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 ...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.展开更多
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...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.展开更多
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 g...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.展开更多
Single-cell RNA sequencing has been broadly applied to head and neck squamous cell carcinoma(HNSCC) for characterizing the heterogeneity and genomic mutations of HNSCC benefiting from the advantage of single-cell reso...Single-cell RNA sequencing has been broadly applied to head and neck squamous cell carcinoma(HNSCC) for characterizing the heterogeneity and genomic mutations of HNSCC benefiting from the advantage of single-cell resolution. We summarized most of the current studies and aimed to explore their research methods and ideas, as well as how to transform them into clinical applications. Through single-cell RNA sequencing, we found the differences in tumor cells’ expression programs and differentiation tracks. The studies of immune microenvironment allowed us to distinguish immune cell subpopulations, the extensive expression of immune checkpoints, and the complex crosstalk network between immune cells and non-immune cells. For cancerassociated fibroblasts(CAFs), single-cell RNA sequencing had made an irreplaceable contribution to the exploration of their differentiation status, specific CAFs markers, and the interaction with tumor cells and immune cells. In addition, we demonstrated in detail how single-cell RNA sequencing explored the HNSCC epithelial-tomesenchymal transition(EMT) model and the mechanism of drug resistance, as well as its clinical value.展开更多
Temporal bone malignant tumors are characterized by atypical clinical symptoms,and easy recurrence and metastasis.They account for 0.2%of head and neck tumors,and the most common pathological type is squamous cell car...Temporal bone malignant tumors are characterized by atypical clinical symptoms,and easy recurrence and metastasis.They account for 0.2%of head and neck tumors,and the most common pathological type is squamous cell carcinoma.Patients with squamous cell carcinoma of the temporal bone are often at advanced stages when diagnosed,and lose the chance for surgery.Neoadjuvant immunotherapy has recently been approved as the first-line treatment for refractory recurrent/metastatic squamous cell carcinoma of the head and neck.However,it remains to be determined whether neoadjuvant immunotherapy can be used as the first-line treatment for temporal bone squamous cell carcinoma to reduce the tumor stage before surgery,or as a palliative treatment for patients with unresectable advanced stage carcinoma.The present study reviews the development of immunotherapy and its clinical application in head and neck squamous cell carcinoma,summarizes the treatment of temporal bone squamous cell carcinoma,and prospects the neoadjuvant immunotherapy as the first-line treatment for temporal bone squamous cell carcinoma.展开更多
We analyzed RNA-sequencing(RNA-seq)and clinical data from head and neck squamous cell carcinoma(HNSCC)patients in The Cancer Genome Atlas(TCGA)Genomic Data Commons(GDC)portal to investigate the prognostic value of ano...We analyzed RNA-sequencing(RNA-seq)and clinical data from head and neck squamous cell carcinoma(HNSCC)patients in The Cancer Genome Atlas(TCGA)Genomic Data Commons(GDC)portal to investigate the prognostic value of anoikis-related genes(ARGs)in HNSCC and develop new targeted drugs.Differentially expressed ARGs were screened using bioinformatics methods;subsequently,a prognostic model including three ARGs(CDKN2A,BIRC5,and PLAU)was constructed.Our results showed that the model-based risk score was a good prognostic indicator,and the potential of the three ARGs in HNSCC prognosis was validated by the TISCH database,the model’s accuracy was validated in two independent cohorts of the Gene Expression Omnibus database.Immune correlation analysis and half-maximal inhibitory concentration were also performed to reveal the different landscapes of TIME between risk groups and to predict immuno-and chemo-therapeutic responses.Potential small-molecule drugs for HNSCC were subsequently predicted using the L1000FWD database.Finally,in vitro experiments were used to verify the