Rami Aqeilan

Publications (75) View all

• Article: Wwox inactivation enhances mammary tumorigenesis.

  S K Abdeen, Z Salah, B Maly, Y Smith, R Tufail, M Abu-Odeh, N Zanesi, C M Croce, Z Nawaz, R I Aqeilan
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  ABSTRACT: Breast cancer is the leading cause of cancer-related death in women worldwide. Expression of the WWOX tumor suppressor is absent or reduced in a large proportion of breast tumors suggesting that loss of WWOX may contribute to breast tumorigenesis. Wwox-deficient mice die by 3-4 weeks of age precluding adult tumor analysis. To evaluate the effect of WWOX-altered expression on mammary tumor formation, the Wwox-heterozygous allele was back crossed onto the C3H mammary tumor-susceptible genetic background (Wwox(C3H)+/-) and incidence of mammary tumor formation was evaluated. Although 50% of the female Wwox(C3H)+/- mice developed mammary carcinomas, only 7% of Wwox(C3H)+/+ mice did. Intriguingly, mammary tumors in Wwox(C3H)+/- mice frequently lost WWOX protein expression suggesting a genetic predisposition toward mammary tumorigenesis. Immunohistochemical staining of hormone receptors revealed loss of estrogen receptor-α (ER) and progesterone receptor in the majority of these tumors. In vitro, depletion of WWOX in MCF7 ER-positive cells led to reduced ER expression and reduced sensitivity to tamoxifen and estrogen treatment and was associated with enhanced survival and anchorage-independent growth. Finally, cDNA array analyses of murine normal mammary epithelial cells and mammary tumors identified 163 significantly downreguated and 129 upregulated genes in the tumors. The majority of differentially expressed genes were part of pathways involved in cellular movement, cell-to-cell signaling and interaction, cellular development, cellular growth and proliferation and cell death. These changes in gene expression of mouse mammary tumors in Wwox(C3H)+/- mice resemble, at least in part, human breast cancer development. Our findings demonstrate the critical role that the WWOX tumor suppressor gene has in preventing tumorigenesis in breast cancer.
  Oncogene 04/2011; 30(36):3900-6. · 6.37 Impact Factor
• Source

  Available from: Zaidoun Salah

  Article: WW domain interactions regulate the Hippo tumor suppressor pathway.

  Z Salah, R I Aqeilan
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  ABSTRACT: The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis in Drosophila and mammalians. Although the signaling of the core kinases is relatively well understood, less is known about the upstream inputs, downstream outputs and regulation of the whole cascade. Enrichment of the Hippo pathway components with WW domains and their cognate proline-rich interacting motifs provides a versatile platform for further understanding the mechanisms that regulate organ growth and tumorigenesis. Here, we review recently discovered mechanisms of WW domain-mediated interactions that contribute to the regulation of the Hippo signaling pathway in tumorigenesis. We further discuss new insights and future directions on the emerging role of such regulation.
  Cell Death & Disease 01/2011; 2:e172. · 5.33 Impact Factor
• Article: MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia.

  R Garzon, F Pichiorri, T Palumbo, M Visentini, R Aqeilan, A Cimmino, H Wang, H Sun, S Volinia, H Alder, G A Calin, C-G Liu, M Andreeff, C M Croce
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  ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs of 19-25 nucleotides that are involved in the regulation of critical cell processes such as apoptosis, cell proliferation and differentiation. However, little is known about the role of miRNAs in granulopoiesis. Here, we report the expression of miRNAs in acute promyelocytic leukemia patients and cell lines during all-trans-retinoic acid (ATRA) treatment by using a miRNA microarrays platform and quantitative real time-polymerase chain reaction (qRT-PCR). We found upregulation of miR-15a, miR-15b, miR-16-1, let-7a-3, let-7c, let-7d, miR-223, miR-342 and miR-107, whereas miR-181b was downregulated. Among the upregulated miRNAs, miR-107 is predicted to target NFI-A, a gene that has been involved in a regulatory loop involving miR-223 and C/EBPa during granulocytic differentiation. Indeed, we have confirmed that miR-107 targets NF1-A. To get insights about ATRA regulation of miRNAs, we searched for ATRA-modulated transcription factors binding sites in the upstream genomic region of the let-7a-3/let-7b cluster and identified several putative nuclear factor-kappa B (NF-kappaB) consensus elements. The use of reporter gene assays, chromatin immunoprecipitation and site-directed mutagenesis revealed that one proximal NF-kappaB binding site is essential for the transactivation of the let-7a-3/let-7b cluster. Finally, we show that ATRA downregulation of RAS and Bcl2 correlate with the activation of known miRNA regulators of those proteins, let-7a and miR-15a/miR-16-1, respectively.
  Oncogene 07/2007; 26(28):4148-57. · 6.37 Impact Factor
• Chapter: Chronic Lymphocytic Leukemia: Molecular Genetics and Animal Models

  Y. Pekarsky, G. Calin, R. Aqeilan, C. Croce
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  ABSTRACT: Chronic lymphocytic leukemia accounts for almost 30% of all adult leukemia cases in the United States and Western Europe. Although several common genomic abnormalities in CLL have been identified, mutational and functional analysis of corresponding genes so far have not proved their involvement in CLL. Our latest studies demonstrated functional involvement of Tcl1 oncoprotein and microRNA genes in the pathogenesis of CLL. Deregulated expressionofTcl1 in transgenic mice resulted in CLL. These CLL tumors showed abnormalities in expression of murine microRNA genes mmu-mir-15a andmmu-mir-16-1. Interestingly, human homologs of these genes, mir-15a and mir-16-1, located at the chromosome 13q14 are also deleted in human CLL samples. In this review we summarize and discuss these new developments. These recently emerged insights into the molecular mechanisms of CLL will allow for the development of new approaches to treat this disease.
  12/2005: pages 51-70;
• Article: miR-15a and miR-16-1 in cancer: discovery, function and future perspectives.

  R I Aqeilan, G A Calin, C M Croce
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  ABSTRACT: MicroRNAs (miRNAs) encoded by the miR-15/16 cluster are known to act as tumor suppressors. Expression of these miRNAs inhibits cell proliferation, promotes apoptosis of cancer cells, and suppresses tumorigenicity both in vitro and in vivo. miR-15a and miR-16-1 function by targeting multiple oncogenes, including BCL2, MCL1, CCND1, and WNT3A. Down-regulation of these miRNAs has been reported in chronic lymphocytic lymphoma (CLL), pituitary adenomas, and prostate carcinoma. This review summarizes the discovery, functions, and clinical relevance of these miRNAs in cancer, particularly CLL.
  Cell death and differentiation 07/2009; 17(2):215-20. · 8.24 Impact Factor