Project description:In order to improve therapy for head and neck squamous cell carcinoma (HNSCC), biomarkers associated with local and/or distant tumor relapses and cancer drug resistance are urgently needed. This study identified a potential biomarker, BAG-1 (Bcl-2 associated athanogene-1), that is implicated in HNSCC insensitive to cisplatin and tumor progression. Advanced HNSCC cells revealed resistant to cisplatin accompanied by increased expression of BAG-1 protein. siRNA knockdown of BAG-1 expression resulted in significant improvement of HNSCC sensitivity to cisplatin. BAG-1 expression enhanced stability of BCL-xL and conferred cisplatin resistant to the HNSCC cells. In addition, high levels of expression of phospho AKT, BAG-1, and BCL- xL were observed in advanced HNSCC compared to in that of primary HNSCC. Conclusion: Increased expression of BAG-1 was associated with cisplatin resistance and tumor progression in HNSCC patients and warrants further validation in larger independent studies. Over expression of BAG-1 may be a biomarker for cisplatin resistance in patients with primary or recurrent HNSCCs and targeting BAG-1 could be helpful in overcoming cisplatin resistance.
Project description:This study represents a proteomic resource for HNSCC and SQCLC with quantitative protein expression data for 7800 proteins and provides a proteomic diagnostic signature for classification for undetermined secondary lung tumors in HNSCC patients. By quantitative mass-spectrometry-based proteomics, we characterized a cohort of 63 squamous cell carcinomas of the lung (SQCLC), 49 of the head and neck region (HNSCC) and 51 HNSCC-correlated lung tumors with squamous cell histology that evolved in the course of the disease.
Project description:Cisplatin resistance is one of the main causes of treatment failure and death of head and neck squamous cell carcinoma (HNSCC). In order to better understand the mechanism of cisplatin resistance and formulate effective treatment strategies, we identified differentially expressed genes related to cisplatin resistance by RNA sequencing, RT-PCR and immunoblotting. CREB5 was selected as the most significantly up-regulated gene in cisplatin resistant cells. Gain- and loss-of-function experiments were performed to detect the effect of CREB5 on cisplatin resistance and mitochondrial apoptosis in HNSCC. Chromatin immunoprecipitation (ChIP) assay, dual-luciferase reporter assay, and immunoblotting experiments were performed to explore the underlying mechanisms of CREB5.
Project description:Head and neck squamous cell carcinomas (HNSCC) driven by human papillomavirus (HPV) generally have a more favourable prognosis. We hypothesized that HPV-positive HNSCC may be identified based on a miRNA signature according to their specific molecular pathogenesis and are characterized by a unique transcriptome compared to HPV-negative HNSCC. We characterized the miRNA-expression patterns of the tumors from 229 head and neck squamous cell carcinoma patients by Agilent miRNA microarrays in order to define a HPV-predicting miRNA signature.
Project description:The aim of the present study was to evaluate miRNAs as response predictors in FFPE head and neck samples from a phase II clinical trial designed to evaluate the feasibility of delivering cisplatin concurrent with radiotherapy after an induction chemotherapy (IC) regimen based on the combination of cisplatin plus paclitaxel in locally advanced head and neck squamous cell carcinoma (HNSCC) patients. For this purpose, we assessed the global miRNA expression profile of 15 HNSCC patients undergoing treatment, in order to identify miRNAs able to segregate resistant tumors from the sensitive ones, thus serving as markers to predict response. The results showed four miRNAs (miR-21, miR-494, miR-720 and miR-923) that were overexpressed in HNSCC FFPE samples.
Project description:Gene expression profiling to predict outcome after chemoradiation in head and neck cancer Purpose. The goal of the present study was to improve prediction of outcome after chemoradiation in advanced head and neck cancer using gene expression analysis. Materials and Methods. We collected 92 biopsies from untreated head and neck cancer patients subsequently given cisplatin-based chemoradiation (RADPLAT) for advanced squamous cell carcinomas (HNSCC). After RNA extraction and labeling we performed dye swap experiments using 35k oligo-microarrays. Supervised analyses were performed to create classifiers to predict local control, locoregional control and disease recurrence. Published gene sets with prognostic value in other studies were also tested. Results. Using supervised classification on the whole series, gene sets separating good and poor outcome could be found for all end-points. However, when splitting tumors into training and validation groups, no robust classifiers could be found. Also previously published signatures with prognostic value have been tested. Conclusion. Gene sets can be found with predictive potential for locoregional control after combined radiation and chemotherapy in HNSCC. How treatment-specific these gene sets are needs further study.
Project description:Head and neck squamous cell carcinoma (HNSCC) is the sixth most commonly diagnosed cancer worldwide, with an incidence of about 600,000 new cases per year, accounting for 1-2% of all cancer deaths worldwide. Current treatment for head and neck cancer includes taxol (docetaxel), platinum compounds (e.g. cisplatin or carboplatin) and the anti metabolite 5 fluorouracil (5 FU), either as single agents or in combination, and also radiotherapy. Response rates to these chemotherapeutic drugs range from 60 to 80%, however there are high rates of resistance, which often leads to locoregional recurrence and metastasis. The therapeutic dose of treatment needed (hormone therapy, radiotherapy or chemotherapy) is often too toxic for the patient to withstand. Therefore, our main objetive in this proyect is the identification of the molecular and cellular mechanisms involved in the acquisition of resistance to chemotherapy as currently key pieces for the discovery of new drugs that allow the development of effective therapies against HNSCC.
Project description:The predictive value of microRNAs for the efficacy of chemoradiation (CRTX) in locally advanced head and neck squamous cell carcinoma (HNSCC) was evaluated. Formalin-fixed, paraffin-embedded tumor material was collected from patients with locally advanced HNSCC treated within the ARO-0401 phase III trial with radiotherapy in combination with either 5-fluorouracil/cisplatin (CDDP-CRTX) or 5-fluorouracil/mitomycin C (MMC-CRTX).
Project description:To investigate the mechanism of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC), we performed single-cell RNA sequencing analysis in biopsy from two HNSCC patients before and after cetuximab treatment.
Project description:Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Out microarray results suggest that resistant cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP 5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC 4 head and neck squamous cell carcinoma (HNSCC) cell lines were treated with either 15 nM cetuximab or PBS during 13 hours. For each cell line, differential gene expression was assessed between cetuximab and PBS treatments.