database findings.The relative ARG mRNA expression levels in HNSCC and surrounding normal tissues remained consistent with the model results.BIRC5 knockdown inhibited anoikis resistance in WSU-HN6 and CAL-27 cells.Molecular docking,real-time PCR,cell counting kit-8(CCK-8),plate clone,and flow cytometry analyses showed that small-molecule drugs predicted by the database may target the ARGs in the prognostic model,inhibit HNSCC cells survival rate,and promote anoikis in vitro.Therefore,we constructed a new ARG model for HNSCC patients that can predict prognosis and immune activity and identify a potential small-molecule drug for HNSCC,paving the way for clinically targeting anoikis in HNSCC.展开更多
Circulating tumor cells(CTCs)play an important role in tumor metastases,which is positively correlated with an increased risk of death.Actin-binding proteins,including cofilin(CFL1),profilin 1(PFN1),and adenylate cycl...Circulating tumor cells(CTCs)play an important role in tumor metastases,which is positively correlated with an increased risk of death.Actin-binding proteins,including cofilin(CFL1),profilin 1(PFN1),and adenylate cyclase-associated protein 1(CAP1),are thought to be involved in tumor cell motility and metastasis,specifically in head and neck squamous cell carcinoma(HNSCC).However,currently,there are no published studies on CFL1,PFN1,and CAP1 in CTCs and leukocytes in HNSCC patients.We assessed serum levels of CFL1,PFN1,and CAP1 and the number of CTCs and leukocytes containing these proteins in blood from 31 HNSCC patients(T1-4N0-2M0).The analysis used flow cytometry and an enzyme-linked immunosorbent assay kit.We found that CAP1+CTCs and CAP1+leukocyte subpopulations were prevalent in these HNSCC patient samples,while the prevalence rates of CFL1+and PFN1+CTCs were relatively low.Patients with stage T2-4N1-2M0 had CFL1+and PFN1+CTCs with an elevated PFN1 serum level,compared with the T1-3N0M0 group.In summary,the PFN1 serum level and the relative number of PFN1+CD326+CTCs could be valuable prognostic markers for HNSCC metastases.The current study is the first to obtain data regarding the contents of actin-binding proteins(ABPs)in CTCs,and leukocytes in blood from HNSCC patients.This is also the first to assess the relationship between the number of CTCs subgroups and disease characteristics.展开更多
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 m...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.展开更多
5-Methylcytosine(m5C)methylation contributes to the development and progression of various malignant tumors.This study aimed to explore the potential role of m5C methylation regulators(m5CMRs)in head and neck squamous...5-Methylcytosine(m5C)methylation contributes to the development and progression of various malignant tumors.This study aimed to explore the potential role of m5C methylation regulators(m5CMRs)in head and neck squamous cell carcinoma(HNSCC).Methods:The transcription data of HNSCC samples were obtained from The Cancer Genome Atlas(TCGA)and the Gene Expression Omnibus(GEO)databases.Subsequently,the m5C patterns in HNSCC were evaluated based on 14 m5CMRs.Then,the m5Cscore was developed to quantify m5C patterns by using principal component analysis(PCA)algorithms.Two single-cell RNA sequencing datasets and various methods were employed to assess the prognostic value and sensitivity to immunotherapy.Finally,key prognostic m5CMRs were identified using univariate COX regression analysis,and their clinical significance was validated based on the Human Protein Atlas(HPA)database and by using immunohistochemistry.Results:Two distinct m5C clusters were identified.m5C cluster A is characterized by an immune-activated microenvironment and is associated with a favorable prognosis.Notable differences were observed in prognosis,immune infiltration,and immunotherapy response between the high-and low-m5Cscore groups.Patients in the high-m5Cscore group exhibited high TMB,which is correlated with poor prognosis.The m5Cscore of epithelial cells in HNSCC was higher than that in other cells.Key prognostic m5CMRs,including NSUN2,DNMT3B,ALKBH1,and Y-Box Binding Protein 1(YBX1),were associated with poor prognosis.Conclusion:Our research indicates that in head and neck squamous cell carcinoma,the m5C modification profoundly affects the TME’s diversity and complexity,influencing prognosis and the success of immunotherapy.Targeting m5C regulatory elements may be a new method for enhancing the efficacy of immunotherapy in HNSCC.展开更多
