Fibroblast activation protein (FAP) as a prognostic biomarker in multiple tumors and its therapeutic potential in head and neck squamous cell carcinoma

Background:Fibroblast activation protein(FAP),a cell surface serine protease,plays roles in tumor invasion and immune regulation.However,there is currently no pan-cancer analysis of FAP.Objective:We aimed to assess the pan-cancer expression profile of FAP,its molecular function,and its potential role in head and neck squamous cell carcinoma(HNSC).Methods:We analyzed gene expression,survival status,immune infiltration,and molecular functional pathways of FAP in The Cancer Genome Atlas(TCGA)and Genotype Tissue Expression(GTEx)tumors.Furthermore,to elucidate the role of FAP in HNSC,we performed proliferation,migration,and invasion assays post-FAP overexpression or knock-down.Results:FAP expression was elevated in nine tumor types and was associated with poor survival in eight of them.In the context of immune infiltration,FAP expression negatively correlated with CD8+T-cell infiltration infive tumor types and positively with regulatory T-cell infiltration in four tumor types.Our enrichment analysis highlighted FAP’s involvement in the PI3K-Akt signaling pathway.In HNSC cells,FAP overexpression activated the PI3K-Akt pathway,promoting tumor proliferation,migration,and invasion.Conversely,FAP knockdown showed inhibitory effects.Conclusion:Our study unveils the association of FAP with poor tumor prognosis across multiple cancers and highlights its potential as a therapeutic target in HNSC.

CES1 is associated with cisplatin resistance and poor prognosis of head and neck squamous cell carcinoma

Background:Head and neck squamous cell carcinoma(HNSCC)is a prevalent form of cancer globally,with chemoresistance posing a major challenge in treatment outcomes.The efficacy of the commonly used chemotherapeutic agent,cisplatin,is diminished in patients with poor prognoses.Methods:Various bioinformatics databases were utilized to examine Carboxylesterase 1(CES1)gene expression,clinicopathologic features,patient survival analysis,and gene function.An organoid model of HNSCC was established,along with the induction of drug-resistant HNSCC in the organoid model.CES1 expression was assessed using qRT-PCR and Western Blot,and differential markers were identified through transcriptome sequencing.Knockdown and overexpression models of CES1 were created in SCC-9 and patient-derived organoid(PDO)cells using shRNA and lentivirus to investigate the tumor biology and cisplatin resistance associated with CES1.Results:Research in bioinformatics has uncovered a strong correlation between the expression level of CES1 and the prognosis of HNSCC.The data suggests a significant link between CES1 expression and tobacco smoking.RNA-sequencing revealed a notable increase in CES1 expression in HNSCC-PDOcis-R cells compared to the parental PDO cells.Subsequently,we performed in vitro studies by HNSCC-PDO and SCC-9 and found that CES1-overexpressing cells exhibited reduced sensitivity to cisplatin and stronger tumor malignant biological behavior compared with CES1-knockdown cells.Conclusion:The observed association between CES1 expression and tobacco smoking implies a potential influence of smoking on the efficacy of cisplatin-based chemotherapy in HNSCC through the regulation of CES1 expression.

PPP1R14A is Associated with Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma Identified by Single-Cell and Bulk RNA-Sequencing

Objective To identify nivolumab resistance-related genes in patients with head and neck squamous cell carcinoma(HNSCC)using single-cell and bulk RNA-sequencing data.Methods The single-cell and bulk RNA-sequencing data downloaded from the Gene Expression Omnibus database were analyzed to screen out differentially expressed genes(DEGs)between nivolumab resistant and nivolumab sensitive patients using R software.The Least Absolute Shrinkage Selection Operator(LASSO)regression and Recursive Feature Elimination(RFE)algorithm were performed to identify key genes associated with nivolumab resistance.Functional enrichment of DEGs was analyzed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses.The relationships of key genes with immune cell infiltration,differentation trajectory,dynamic gene expression profiles,and ligand-receptor interaction were explored.Results We found 83 DEGs.They were mainly enriched in T-cell differentiation,PD-1 and PD-L1 checkpoint,and T-cell receptor pathways.Among six key genes identified using machine learning algorithms,only PPP1R14A gene was differentially expressed between the nivolumab resistant and nivolumab sensitive groups both before and after immunotherapy(P<0.05).The high PPP1R14A gene expression group had lower immune score(P<0.01),higher expression of immunosuppressive factors(such as PDCD1,CTLA4,and PDCD1LG2)(r>0,P<0.05),lower differentiation of infiltrated immune cells(P<0.05),and a higher degree of interaction between HLA and CD4(P<0.05).Conclusions PPP1R14A gene is closely associated with resistance to nivolumab in HNSCC patients.Therefore,PPP1R14A may be a target to ameliorate nivolumab resistance of HNSCC patients.

