Protumorigenic effects of mir-145 loss in malignant pleural mesothelioma.
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.
Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York, NY, USA.
M
M
Cioce
Translational Oncogenomic Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
F
F
Ganci
Translational Oncogenomic Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
V
V
Canu
Translational Oncogenomic Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
A
A
Sacconi
Molecular Chemoprevention Group, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
F
F
Mori
Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York, NY, USA.
C
C
Canino
Translational Oncogenomic Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
E
E
Korita
Department of Pathology Italian National Cancer Institute, Rome, Italy.
B
B
Casini
Unit of Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy.
G
G
Alessandrini
Department of Surgical Oncology San Vincenzo Hospital, Taormina, Italy.
A
A
Cambria
Department of Pathology Italian National Cancer Institute, Rome, Italy.
M A
MA
Carosi
Department of Surgical Oncology San Vincenzo Hospital, Taormina, Italy.
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R
Blandino
Department of Surgical Oncology San Vincenzo Hospital, Taormina, Italy.
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V
Panebianco
Unit of Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy.
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F
Facciolo
Department of Pathology Italian National Cancer Institute, Rome, Italy.
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P
Visca
Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
S
S
Volinia
Department of Oncology, McMaster University, Hamilton, ON, Canada.
P
P
Muti
Molecular Chemoprevention Group, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
S
S
Strano
Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
C M
CM
Croce
Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York, NY, USA.
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HI
Pass
Translational Oncogenomic Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
G
G
Blandino
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D019175:DNA Methylation; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000086002:Mesothelioma, Malignant; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid
D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D005971:Glutamates; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D000068437:Pemetrexed; D006147:Guanine