[Objectives] To optimize the culture medium for head and neck squamous cell carcinoma patient-derived organoid and screen suitable cytokines;compare the transfection efficiency of direct transfection and short-term su...[Objectives] To optimize the culture medium for head and neck squamous cell carcinoma patient-derived organoid and screen suitable cytokines;compare the transfection efficiency of direct transfection and short-term suspension transfection for organoid in matrigel. [Methods] Advanced DMEM/F12 medium, GlutaMax and HEPES buffer, nicotinamide, N-acetylcysteine, B27, A83-01, EGF, Y-27632 and Primocin primary cell antibiotics were prepared. On this basis, fibroblast growth factor 10(FGF10), Neuregulin 1, Noggin and R-spondin-1 were added in turn to prepare the selection medium, and the organoid diameter was used as the evaluation index to evaluate the effect of organoid medium. Using lentivirus, mCherry red fluorescent protein was transfected into HNSCC—PDO in different ways, and the transfection effect was evaluated by the fluorescence intensity of organoid sphere. [Results] Nrg1 Noggin and R-Spondin-1 promoted the growth of head and neck squamous cell carcinoma sphere(P<0.05) while FGF10 did not significantly promote the growth of head and neck squamous cell carcinoma sphere(P>0.05). Compared with direct transfection, short-term suspension transfection had higher transfection efficiency for HNSCC—PDO in matrigel. [Conclusions] R-Spondin-1 Nrg1 and Noggin may be the key cytokines in culture of HNSCC—PDO whereas FGF10 played an insignificant role in this study. Short-term suspension transfection could improve the transfection efficiency of lentivirus to HNSCC—PDO.展开更多
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 ...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.展开更多
AIM To evaluate the clinical impact of surveillance for head and neck(HN) region with narrow band imaging(NBI) in patients with esophageal squamous cell carcinoma(ESCC).METHODS Since 2006, we introduced the surveillan...AIM To evaluate the clinical impact of surveillance for head and neck(HN) region with narrow band imaging(NBI) in patients with esophageal squamous cell carcinoma(ESCC).METHODS Since 2006, we introduced the surveillance for HN region using NBI for all patients with ESCC beforetreatment, and each follow-up. The patients with newly diagnosed stage Ⅰ to Ⅲ ESCC were enrolled and classified into two groups as follows: Group A(no surveillance for HN region); between 1992 and 2000), and Group B (surveillance for HN region with NBI; between 2006 and 2008). We comparatively evaluated the detection rate of superficial head and neck squamous cell carcinoma (HNSCC), and the serious events due to metachronous advanced HNSCC during the follow-up.RESULTS A total 561 patients(group A: 254, group B: 307) were enrolled. Synchronous superficial HNSCC was detected in 1 patient (0.3%) in group A, and in 12 (3.9%) in group B (P=0.008). During the follow up period, metachronous HNSCC were detected in 10 patients(3.9%) in group A and in 30 patients(9.8%) in group B(P = 0.008). All metachronous lesions in group B were early stage, and 26 patients underwent local resection, however, 6 of 10 patients (60%) in group A lost their laryngeal function and died with metachronous HNSCC.CONCLUSION Surveillance for the HN region by using NBI endoscopy increase the detection rate of early HNSCC in patients with ESCC, and led to decrease serious events related to advanced metachronous HNSCC.展开更多
Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates.Amongst oral cavity cancers,tongue carcinoma is a very common and aggressive oral cavity carcinoma.Despite th...Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates.Amongst oral cavity cancers,tongue carcinoma is a very common and aggressive oral cavity carcinoma.Despite the implementation of a multimodality treatment regime including surgical intervention,chemo-radiation as well as targeted therapy,tongue carcinoma shows a poor overall 5-year survival pattern,which is attributed to therapy resistance and recurrence of the disease.The presence of a rare population,i.e.,cancer stem cells(CSCs)within the tumor,are involved in therapy resistance,recurrence,and distant metastasis that results in poor survival patterns.Therapeutic agents targeting CSCs have been in clinical trials,although they are unable to reach into therapy stage which is due to their failure in trials.A more detailed understanding of the CSCs is essential for identifying efficient targets.Molecular signaling pathways,which are differentially regulated in the CSCs,are one of the promising targets to manipulate the CSCs that would provide an improved outcome.In this review,we summarize the current understanding of molecular signaling associated with the maintenance and regulation of CSCs in tongue squamous cell carcinoma in order to emphasize the need of the hour to get a deeper understanding to unravel novel targets.展开更多
Head and neck squamous cell carcinoma(HNSCC) is the sixth most common cancer worldwide, and is responsible for a quarter of a million deaths annually. The survival rate for HNSCC patients is poor, showing only minor i...Head and neck squamous cell carcinoma(HNSCC) is the sixth most common cancer worldwide, and is responsible for a quarter of a million deaths annually. The survival rate for HNSCC patients is poor, showing only minor improvement in the last three decades. Despite new surgical techniques and chemotherapy protocols, tumor resistance to chemotherapy remains a significant challenge for HNSCC patients. Numerous mechanisms underlie chemoresistance, including genetic and epigenetic alterations in cancer cells that may be acquired during treatment and activation of mitogenic signaling pathways, such as nuclear factor kappa-light-chain-enhancer-of activated B cell, that cause reduced apoptosis. In addition to dysfunctional molecular signaling, emerging evidence reveals involvement of cancer stem cells(CSCs) in tumor development and in tumor resistance to chemotherapy and radiotherapy. These observations have sparked interest in understanding the mechanisms involved in the control of CSC function and fate. Post-translational modifications of histones dynamically influence gene expression independent of alterations to the DNA sequence. Recent findings from our group have shown that pharmacological induction of posttranslational modifications of tumor histones dynamically modulates CSC plasticity. These findings suggest that a better understanding of the biology of CSCs in response to epigenetic switches and pharmacological inhibitors of histone function may directly translate to the development of a mechanism-based strategy to disrupt CSCs. In this review, we present and discuss current knowledge on epigenetic modifications of HNSCC and CSC response to DNA methylation and histone modifications. In addition, we discuss chromatin modifications and their role in tumor resistance to therapy.展开更多
Lymphatic metastasis is a continuous and complicated process. The detailed mechanisms of lymphatic metastasis are still not very clear, despite considerable research efforts in recent years. Previously, it was commonl...Lymphatic metastasis is a continuous and complicated process. The detailed mechanisms of lymphatic metastasis are still not very clear, despite considerable research efforts in recent years. Previously, it was commonly accepted that there were no lymphatic vessels in the primary tumor. However, recent studies have demonstrated that lymphatic vessels are detectable in certain types of cancer, and more and more evidence has shown that cancer cells invade into local lymph nodes mainly via peritumoral lymphatic vessels, Moreover, activated endothelial cells may also be important, having an influence on lymphatic metastasis of cancer cells. This article, based on recent research findings, provides an in-depth discussion of the relationship between lymphangiogenesis, tumor-derived lymphatic endothelial cells and lymphatic metastasis in head and neck cancer.展开更多
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 pla...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.展开更多
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...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.展开更多
