Long Non-coding MIR205HG Depletes Hsa-miR-590-3p Leading to Unrestrained Proliferation in Head and Neck Squamous Cell Carcinoma

• Published in: Theranostics 2018-01, Vol.8 (7), p.1850-1868
• Main Authors: Di Agostino, Silvia, Valenti, Fabio, Sacconi, Andrea, Fontemaggi, Giulia, Pallocca, Matteo, Pulito, Claudio, Ganci, Federica, Muti, Paola, Strano, Sabrina, Blandino, Giovanni
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cell Proliferation; Chromatin Immunoprecipitation; Gene Expression Profiling; Gene Regulatory Networks; Gene Silencing; Humans; MicroRNAs - antagonists & inhibitors; MicroRNAs - biosynthesis; Mutant Proteins - metabolism; Real-Time Polymerase Chain Reaction; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; Squamous Cell Carcinoma of Head and Neck - pathology; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.22167

Over 70% of head & neck squamous cell carcinoma (HNSCC) patients carry oncogenic mutations. Here we studied the role of specific tumor-derived mutant p53 proteins in the aberrant transcription of long non-coding (lnc) gene in head and neck cancer cells. To understand the role of lncMIR205HG, that we showed to be transcriptionally regulated by mutant p53 in HNSCC, we have employed siRNA and shRNA in CAL27 and FaDu HNSCC cell lines to suppress p53 gene expression in ChIP assays and RT-qPCR. We validated our findings in a cohort of 522 HNSCC patients from The Cancer Genome Atlas Data Portal (TCGA). We further evaluated our results in 63 HNSCC tumor samples collected at our institute, 32 of which were characterized by mutated (missense mutations) while 31 were characterized by wild-type . Maturation of pre-MIR205HG transcript produces two non-coding RNAs, lncMIR205HG and hsa-miR-205-5p. Down-regulation of lncMIR205HG expression significantly reduced cell proliferation, cell migration and clonogenic activity of head and neck cancer cells. Expression of MIR205HG was significantly increased in HNSCC with mutated when compared with matched non-tumoral tissues. Furthermore, MIR205HG expression levels were significantly higher in tumoral samples with mutant p53 than in tumoral tissues expressing wild-type p53. Mechanistically, MIR205HG depletes endogenous miR-590-3p leading to increased cyclin B, cdk1, and YAP protein expression. Taken together, these findings identify a transcriptional and post-transcriptional molecular network that includes mutant p53 protein, lncMIR205HG, YAP, and other proliferation-related genes, which are enriched in HNSCC patients with poor prognosis.