Nanomaterials for refining tumor microenvironment and enhancing therapy in head and neck squamous cell carcinoma: a review

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal solid tumor with a high mortality rate. Conventional cancertreatments, including surgery, radiotherapy, and chemotherapy, primarily target cancer cell eradication. However, uncontrolled proliferation and metabolic activities of these cells result in abnormalities in nutrient levels, hypoxia, and immunosuppression within the tumor microenvironment (TME). These factors constrain the efficacy of traditional treatments by promoting drug resistance, recurrence, and metastasis. Nanomaterials (NMs), such as nanozymes, can exhibit enzymatic activity similar to that of natural enzymes and offer a promising avenuefor the direct modification of the TME through catalytic oxidation-reduction processes. Moreover, they can serve as sensitizers or drug deliverycarriers, enhancing the efficacy of traditional treatment methods. Recently, NMs have garnered significant attention from oncologists. Thisreview begins with an overview of the composition and unique characteristics of the TME. Subsequently, we comprehensively exploredthe application of NMs in the treatment of HNSCC. Finally, we discuss the potential prospects and challenges associated with usingNMs in biomedical research.

ATM is a Prognostic Biomarker of Survival in Head and Neck Squamous Cell Carcinoma Patients

This review examines the role of ATM expression in head and neck squamous cell carcinoma(HNSCC).Analysis revealed significant overexpression of ATM in HNSCC cells compared to normal control samples,suggesting its involvement in cancer proliferation.ATM expression was notably upregulated across various clinical parameters,including different stages of cancer,racial groups,genders,and age groups,highlighting its role in cancer progression.Validation using the GEPIA2 tool confirmed strong ATM expression throughout all four stages of HNSCC,with the highest levels in stage II and the lowest in stage I.Promoter methylation analysis of ATM showed distinct patterns across different demographics and cancer stages,reinforcing its significance.The study also explored the relationship between ATM expression and patient outcomes using the KM plotter tool,finding that high ATM expression was associated with better overall survival(OS),while low ATM expression correlated with better disease-free survival(DFS).Genetic mutation analysis via cBioPortal identified minimal ATM mutations in HNSCC,including in-frame,splice,truncating,and missense mutations,suggesting their role in ATM dysregulation.The STRING tool was used to construct a protein-protein interaction(PPI)network,revealing that the ATM gene interacts with ten key genes(NBN,ATR,CHEK2,MDC1,MSH2,MSH6,MRE11,TP53,TP53BP1,BRCA1),indicating its involvement in various biological functions.Functional annotation of differentially expressed genes(DEGs)through the DAVID web server revealed their participation in critical biological processes,including double-strand break repair,cellular response to DNA damage,and DNA damage checkpoints.KEGG pathway analysis further linked DEGs to cellular senescence,platinum drug resistance,homologous recombination,p53 signaling,and the cell cycle,underscoring ATM’s multifaceted role in HNSCC.