Background:p53 and DIRAS3 are tumor suppressors that are frequently silenced in tumors.In this study,we sought to determine whether the concurrent re-expression of p53 and DIRAS3 could effectively induce head and neck...Background:p53 and DIRAS3 are tumor suppressors that are frequently silenced in tumors.In this study,we sought to determine whether the concurrent re-expression of p53 and DIRAS3 could effectively induce head and neck squamous cell carcinoma(HNSCC)cell death.Methods:CAL-27 and SCC-25 cells were treated with Ad-DIRAS3 and rAd-p53 to induce re-expression of DIRAS3 and p53 respectively.The effects of DIRAS3 and p53 re-expression on the growth and apoptosis of HNSCC cells were examined by TUNEL assay,flow cytometric analysis and MTT.The effects of DIRAS3 and p53 re-expression on Akt phosphorylation,oncogene expression,and the interaction of 4 E-BP1 with eIF4 E were determined by real-time PCR,Western blotting and immunoprecipitation analysis.The ability of DIRAS3 and p53 re-expression to induce autophagy was evaluated by transmission electron microscopy,LC3 fluorescence microscopy and Western blotting.The effects of DIRAS3 and p53 re-expression on HNSCC growth were evaluated by using an orthotopic xenograft mouse model.Results:TUNEL assay and flow cytometric analysis showed that the concurrent re-expression of DIRAS3 and p53 significantly induced apoptosis(P<0.001).MTT and flow cytometric analysis revealed that DIRAS3 and p53 reexpression significantly inhibited proliferation and induced cell cycle arrest(P<0.001).Mechanistically,the concurrent re-expression of DIRAS3 and p53 down-regulated signal transducer and activation of transcription 3(STAT3)and upregulated p21WAF1/CIP1 and Bax(P<0.001).DIRAS3 and p53 re-expression also inhibited Akt phosphorylation,increased the interaction of eIF4 E with 4 E-BP1,and reduced the expression of c-Myc,cyclin D1,vascular endothelial growth factor(VEGF),fibroblast growth factor(FGF),epidermal growth factor receptor(EGFR)and Bcl-2(P<0.001).Moreover,the concurrent re-expression of DIRAS3 and p53 increased the percentage of cells with GFP-LC3 puncta compared with that in cells treated with control adenovirus(50.00%±4.55%vs.4.67%±1.25%,P<0.001).LC3 fluorescence microscopy and Western blotting further showed that DIRAS3 and p53 re-expression significantly promoted autophagic activity but also inhibited autophagic flux,resulting in overall impaired autophagy.Finally,the concurrent re-expression of DIRAS3 and p53 significantly decreased the tumor volume compared with the control group in a HNSCC xenograft mouse model[(3.12±0.75)mm^(3) vs.(189.02±17.54)mm^(3),P<0.001].Conclusions:The concurrent re-expression of DIRAS3 and p53 is a more effective approach to HNSCC treatment than current treatment strategies.展开更多
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 o...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.展开更多
Locally recurrent head and neck squamous cell carcinoma(HNSCC)is often unresectable,and a repeat course of radiotherapy is associated with incremental toxicities.Boron neutron capture therapy(BNCT)is a novel targeted ...Locally recurrent head and neck squamous cell carcinoma(HNSCC)is often unresectable,and a repeat course of radiotherapy is associated with incremental toxicities.Boron neutron capture therapy(BNCT)is a novel targeted radiotherapy modality that can achieve a high dose gradient between cancerous and adjacent normal tissues.However,the relationships among the dose resulting from BNCT,tumor response to BNCT,and survival are not completely understood.Recently,a study published in Radiotherapy and Oncology investigated the efficacy of BNCT in the treatment of patients with locally recurrent HNSCC and the factors associated with favorable treatment response and survival.In this article,the findings,strengths and limitations of this study are discussed in depth,and the significance of the study and motivations for future research are highlighted.展开更多
文摘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.
基金supported by the National Innovation and Enterpreneurship Training Program for College Students(202210367002)the Key Laboratory Open Project of An-hui Province(AHCM2022Z004).
文摘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.
基金supported by the Research Funding(No.RCDWJS 2020-20)Research and Development Program(RD-02-202002)from West China School/Hospital of Stomatology Sichuan University+1 种基金the Natural Science Foundation of China(81902784&81872207)Sichuan Provincial Fund of China(2022YFSY0058).
文摘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.
