An Integrated Approach Identifies Mediators of Local Recurrence in Head and Neck Squamous Carcinoma

Abstract

Head and neck squamous cell carcinomas (HNSCCs) cause more than 300,000 deaths worldwide each year. Locoregional and distant recurrences represent worse prognostic events and accepted surrogate markers of patients' overall survival. No valid biomarker and salvage therapy exist to identify and treat patients at high-risk of recurrence. We aimed to verify if selected miRNAs could be used as biomarkers of recurrence in HNSCC. A NanoString array was used to identify miRNAs associated with locoregional recurrence in 44 patients with HNSCC. Bioinformatic approaches validated the signature and identified potential miRNA targets. Validation experiments were performed using an independent cohort of primary HNSCC samples and a panel of HNSCC cell lines. experiments validated the results. Our data identified a four-miRNA signature that classified HNSCC patients at high- or low-risk of recurrence. These miRNAs collectively impinge on the epithelial-mesenchymal transition process. and wet lab approaches showed that miR-9, expressed at high levels in recurrent HNSCC, targets SASH1 and KRT13, whereas miR-1, miR-133, and miR-150, expressed at low levels in recurrent HNSCC, collectively target SP1 and TGFβ pathways. A six-gene signature comprising these targets identified patients at high risk of recurrences, as well. Combined pharmacological inhibition of SP1 and TGFβ pathways induced HNSCC cell death and, when timely administered, prevented recurrence formation in a preclinical model of HNSCC recurrence. By integrating different experimental approaches and competences, we identified critical mediators of recurrence formation in HNSCC that may merit to be considered for future clinical development. .

TGF-β1-induced epithelial–mesenchymal transition in lung cancer cells involves upregulation of miR-9 and downregulation of its target, E-cadherin

“…Originally identified in the nervous system, miR-9 regulates neurodevelopment through its role in nerve or non-neural cell lines by targeting the 3 ‘UTR of various genes. It was recently demonstrated that miR-9 is irregularly expressed in cancers including head and neck squamous cell carcinoma (HNSCC) [ 21 ], bladder cancer [ 22 ], papillary thyroid cancer [ 23 ], and NSCLC [ 24 ]. miR-9 was expressed at high levels in recurrent HNSCC, where it targeted SASH1 and KRT13 [ 21 ].…”

Transcriptomics and Epigenomics in head and neck cancer: available repositories and molecular signatures

“…A large portion of the studies regarded mRNA signatures (33/61) , while a minor portion of the studies considered miRNA signatures (11/61) [52][53][54][55][56][57][58][59][60][61][62] and other non-coding RNA signatures (13/61) [63][64][65][66][67][68][69][70][71][72][73][74][75][76]. Only 4/61 [77][78][79][80] studies identified signatures by a high-throughput omics analysis of methylated DNA.…”

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

“…Finally, RNA interference can also alter gene expression by forming antisense transcripts, which prevent the accumulation of homologous transcripts. For example, non-coding RNA such as microRNAs, small RNA molecules of~22 bp, display a pleiotropic activity by canonically binding thousands of complementary mRNA transcripts and, in turn, perturbing their stability and subsequent translation [35,36]. Other involved mechanisms are the long non-coding RNAs (lnRNAs) that may serve as adaptors to drive epigenetic modulators or may sequestrate epigenetic complexes or transcription factors away from the chromatin [37,38] (Figure 1).…”