Oncotarget

Priority Research Papers:

Epigenetic silencing of miR-145-5p contributes to brain metastasis

Sara Donzelli, Federica Mori, Teresa Bellissimo, Andrea Sacconi, Beatrice Casini, Tania Frixa, Giuseppe Roscilli, Luigi Aurisicchio, Francesco Facciolo, Alfredo Pompili, Maria Antonia Carosi, Edoardo Pescarmona, Oreste Segatto, Greg Pond, Paola Muti, Stefano Telera, Sabrina Strano, Yosef Yarden and Giovanni Blandino _

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Oncotarget. 2015; 6:35183-35201. https://doi.org/10.18632/oncotarget.5930

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Abstract

Sara Donzelli1, Federica Mori2, Teresa Bellissimo1, Andrea Sacconi1, Beatrice Casini3, Tania Frixa1, Giuseppe Roscilli4, Luigi Aurisicchio4, Francesco Facciolo5, Alfredo Pompili6, Maria Antonia Carosi3, Edoardo Pescarmona3, Oreste Segatto7, Greg Pond8, Paola Muti8, Stefano Telera6, Sabrina Strano2,8, Yosef Yarden9 and Giovanni Blandino1,8

1 Translational Oncogenomics Unit, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy

2 Molecular Chemoprevention Unit, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy

3 Department of Pathology, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy

4 Takis s.r.l., Roma, Italy

5 Unit of Thoracic Surgery, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy

6 Department of Neurosurgery, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy

7 Laboratory of Cell Signaling, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy

8 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada

9 Weizmann Institute of Science, Department of Biological Regulation, Rehovot, Israel

Correspondence to:

Giovanni Blandino, email:

Keywords: brain metastases; lung cancer; mir-145-5p; epigenetic modifications; migration

Received: June 27, 2015 Accepted: September 14, 2015 Published: September 30, 2015

Abstract

Brain metastasis is a major cause of morbidity and mortality of lung cancer patients. We assessed whether aberrant expression of specific microRNAs could contribute to brain metastasis. Comparison of primary lung tumors and their matched metastatic brain disseminations identified shared patterns of several microRNAs, including common down-regulation of miR-145-5p. Down-regulation was attributed to methylation of miR-145’s promoter and affiliated elevation of several protein targets, such as EGFR, OCT-4, MUC-1, c-MYC and, interestingly, tumor protein D52 (TPD52). In line with these observations, restored expression of miR-145-5p and selective depletion of individual targets markedly reduced in vitro and in vivo cancer cell migration. In aggregate, our results attribute to miR-145-5p and its direct targets pivotal roles in malignancy progression and in metastasis.


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