PTEN as a Novel Diagnostic and Prognostic Biomarker of Head and Neck Squamous Cell Carcinoma

This review article explores phosphatase and tensin homolog(PTEN)’s role in head and neck squamous cell carcinoma(HNSCC)through comprehensive expression and methylation examinations,genetic mutation investigation,and prognostic evaluation.Using the UALCAN informational collection,PTEN expression examination uncovered a critical over-expression in HNSCC cells isolated from normal control samples,proposing its role in HNSCC multiplication.Further,analysis of PTEN expression across various clinical limits has shown critical up-regulation in different cancer development stages,racial groups,gender,and age classes within the context of HNSCC patients,suggesting its major role in cancer duplication.PTEN expression was validated by utilizing the GEPIA2.0 online tool,which showed PTEN expression was particularly significantly expressed in HNSCC cancer improvement when it appeared differently from normal control samples.Accordingly,examining PTEN validation across different phases of cancer advancement showed dysregulation in each of the four phases with the most raised expression in stage I and the least expression in stage IV.Thus,this study investigated the promoter methylation level of PTEN,figuring out a basic relationship between HNSCC samples and normal control samples.Analyzing promoter methylation across various clinical limits uncovered massive variations,with specific methylation patterns seen across malignant growth stages,race groups,gender,and age groups.Overall survival and disease-free survival(OS and DFS)utilizing the KM plotter tool showed a critical relationship between PTEN expression levels in HNSCC patients,showing high PTEN expression exhibited good overall survival when showed up distinctively comparable to low PTEN expression levels.In addition,in disease-free survival(DFS)evaluation HNSCC patients showing low PTEN expression experienced great DFS relative to HNSCC patients with high PTEN expression.Moreover,to validate PTEN expression against survival,the study examined the HNSCC patients into low and high-expression groups of PTEN.In HNSCC,low PTEN expression was connected with great overall survival(OS)when it appeared contrastingly relative to the high PTEN expression.In like manner,the study found that low PTEN expression level was connected with great DFS in HNSCC when it appeared contrastingly related to the high PTEN expression group.Genetic mutation analysis via cBioPortal identifies a minimal proportion of PTEN mutations in HNSCC,predominantly in-frame mutation,missense mutation,splice mutation,truncating mutation,and structural variant,indicating their basal significance in PTEN dysregulation within HNSCC.Further investigation of PTEN molecular components and their exchange inside the HNSCC microenvironment might disclose novel roads for designated treatment and accurate medication approaches in battling this harmful disease.

Nimotuzumab with Concurrent Chemo-Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN)

Background: Head and neck cancers (HNCs) constitute 5% of all cancers globally and are the most common cancers in India. Chemotherapy and radiotherapy have not been proved to be effective in advanced cases and the prognosis remains dismal. This underscores the need for newer treatment options in these cases. Nimotuzumab, an anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, was safer when combined with chemo- or radio-therapy. Aim: To evaluate the safety and efficacy of concurrently administered nimotuzumab with chemo-radiotherapy in patients with advanced inoperable squamous cell carcinomas of head and neck (LASCCHN). Methods:?This was an open-label, single arm study evaluating 57 patients with histologically confirmed inoperable LASCCHN (stages III and IV) and eastern co-operative oncology group (ECOG) performance status < 2. Informed consent was obtained from all patients. The patients were administered IV cisplatin 30 mg/m2?and IV nimotuzumab 200 mg weekly for 6 weeks, along with radiotherapy of 6600 cGy over 33 fractions. Patients were evaluated over response evaluation criteria in solid tumors (RECIST) criteria 24 weeks after the last cycle of chemotherapy. Results: Mean age of patient was 50 years old (29 - 79 years old). The most common site of cancer was oral cavity (56.1%). Forty six patients (80.7%) completed 6 cycles of therapy. Objective response rate (ORR) was 80.7%, with 34 patients (59.6%) achieving complete response (CR), and 12 (21%) achieving partial response (PR). Stable disease (SD) was noted in 8 (14%) patients and progressive disease in 3 (5.2%) patients. Conclusion: Addition of nimotuzumab is a safe and efficacious option in patients with inoperable LASCCHN. Our observations confirm the available Phase II data. The long term survival benefits based on this encouraging response rate need to be further evaluated in this subset of cancer patients.

