Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation

Teresa Bellissimo, Federica Ganci, Enzo Gallo, Andrea Sacconi, Claudia Tito, Luciana De Angelis, Claudio Pulito, Silvia Masciarelli, Daniele Diso, Marco Anile, Vincenzo Petrozza, Felice Giangaspero, Edoardo Pescarmona, Francesco Facciolo, Federico Venuta, Mirella Marino, Giovanni Blandino, Francesco Fazi

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: Thymoma and thymic carcinoma are the most frequent subtypes of thymic epithelial tumors (TETs). A relevant advance in TET management could derive from a deeper molecular characterization of these neoplasms. We previously identified a set of microRNA (miRNAs) differentially expressed in TETs and normal thymic tissues and among the most significantly deregulated we described the down-regulation of miR-145-5p in TET. Here we describe the mRNAs diversely regulated in TETs and analyze the correlation between these and the miRNAs previously identified, focusing in particular on miR-145-5p. Then, we examine the functional role of miR-145-5p in TETs and its epigenetic transcriptional regulation. Methods: mRNAs expression profiling of a cohort of fresh frozen TETs and normal tissues was performed by microarray analysis. MiR-145-5p role in TETs was evaluated in vitro, modulating its expression in a Thymic Carcinoma (TC1889) cell line. Epigenetic transcriptional regulation of miR-145-5p was examined by treating the TC1889 cell line with the HDAC inhibitor Valproic Acid (VPA). Results: Starting from the identification of a 69-gene signature of miR-145-5p putative target mRNAs, whose expression was inversely correlated to that of miR-145-5p, we followed the expression of some of them in vitro upon overexpression of miR-145-5p; we observed that this resulted in the down-regulation of the target genes, impacting on TETs cancerous phenotype. We also found that VPA treatment of TC1889 cells led to miR-145-5p up-regulation and concomitant down-regulation of miR-145-5p target genes and exhibited antitumor effects, as indicated by the induction of cell cycle arrest and by the reduction of cell viability, colony forming ability and migration capability. The importance of miR-145-5p up-regulation mediated by VPA is evidenced by the fact that hampering miR-145-5p activity by a LNA inhibitor reduced the impact of VPA treatment on cell viability and colony forming ability of TET cells. Finally, we observed that VPA was also able to enhance the response of TET cells to cisplatin and erlotinib. Conclusions: Altogether our results suggest that the epigenetic regulation of miR-145-5p expression, as well as the modulation of its functional targets, could be relevant players in tumor progression and treatment response in TETs.

Original languageEnglish
Article number88
JournalMolecular Cancer
Volume16
Issue number1
DOIs
Publication statusPublished - May 10 2017

Fingerprint

Epigenomics
Phenotype
Valproic Acid
Thymoma
Down-Regulation
MicroRNAs
Messenger RNA
Thymic epithelial tumor
Cell Survival
Up-Regulation
Epithelial Cells
Genes
Cell Line
Histone Deacetylase Inhibitors
Microarray Analysis
Cell Cycle Checkpoints
Cisplatin
Neoplasms

Keywords

  • Epigenetic regulation
  • MicroRNA
  • MiR-145-5p
  • Thymic carcinoma
  • Thymic epithelial tumors
  • Thymoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

Cite this

Bellissimo, T., Ganci, F., Gallo, E., Sacconi, A., Tito, C., De Angelis, L., ... Fazi, F. (2017). Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation. Molecular Cancer, 16(1), [88]. https://doi.org/10.1186/s12943-017-0655-2

Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation. / Bellissimo, Teresa; Ganci, Federica; Gallo, Enzo; Sacconi, Andrea; Tito, Claudia; De Angelis, Luciana; Pulito, Claudio; Masciarelli, Silvia; Diso, Daniele; Anile, Marco; Petrozza, Vincenzo; Giangaspero, Felice; Pescarmona, Edoardo; Facciolo, Francesco; Venuta, Federico; Marino, Mirella; Blandino, Giovanni; Fazi, Francesco.

In: Molecular Cancer, Vol. 16, No. 1, 88, 10.05.2017.

Research output: Contribution to journalArticle

Bellissimo, T, Ganci, F, Gallo, E, Sacconi, A, Tito, C, De Angelis, L, Pulito, C, Masciarelli, S, Diso, D, Anile, M, Petrozza, V, Giangaspero, F, Pescarmona, E, Facciolo, F, Venuta, F, Marino, M, Blandino, G & Fazi, F 2017, 'Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation', Molecular Cancer, vol. 16, no. 1, 88. https://doi.org/10.1186/s12943-017-0655-2
Bellissimo T, Ganci F, Gallo E, Sacconi A, Tito C, De Angelis L et al. Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation. Molecular Cancer. 2017 May 10;16(1). 88. https://doi.org/10.1186/s12943-017-0655-2
Bellissimo, Teresa ; Ganci, Federica ; Gallo, Enzo ; Sacconi, Andrea ; Tito, Claudia ; De Angelis, Luciana ; Pulito, Claudio ; Masciarelli, Silvia ; Diso, Daniele ; Anile, Marco ; Petrozza, Vincenzo ; Giangaspero, Felice ; Pescarmona, Edoardo ; Facciolo, Francesco ; Venuta, Federico ; Marino, Mirella ; Blandino, Giovanni ; Fazi, Francesco. / Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation. In: Molecular Cancer. 2017 ; Vol. 16, No. 1.
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T1 - Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation

AU - Bellissimo, Teresa

AU - Ganci, Federica

AU - Gallo, Enzo

AU - Sacconi, Andrea

AU - Tito, Claudia

AU - De Angelis, Luciana

AU - Pulito, Claudio

AU - Masciarelli, Silvia

AU - Diso, Daniele

AU - Anile, Marco

AU - Petrozza, Vincenzo

AU - Giangaspero, Felice

AU - Pescarmona, Edoardo

AU - Facciolo, Francesco

AU - Venuta, Federico

AU - Marino, Mirella

AU - Blandino, Giovanni

AU - Fazi, Francesco

PY - 2017/5/10

Y1 - 2017/5/10

N2 - Background: Thymoma and thymic carcinoma are the most frequent subtypes of thymic epithelial tumors (TETs). A relevant advance in TET management could derive from a deeper molecular characterization of these neoplasms. We previously identified a set of microRNA (miRNAs) differentially expressed in TETs and normal thymic tissues and among the most significantly deregulated we described the down-regulation of miR-145-5p in TET. Here we describe the mRNAs diversely regulated in TETs and analyze the correlation between these and the miRNAs previously identified, focusing in particular on miR-145-5p. Then, we examine the functional role of miR-145-5p in TETs and its epigenetic transcriptional regulation. Methods: mRNAs expression profiling of a cohort of fresh frozen TETs and normal tissues was performed by microarray analysis. MiR-145-5p role in TETs was evaluated in vitro, modulating its expression in a Thymic Carcinoma (TC1889) cell line. Epigenetic transcriptional regulation of miR-145-5p was examined by treating the TC1889 cell line with the HDAC inhibitor Valproic Acid (VPA). Results: Starting from the identification of a 69-gene signature of miR-145-5p putative target mRNAs, whose expression was inversely correlated to that of miR-145-5p, we followed the expression of some of them in vitro upon overexpression of miR-145-5p; we observed that this resulted in the down-regulation of the target genes, impacting on TETs cancerous phenotype. We also found that VPA treatment of TC1889 cells led to miR-145-5p up-regulation and concomitant down-regulation of miR-145-5p target genes and exhibited antitumor effects, as indicated by the induction of cell cycle arrest and by the reduction of cell viability, colony forming ability and migration capability. The importance of miR-145-5p up-regulation mediated by VPA is evidenced by the fact that hampering miR-145-5p activity by a LNA inhibitor reduced the impact of VPA treatment on cell viability and colony forming ability of TET cells. Finally, we observed that VPA was also able to enhance the response of TET cells to cisplatin and erlotinib. Conclusions: Altogether our results suggest that the epigenetic regulation of miR-145-5p expression, as well as the modulation of its functional targets, could be relevant players in tumor progression and treatment response in TETs.

AB - Background: Thymoma and thymic carcinoma are the most frequent subtypes of thymic epithelial tumors (TETs). A relevant advance in TET management could derive from a deeper molecular characterization of these neoplasms. We previously identified a set of microRNA (miRNAs) differentially expressed in TETs and normal thymic tissues and among the most significantly deregulated we described the down-regulation of miR-145-5p in TET. Here we describe the mRNAs diversely regulated in TETs and analyze the correlation between these and the miRNAs previously identified, focusing in particular on miR-145-5p. Then, we examine the functional role of miR-145-5p in TETs and its epigenetic transcriptional regulation. Methods: mRNAs expression profiling of a cohort of fresh frozen TETs and normal tissues was performed by microarray analysis. MiR-145-5p role in TETs was evaluated in vitro, modulating its expression in a Thymic Carcinoma (TC1889) cell line. Epigenetic transcriptional regulation of miR-145-5p was examined by treating the TC1889 cell line with the HDAC inhibitor Valproic Acid (VPA). Results: Starting from the identification of a 69-gene signature of miR-145-5p putative target mRNAs, whose expression was inversely correlated to that of miR-145-5p, we followed the expression of some of them in vitro upon overexpression of miR-145-5p; we observed that this resulted in the down-regulation of the target genes, impacting on TETs cancerous phenotype. We also found that VPA treatment of TC1889 cells led to miR-145-5p up-regulation and concomitant down-regulation of miR-145-5p target genes and exhibited antitumor effects, as indicated by the induction of cell cycle arrest and by the reduction of cell viability, colony forming ability and migration capability. The importance of miR-145-5p up-regulation mediated by VPA is evidenced by the fact that hampering miR-145-5p activity by a LNA inhibitor reduced the impact of VPA treatment on cell viability and colony forming ability of TET cells. Finally, we observed that VPA was also able to enhance the response of TET cells to cisplatin and erlotinib. Conclusions: Altogether our results suggest that the epigenetic regulation of miR-145-5p expression, as well as the modulation of its functional targets, could be relevant players in tumor progression and treatment response in TETs.

KW - Epigenetic regulation

KW - MicroRNA

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KW - Thymic carcinoma

KW - Thymic epithelial tumors

KW - Thymoma

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