Protumorigenic effects of mir-145 loss in malignant pleural mesothelioma
| Autor: | P. Visca, Beatrice Casini, Francesco Facciolo, Giovanni Blandino, Claudia Canino, Etleva Korita, Carlo M. Croce, Andrea Sacconi, Valeria Panebianco, Mariantonia Carosi, Sabrina Strano, Federica Mori, A. M. Cambria, Mario Cioce, Federica Ganci, Stefano Volinia, R. Blandino, Gabriele Alessandrini, Harvey I. Pass, V. Canu, Paola Muti |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Senescence
Male Mesothelioma Cancer Research Guanine Lung Neoplasms Cell Survival Pleural Neoplasms Down-Regulation Antineoplastic Agents Mice SCID Pemetrexed Biology Article Cell Line NO Glutamates Cell Movement Cell Line Tumor Sequence Homology Nucleic Acid Genetics medicine Animals Humans Pleural Neoplasm Clonogenic assay Molecular Biology 3' Untranslated Regions Cellular Senescence Base Sequence Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Mesothelioma Malignant Cell migration DNA Methylation medicine.disease Gene Expression Regulation Neoplastic MicroRNAs HEK293 Cells Cell culture Gene Knockdown Techniques Immunology Cancer research Cell aging Octamer Transcription Factor-3 medicine.drug |
| Popis: | We identified a discrete number of microRNAs differentially expressed in benign or malignant mesothelial tissues. We focused on mir-145 whose levels were significantly downregulated in malignant mesothelial tissues and malignant pleural mesothelioma (MPM) cell lines as compared to benign tissues (pleura, peritoneum or cysts). We show that promoter hyper-methylation caused very low levels in MPM cell lines and specimens. Treatment of MPM cell lines with mir-145 agonists negatively modulated some protumorigenic properties of MPM cells, such as clonogenicity, cell migration and resistance to pemetrexed treatment. The main effector mechanism of the clonogenic death induced by mir-145 was that of accelerated senescence. We found that mir-145 targeted OCT4 via specific binding to its 3'-UTR. Increased intracellular levels of mir-145 decreased the levels of OCT4 and its target gene ZEB1, thereby counteracting the increase of OCT4 induced by pemetrexed treatment which is known to favor the development of chemoresistant cells. In line with this, reintroduction of OCT4 into mimic-145 treated cells counteracted the effects on clonogenicity and replicative senescence. This further supports the relevance of the mir-145-OCT4 interaction for the survival of MPM cells. The potential use of mir-145 expression levels to classify benign vs malignant mesothelial tissues and the differences between pemetrexed-induced senescence and that induced by the re-expression of mir-145 are discussed. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|