The prognostic value of Tiaml proteinexpression in head and neck squamous cellcarcinoma： a retrospective study

Introduction Head and neck squamous cell carcinoma （HNSCC） is a common cancer worldwide and has a poorprognosis. A biomarker predicting the clinical outcome of HNSCC patients could be useful in guiding treatment planning.Overexpression of theT lymphoma invasion and metastasis 1 （Tiaml） protein has been implicated in the migrationand invasion of neoplasms. However, its role in HNSCC progression needs to be further validated. We detectedthe expression of Tiaml in normal and tumor tissues and determined its association with clinical outcomes in patientswith HNSCCMethods： We measured the expression of Tiaml in normal and cancerous tissue samples from the patients withHNSCC treated at Sun Yat-sen University Cancer Center between 2001 and 2008. The Tiaml expression was scoredfrom 0 to 12 based on the percentage of positively stained cells and the staining intensity. We then determined thediagnostic performance of this score in predicting overall survival （OS） and disease-free survival （DFS）.Results： Of the 194 evaluable patients, those with advanced disease, lymph node metastasis at diagnosis, and recurrenceor metastasis during follow-up had a highertendency of having high Tiaml expression as compared with theircounterparts （P 〈 0.05）. The proportion of samples with high Tiaml expression was also higher in cancerous tissuesthan in non-cancerous tissues （57.7% vs. 13.9%, P 〈 0.001）. Cox proportional hazards regression analysis revealed thatTiaml expression scores of 5 and greater independently predicted short OS and DFS.Conclusion： TheTiaml expression is shown as a promising biomarker of clinical outcomes in patients with HNSCCand should be evaluated in prospective trials.

Association of microRNA polymorphisms with the risk of head and neck squamous cell carcinoma in a Chinese population:a case-control study

Background:MicroRNA(miRNA) polymorphisms may alter miRNA-related processes,and they likely contribute to cancer susceptibility.Various studies have investigated the associations between genetic variants in several key miRNAs and the risk of human cancers;however,few studies have focused on head and neck squamous cell carcinoma(HNSCC) risk.This study aimed to evaluate the associations between several key miRNA polymorphisms and HNSCC risk in a Chinese population.Methods:In this study,we genotyped five common single-nucleotide polymorphisms(SNPs) in several key miRNAs(miR-149 rs2292832,miR-146 a rs2910164,miR-605 rs2043556,miR-608 rs4919510,and miR-196a2 rs11614913) and evaluated the associations between these SNPs and HNSCC risk according to cancer site with a case-control study including 576 cases and 1552 controls,which were matched by age and sex in a Chinese population.Results:The results revealed that miR-605 rs2043556[dominant model:adjusted odds ratio(OR) 0.71,95%confidence interval(CI) 0.58-0.88;additive model:adjusted OR 0.74,95%CI 0.62-0.89]and miR-196a2 rs11614913(dominant model:adjusted OR 1.36,95%C11.08-1.72;additive model:adjusted OR 1.28,95%C11.10-1.48) were significantly associated with the risk of oral squamous cell carcinoma(OSCC).Furthermore,when these two loci were evaluated together based on the number of putative risk alleles(rs2043556 A and rs11614913 G),a significant locus-dosage effect was noted on the risk of OSCC(P_(trend) < 0.001).However,no significant association was detected between the other three SNPs(miR-149 rs2292832,miR- 146 a rs2910164,and miR-608 rs4919510) and HNSCC risk.Conclusion:Our study provided the evidence that miR-605 rs2043556 and miR-196a2 rs11614913 may have an impact on genetic susceptibility to OSCC in Chinese population.

New perspectives on biology,disease progression,and therapy response of head and neck cancer gained from single cell RNA sequencing and spatial transcriptomics

