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1.
J Endocrinol Invest ; 43(7): 947-958, 2020 Jul.
Article in English | MEDLINE | ID: mdl-31939196

ABSTRACT

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level, having a role in many biological processes, such as control of cell proliferation, cell cycle, and cell death. Altered miRNA expression has been reported in many neoplasms, including pituitary adenomas (PAs). PURPOSE: In this study, we aimed to evaluate the expression of 20 miRNAs involved in pathways relevant to pituitary pathophysiology, in PAs and normal pituitary tissue and to correlate their expression profile with clinical and pathological features. METHODS: Pituitary tumor samples were obtained during transphenoidal surgery from patients with non-functioning (NFPA, n = 12) and functioning (n = 11, 5 GH-, 3 ACTH-, 3 PRL-omas) PAs. The expression of selected miRNAs in PAs and in normal pituitary was analyzed by RT-qPCR. miRNAs expression was correlated with demographic, clinical, and neuroradiological data and with histopathological features including pituitary hormones immunostaining, Ki-67 proliferation index, and p53 immunohistochemistry evaluation. RESULTS: All evaluated miRNAs except miR-711 were expressed in both normal and tumor pituitary tissue. Seventeen miRNAs were significantly down-regulated in pituitary tumors compared to normal pituitary. miRNAs were differentially expressed in functioning PAs or in NFPAs, as in the latter group miR-149-3p (p = 0.036), miR-130a-3p (p = 0.014), and miR-370-3p (p = 0.026) were significantly under expressed as compared to functioning tumors. Point-biserial correlation analysis demonstrated a negative correlation between miR-26b-5p and Ki-67 (p = 0.031) and between miR-30a-5p and 'atypical' morphological features (p = 0.038) or cavernous sinus invasion (p = 0.049), while 508-5p was inversely correlated with clinical aggressiveness (p = 0.043). CONCLUSIONS: In this study, we found a significant down-regulation of 17 miRNAs in PAs vs normal pituitary, with differential expression profile related to functional status and tumor aggressiveness.


Subject(s)
Adenoma/genetics , Adenoma/pathology , MicroRNAs/genetics , Pituitary Neoplasms/genetics , Pituitary Neoplasms/pathology , Adenoma/diagnosis , Adenoma/therapy , Adult , Aged , Cell Proliferation/genetics , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Staging , Pituitary Function Tests , Pituitary Gland/metabolism , Pituitary Gland/physiology , Pituitary Neoplasms/diagnosis , Pituitary Neoplasms/therapy , Prognosis
2.
Pigment Cell Melanoma Res ; 26(2): 193-204, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23176534

ABSTRACT

Here, we explored the effects of the novel class II-specific histone deacetylase inhibitors (HDACis) MC1568 and MC1575 on interleukin-8 (IL-8) expression and cell proliferation in cutaneous melanoma cell line GR-M and uveal melanoma cell line OCM-3 upon stimulation with phorbol 12-myristate 13-acetate (PMA). We found that PMA upregulated IL-8 transcription via the AP-1 binding site and identified c-Jun as the transcription factor involved in this eventS. MC1568 and MC1575 inhibited IL-8 levels and cell proliferation in either unstimulated or PMA-stimulated melanoma cells. They acted by suppressing (i) c-Jun binding to the IL-8 promoter, (ii) recruitment of histones 3 and 4, RNA polymerase II and TFIIB to the c-Jun promoter, and (iii) c-Jun expression. Our findings provide new insights into mechanisms underlying anti-tumoral activities of class II-specific HDACis in human melanoma and suggest that they may constitute a novel therapeutic strategy for improving the treatment of this cancer.


Subject(s)
Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Hydroxamic Acids/pharmacology , Interleukin-8/genetics , Melanoma/genetics , Pyrroles/pharmacology , Skin Neoplasms/genetics , Acetylation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , DNA-Directed RNA Polymerases/metabolism , Drug Screening Assays, Antitumor , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockdown Techniques , Histone Deacetylases/genetics , Histones/metabolism , Humans , Interleukin-8/metabolism , Melanoma/enzymology , Melanoma/pathology , Promoter Regions, Genetic , Protein Binding/drug effects , Protein Binding/genetics , Proto-Oncogene Proteins c-jun/genetics , Proto-Oncogene Proteins c-jun/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Skin Neoplasms/enzymology , Skin Neoplasms/pathology , Tetradecanoylphorbol Acetate/pharmacology , Transcription Factor AP-1/metabolism , Transcription Factor TFIIB/metabolism , Transcription, Genetic/drug effects , Uveal Neoplasms/enzymology , Uveal Neoplasms/genetics , Uveal Neoplasms/pathology
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