Theranostics 2018; 8(7):1850-1868. doi:10.7150/thno.22167

Research Paper

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

Silvia Di Agostino1✉, Fabio Valenti1, Andrea Sacconi1, Giulia Fontemaggi1, Matteo Pallocca2, Claudio Pulito3, Federica Ganci1, Paola Muti4, Sabrina Strano3, Giovanni Blandino1✉

1. Oncogenomic and Epigenetic Unit, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
2. SAFU Unit, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
3. Molecular Chemoprevention Group, Department of Diagnostic Research and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
4. Dofasco Chair Cancer Experimental Therapeutics, Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada

Abstract

Over 70% of head & neck squamous cell carcinoma (HNSCC) patients carry TP53 oncogenic mutations. Here we studied the role of specific tumor-derived mutant p53 proteins in the aberrant transcription of long non-coding (lnc) MIR205HG gene in head and neck cancer cells.

Methods: 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 TP53 (missense mutations) while 31 were characterized by wild-type TP53.

Results: 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 TP53 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.

Conclusions: 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.

Keywords: gene-expression/non-coding RNA/proliferation/HNSCC/mutant p53/YAP

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How to cite this article:
Di Agostino S, Valenti F, Sacconi A, Fontemaggi G, Pallocca M, Pulito C, Ganci F, Muti P, Strano S, Blandino G. Long Non-coding MIR205HG Depletes Hsa-miR-590-3p Leading to Unrestrained Proliferation in Head and Neck Squamous Cell Carcinoma. Theranostics 2018; 8(7):1850-1868. doi:10.7150/thno.22167. Available from http://www.thno.org/v08p1850.htm