Head and neck squamous cell carcinoma(HNSCC)is one of the most frequent cancers worldwide.The main risk factors are consumption of tobacco products and alcohol,as well as infection with human papilloma virus.Approved therapeutic options comprise surgery,radiation,chemotherapy,targeted therapy through epidermal growth factor receptor inhibition,and immunotherapy,but outcome has remained unsatisfactory due to recurrence rates of~50%and the frequent occurrence of second primaries.The availability of the human genome sequence at the beginning of the millennium heralded the omics era,in which rapid technological progress has advanced our knowledge of the molecular biology of malignant diseases,including HNSCC,at an unprecedented pace.Initially,microarray-based methods,followed by approaches based on next-generation sequencing,were applied to study the genetics,epigenetics,and gene expression patterns of bulk tumors.More recently,the advent of single-cell RNA sequencing(scRNAseq)and spatial transcriptomics methods has facilitated the investigation of the heterogeneity between and within different cell populations in the tumor microenvironment(e.g.,cancer cells,fibroblasts,immune cells,endothelial cells),led to the discovery of novel cell types,and advanced the discovery of cell-cell communication within tumors.This review provides an overview of scRNAseq,spatial transcriptomics,and the associated bioinformatics methods,and summarizes how their application has promoted our understanding of the emergence,composition,progression,and therapy responsiveness of,and intercellular signaling within,HNSCC.

Sustained complete response to erlotinib in squamous cell carcinoma of the head and neck:A case report

BACKGROUND Squamous cell carcinoma of head and neck(SCCHN) is the fifth most common cancer worldwide. Inhibition of epidermal growth factor receptor signaling has been shown to be a critical component of therapeutic option. Herein, we report a case of durable complete response to erlotinib.CASE SUMMARY An 81-year-old Caucasian male who presented with metastatic poorly differentiated squamous cell carcinoma of right cervical lymph nodes(levels 2 and 3). Imaging studies including(18)F-fluorodeoxyglucose positron emission tomography/computed tomography(CT) and contrast-enhanced CT scan of neck and chest did not reveal any other disease elsewhere. Panendoscopic examination with random biopsy did not reveal malignant lesion in nasopharynx,oropharynx, and larynx. He underwent modified neck dissection and postoperative radiation. Within 2 mo after completion of radiation, he developed local recurrence at right neck, which was surgically removed. Two mo after the salvage surgery, he developed a second recurrence at right neck. Due to suboptimal performance status and his preference, he started erlotinib treatment.He achieved partial response after first 2 mo of erlotinib treatment, then complete response after total 6 mo of erlotinib treatment. He developed sever skin rash and diarrhea including Clostridium difficile infection during the course of erlotinib treatment requiring dose reduction and eventual discontinuation. He remained in complete remission for more than two years after discontinuation of erlotinib.CONCLUSION We report a case of metastatic SCCHN achieving durable complete response from erlotinib. Patient experienced skin rash and diarrhea toxicities which were likely predictors of his treatment response.

Classificatory updates in verrucous and cuniculatum carcinomas:Insights from the 5^(th) edition of WHO-IARC head and neck tumor classification

The International Agency for Research on Cancer(IARC)and World Health Organization(WHO)collaboratively produce the'WHO Blue Books'essential tools standardizing the diagnostic process for human cancers.Regular updates in this classification accommodate emerging molecular discoveries,advances in immunohistochemical techniques,and evolving clinical insights.The 5th edition of the WHO/IARC classification of head and neck tumors refines the'Oral Cavity and Mobile Tongue'chapter,including sections for non-neoplastic lesions,epithelial tumors,and tumors of uncertain histogenesis.Notably,the epithelial tumors section is rearranged by tumor behavior,starting with benign squamous papillomas and progressing through potentially malignant oral disorders to oral squamous cell carcinoma(OSCC).The section on OSCC reflects recent information on epidemiology,pathogenesis,and histological prognostic factors.Noteworthy is the specific categorization of verrucous carcinoma(VC)and carcinoma cuniculatum(CC),both associated with the oral cavity and distinct in clinical and histologic characteristics.This classification adjustment emphasizes the oral cavity as their predominant site in the head and neck.Designating specific sections for VC and CC aims to provide comprehensive insights into these unique subtypes,elucidating their clinical features,distinct histological characteristics,prevalence,significance,and clinical relevance.By categorizing these subtypes into specific sections,the 5th edition of the WHO classification aims to provide a more nuanced and detailed account,enhancing our understanding of these specific variants within the broader spectrum of head and neck tumors.

