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3614DOI Listing
May 2018

TCL1A interacts with TP63 and enhances the survival of Raji Burkitt lymphoma cell line.

Br J Haematol 2018 11 19;183(3):509-512. Epub 2017 Oct 19.

Department of Experimental and Clinical Medicine, University 'Magna Graecia' of Catanzaro, Catanzaro, Italy.

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http://dx.doi.org/10.1111/bjh.14989DOI Listing
November 2018

RUNX1, a new regulator of EMT in breast cancer.

Oncotarget 2017 03;8(11):17407-17408

Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem.

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http://dx.doi.org/10.18632/oncotarget.15623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392256PMC
March 2017

Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response.

PLoS Genet 2016 Dec 15;12(12):e1006436. Epub 2016 Dec 15.

Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

The role of common fragile sites (CFSs) in cancer remains controversial. Two main views dominate the discussion: one suggests that CFS loci are hotspots of genomic instability leading to inactivation of genes encoded within them, while the other view proposes that CFSs are functional units and that loss of the encoded genes confers selective pressure, leading to cancer development. The latter view is supported by emerging evidence showing that expression of a given CFS is associated with genome integrity and that inactivation of CFS-resident tumor suppressor genes leads to dysregulation of the DNA damage response (DDR) and increased genomic instability. These two viewpoints of CFS function are not mutually exclusive but rather coexist; when breaks at CFSs are not repaired accurately, this can lead to deletions by which cells acquire growth advantage because of loss of tumor suppressor activities. Here, we review recent advances linking some CFS gene products with the DDR, genomic instability, and carcinogenesis and discuss how their inactivation might represent a selective advantage for cancer cells.
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http://dx.doi.org/10.1371/journal.pgen.1006436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157955PMC
December 2016

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma.

Cancer Res 2016 10 22;76(20):6107-6117. Epub 2016 Aug 22.

The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel. Department of Cancer Biology and Genetics (CBG), The Ohio State University Wexner Medical Center, Columbus, Ohio. Department of Biochemistry, University of Vermont College of Medicine, Burlington, Vermont.

Osteosarcoma is a highly metastatic form of bone cancer in adolescents and young adults that is resistant to existing treatments. Development of an effective therapy has been hindered by very limited understanding of the mechanisms of osteosarcomagenesis. Here, we used genetically engineered mice to investigate the effects of deleting the tumor suppressor Wwox selectively in either osteoblast progenitors or mature osteoblasts. Mice with conditional deletion of Wwox in preosteoblasts (Wwox) displayed a severe inhibition of osteogenesis accompanied by p53 upregulation, effects that were not observed in mice lacking Wwox in mature osteoblasts. Deletion of p53 in Wwox mice rescued the osteogenic defect. In addition, the Wwox;p53 double knockout mice developed poorly differentiated osteosarcomas that resemble human osteosarcoma in histology, location, metastatic behavior, and gene expression. Strikingly, the development of osteosarcomas in these mice was greatly accelerated compared with mice lacking p53 only. In contrast, combined WWOX and p53 inactivation in mature osteoblasts did not accelerate osteosarcomagenesis compared with p53 inactivation alone. These findings provide evidence that a WWOX-p53 network regulates normal bone formation and that disruption of this network in osteoprogenitors results in accelerated osteosarcoma. The Wwox;p53 double knockout establishes a new osteosarcoma model with significant advancement over existing models. Cancer Res; 76(20); 6107-17. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5146760PMC
October 2016

WWOX guards genome stability by activating ATM.

Mol Cell Oncol 2015 Oct-Dec;2(4):e1008288. Epub 2015 Feb 23.

The Lautenberg Center for General and Tumor Immunology; Department of Immunology and Cancer Research-IMRIC; Hebrew University-Hadassah Medical School ; Jerusalem, Israel.

Common fragile sites (CFSs) tend to break upon replication stress and have been suggested to be "hot spots" for genomic instability. Recent evidence, however, implies that in the wake of DNA damage, WW domain-containing oxidoreductase (WWOX, the gene product of the FRA16D fragile site), associates with ataxia telangiectasia-mutated (ATM) and regulates its activation to maintain genomic integrity.
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http://dx.doi.org/10.1080/23723556.2015.1008288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905350PMC
June 2016