Multimodality functional imaging using DW-MRI and 18F-FDG-PET/CT during radiation therapy for human papillomavirus negative head and neck squamous cell carcinoma: Meixoeiro Hospital of Vigo Experience

AIMTo noninvasively investigate tumor cellularity measured using diffusion-weighted magnetic resonance imaging (DW-MRI) and glucose metabolism measured by 18F-labeled fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) during radiation therapy (RT) for human papillomavirus negative (HPV-) head and neck squamous cell carcinoma (HNSCC).METHODSIn this prospective study, 6 HPV- HNSCC patients underwent a total of 34 multimodality imaging examinations DW-MRI at 1.5 T Philips MRI scanner [(n = 24) pre-, during- (2-3 wk), and post-treatment (Tx), and 18F-FDG PET/CT pre- and post-Tx (n = 10)]. All patients received RT. Monoexponential modeling of the DW-MRI data yielded the imaging metric apparent diffusion coefficient (ADC) and the mean of standardized uptake value (SUV) was measured from 18F-FDG PET uptake. All patients had a clinical follow-up as the standard of care and survival status was documented at 1 year.RESULTSThere was a strong negative correlation between the mean of pretreatment ADC (ρ = -0.67, P = 0.01) and the pretreatment 18F-FDG PET SUV. The percentage (%) change in delta (∆) ADC for primary tumors and neck nodal metastases between pre- and Wk2-3 Tx were as follows: 75.4% and 61.6%, respectively, for the patient with no evidence of disease, 27.5% and 32.7%, respectively, for those patients who were alive with disease, and 26.9% and 7.31%, respectively, for those who were dead with disease.CONCLUSIONThese results are preliminary in nature and are indicative, and not definitive, trends rendered by the imaging metrics due to the small sample size of HPV- HNSCC patients in a Meixoeiro Hospital of Vigo Experience.

Collision tumor of squamous cell carcinoma and neuroendocrine carcinoma in the head and neck:A case report

BACKGROUND There are many disputes about the definition,diagnosis,therapy,and prognosis of collision tumors.CASE SUMMARY We describe a rare patient with a collision tumor consisting of neuroendocrine carcinoma(NEC)and squamous cell carcinoma(SCC)in the nasal cavity and paranasal sinus.She received operation,concurrent chemoradiotherapy,and then two cycles of palliative chemotherapy.Follow-up at 12 mo after diagnosis showed that this patient experienced a complete response with no signs of recurrence or metastasis.A literature review of previous 26 cases diagnosed with collision tumor of NEC and SCC in the head and neck was also undertaken.CONCLUSION It is challenging to manage collision tumors because there are two morphologically and etiologically distinct tumors.Well-designed multimodality therapy including surgery and chemoradiotherapy might lead to a long survival in these patients.

Long-term survivor of metastatic squamous-cell head and neck carcinoma with occult primary after cetuximab-based chemotherapy:A case report

BACKGROUND Cancer of unknown primary(CUP)is a histological proven malignant tumor whose origin cannot be detected despite careful examination.Most cervical lymph node metastases in CUP(80%)will originate from head and neck sites,and 15%show infiltration of squamous carcinoma cells.The survival rates of CUP are poor:The 5-year-survival rate ranges from 10%to 15%.First-line treatment recommendation for advanced,inoperable squamous cell carcinoma of head/neck(HNSCC)was cetuximab plus platinum-fluorouracil chemotherapy until recently,when checkpoint inhibitors proved clinically beneficial therapies.CASE SUMMARY Here,we report a case of a 42-year-old female patient with cervical and abdominal lymph node and distant bone metastases of an occult primary of the head and neck(squamous cell carcinoma,human papillomavirus positive).The cancer was diagnosed during pregnancy 10 years ago,and after giving birth,the patient was treated with cetuximab plus platinum-fluorouracil chemotherapy achieving complete remission(CR).CR lasted 26 mo when new metastases(abdominal lymph node,lumbar vertebral body)emerged.Both manifestations were irradiated.From then on,the patient has not received any further treatment,and her disease has remained controlled.Ten years after the initial cancer diagnosis,the patient is still alive and in good health,representing an exceptional case of HNSCC.CONCLUSION This case illustrates the exceptional clinical course and benefits of combined therapy approaches in advanced metastatic HNSCC with occult primary.

A Review of Literature Pertaining to Head and Neck Squamous Cell Carcinoma with Emphasis on the Role of the Human Papilloma Virus

Over the last decades the United Kingdom has seen a general increase in the incidence of head and neck squamous cell carcinoma (HNSCC). In addition to the classical risk factors of smoking and alcohol consumption there now appears that a viral aetiology is attributed to a significant proportion of HNSCC. A number of studies have indicated that human papillomavirus (HPV) infection is implicated with the subtype HPV 16 being found in many histopathological specimens. Further evidence suggests that HPV positive status is a prognostic factor related to a favourable outcome in head and neck cancers. This premise may have a significant impact on our approach to treating HNSCC. Patients belonging to stages I/II are traditionally treated with curative intent, single modality treatments that are either radiation or surgery alone. These treatment regimens are relatively aggressive and may lead to severe functional impairment. HPV patients may not require such an approach. This dissertation examines the current evidence which has given rise to these assertions, and explores the unresolved issues preventing HPV positive status becoming part of the management convention. The methodology involved a comprehensive literature review. The literature conclusions and limitations are discussed with reference to what is becoming accepted universally in this field and what remains to be elucidated. The different prognosis and treatment reaction to radiotherapy and chemotherapy by HPV positive tumours could be extrapolated to suggest that HPV status detection is required to plan treatment regimes. Indeed a separate subset of patients could potentially be categorised with an improvement in morbidity.

Downregulation of iASPP Expression Suppresses Proliferation, Invasion and Increases Chemosensitivity to Paclitaxel of Head and Neck Squamous Cell Carcinoma In Vitro

Objective Our previous study has revealed that iASPP is elevated in human head and neck squamous cell carcinoma(HNSCC)and iASPP overexpression signifcantly correlates with tumor malignant progression and poor survival of HNSCC.This study investigated the function of iASPP playing in proliferation and invasion of HNSCC in vitro.Methods HNSCC cell line Tu686 transfected with Lentiviral vector-mediated iASPP-specific shRNA and control shRNA were named the shRNA-iASPP group and shRNA-NC group,respectively.The non-infected Tu686 cells were named the CON group.CCK-8 assay,flow cytometry,transwell invasion assay were performed to detect the effects of iASPP inhibition in vitro.Results Our results demonstrated that the proliferation of shRNA-iASPP cells at the time of 72 h(F=32.459,P=0.000),96 h(F=51.407,P=0.000),120 h(F=35.125,P=0.000)post-transfection,was significantly lower than that of shRNANC cells and CON cells.The apoptosis ratio of shRNA-iASPP cells was 9.42%±0.39%(F=299.490,P=0.000),which was significantly higher than that of CON cells(2.80%±0.42%)and shRNA-NC cells(3.18%±0.28%).The percentage of shRNA-iASPP cells in G0/G1 phase was 74.65%±1.09%(F=388.901,P=0.000),which was strikingly increased,compared with that of CON cells(55.19%±1.02%)and shRNA-NC cells(54.62%±0.88%).The number of invading cells was 56±4 in the shRNA-iASPP group(F=84.965,P=0.000),which decreased significantly,compared with the CON group(111±3)and the shRNA-NC group(105±8).The survival rate of shRNA-iASPP cells administrated with paclitaxel was highly decreased,compared with CON cells and shRNA-NC cells(F=634.841,P=0.000).Conclusion These results suggest iASPP may play an important role in progression and aggressive behavior of HNSCC and may be an efficient chemotherapeutic target for the treatment of HNSCC.

Glucocorticoid reduces the efficacy of afatinib on the head and neck squamous cell carcinoma

Glucocorticoids(GC)are widely used to counter the adverse events during cancer therapy;nonetheless,previous studies pointed out that GC may reduce the efficacy of chemotherapy on cancer cells,especially in epidermal growth factor receptor(EGFR)-targeted therapy of head and neck squamous cell carcinoma(HNSCC)remaining to be elucidated.The primary aim of the present study was to probe into the GC-induced resistance of EGFR-targeted drug afatinib and the underlying mechanism.HNSCC cell lines(HSC-3,SCC-25,SCC-9,and H-400)and the human oral keratinocyte(HOK)cell lines were assessed for GC receptor(GR)expression.The promoting tumor growth effect of GC was evaluated by the CCK-8 assay and flow cytometry.Levels of signaling pathways participants GR,mTOR,and EGFR were determined by quantitative polymerase chain reaction and western blotting.GC increased the proliferation of HNSCC cells in a GR-dependent manner and promoted AKT/mTOR signaling.But GC failed in counteracting the inhibition of rapamycin in the mTOR signaling pathway.Besides,GC also induced resistance to EGFR-targeted drug afatinib through AKT/mTOR instead of the EGFR/ERK signaling pathway.Thus,GCs reduce the efficacy of afatinib on HNSCC,implicating a cautious use of glucocorticoids in clinical practice.

Towards system genetics analysis of head and neck squamous cell carcinoma using the mouse model,cellular platform,and clinical human data

Head and neck squamous cell cancer(HNSCC)is a leading global malignancy.Every year,More than 830000 people are diagnosed with HNSCC globally,with more than 430000 fatalities.HNSCC is a deadly diverse malignancy with many tumor locations and biological characteristics.It originates from the squamous epithelium of the oral cavity,oropharynx,nasopharynx,larynx,and hypopharynx.The most frequently impacted regions are the tongue and larynx.Previous investigations have demonstrated the critical role of host genetic susceptibility in the progression of HNSCC.Despite the advances in our knowledge,the improved survival rate of HNSCC patients over the last 40 years has been limited.Failure to identify the molecular origins of development of HNSCC and the genetic basis of the disease and its biological heterogeneity impedes the development of new therapeutic methods.These results indicate a need to identify more genetic factors underlying this complex disease,which can be better used in early detection and prevention strategies.The lack of reliable animal models to investigate the underlying molecular processes is one of the most significant barriers to understanding HNSCC tumors.In this report,we explore and discuss potential research prospects utilizing the Collaborative Cross mouse model and crossing it to mice carrying single or double knockout genes(e.g.Smad 4 and P53 genes)to identify genetic factors affecting the development of this complex disease using genome-wide association studies,epigenetics,micro RNA,long noncoding RNA,lnc RNA,histone modifications,methylation,phosphorylation,and proteomics.

High Incidence of Null-Type Mutations of the <i>TP</i>53 Gene in Japanese Patients with Head and Neck Squamous Cell Carcinoma

Objective: Molecular targeting therapy has not been generally established in head and neck squamous cell carcinoma (HNSCC) except for cetuximab treatment for targeting epidermal growth factor receptor (EGFR). We analyzed alterations of the TP53, KRAS2, and EGFR genes in Japanese HNSCC to identify subpopulations of tumors potentially susceptible or not susceptible to specific therapy based on their genetic alterations. Materials and Methods: A total of 56 Japanese subjects were included in this study. Genomic DNA of exons 5 - 9 of the TP53, exons 1 and 2 of the KRAS2, exons 19 - 22 of the EGFR, and their flanking sequences were amplified by polymerase chain reaction (PCR) followed by direct sequencing. Splicing variants of EGFR were examined by reverse transcription (RT)-PCR. Results: Mutations of the TP53 and KRAS genes were detected in 25 (45%) and 2 (4%) of 56 HNSCC cases, respectively, while neither mutation nor splicing variant of EGFR was observed. The TP53 mutation did not correlate with clinical stages or primary sites of the tumors. The patterns of nucleotide substitutions specific to HNSCC were not observed. However, the incidence of null-type mutations of the TP53, which cannot be detected as abnormal by conventional immunohistochemical (IHC) studies, was significantly higher (10/25;40%) than that of HNSCC reported in other countries. Conclusion: Frequent TP53 mutations, especially null-type mutations, but infrequent or no alterations of the KRAS and EGFR suggest that the sequencing analysis of theTP53 mutation rather than IHC analysis of p53 provides a potentially useful marker to predict the response of HNSCC to chemotherapy or radiotherapy.