基金funded by Beijing Hope Run Special Fund of Cancer Foundation of China (No.LC2020A19)。
文摘Single-cell RNA sequencing has been broadly applied to head and neck squamous cell carcinoma(HNSCC) for characterizing the heterogeneity and genomic mutations of HNSCC benefiting from the advantage of single-cell resolution. We summarized most of the current studies and aimed to explore their research methods and ideas, as well as how to transform them into clinical applications. Through single-cell RNA sequencing, we found the differences in tumor cells’ expression programs and differentiation tracks. The studies of immune microenvironment allowed us to distinguish immune cell subpopulations, the extensive expression of immune checkpoints, and the complex crosstalk network between immune cells and non-immune cells. For cancerassociated fibroblasts(CAFs), single-cell RNA sequencing had made an irreplaceable contribution to the exploration of their differentiation status, specific CAFs markers, and the interaction with tumor cells and immune cells. In addition, we demonstrated in detail how single-cell RNA sequencing explored the HNSCC epithelial-tomesenchymal transition(EMT) model and the mechanism of drug resistance, as well as its clinical value.
基金supported by grants from The National Natural Science Foundation of China(No.81771003 and 82071508).
文摘Temporal bone malignant tumors are characterized by atypical clinical symptoms,and easy recurrence and metastasis.They account for 0.2%of head and neck tumors,and the most common pathological type is squamous cell carcinoma.Patients with squamous cell carcinoma of the temporal bone are often at advanced stages when diagnosed,and lose the chance for surgery.Neoadjuvant immunotherapy has recently been approved as the first-line treatment for refractory recurrent/metastatic squamous cell carcinoma of the head and neck.However,it remains to be determined whether neoadjuvant immunotherapy can be used as the first-line treatment for temporal bone squamous cell carcinoma to reduce the tumor stage before surgery,or as a palliative treatment for patients with unresectable advanced stage carcinoma.The present study reviews the development of immunotherapy and its clinical application in head and neck squamous cell carcinoma,summarizes the treatment of temporal bone squamous cell carcinoma,and prospects the neoadjuvant immunotherapy as the first-line treatment for temporal bone squamous cell carcinoma.
基金supported by the National Nature Science Foundation of China(Grant Numbers 81072214,30371547)the National Key R&D Program of China(Grant Number 2016YFC1102603).
文摘We analyzed RNA-sequencing(RNA-seq)and clinical data from head and neck squamous cell carcinoma(HNSCC)patients in The Cancer Genome Atlas(TCGA)Genomic Data Commons(GDC)portal to investigate the prognostic value of anoikis-related genes(ARGs)in HNSCC and develop new targeted drugs.Differentially expressed ARGs were screened using bioinformatics methods;subsequently,a prognostic model including three ARGs(CDKN2A,BIRC5,and PLAU)was constructed.Our results showed that the model-based risk score was a good prognostic indicator,and the potential of the three ARGs in HNSCC prognosis was validated by the TISCH database,the model’s accuracy was validated in two independent cohorts of the Gene Expression Omnibus database.Immune correlation analysis and half-maximal inhibitory concentration were also performed to reveal the different landscapes of TIME between risk groups and to predict immuno-and chemo-therapeutic responses.Potential small-molecule drugs for HNSCC were subsequently predicted using the L1000FWD database.Finally,in vitro experiments were used to verify the database findings.The relative ARG mRNA expression levels in HNSCC and surrounding normal tissues remained consistent with the model results.BIRC5 knockdown inhibited anoikis resistance in WSU-HN6 and CAL-27 cells.Molecular docking,real-time PCR,cell counting kit-8(CCK-8),plate clone,and flow cytometry analyses showed that small-molecule drugs predicted by the database may target the ARGs in the prognostic model,inhibit HNSCC cells survival rate,and promote anoikis in vitro.Therefore,we constructed a new ARG model for HNSCC patients that can predict prognosis and immune activity and identify a potential small-molecule drug for HNSCC,paving the way for clinically targeting anoikis in HNSCC.
文摘Circulating tumor cells(CTCs)play an important role in tumor metastases,which is positively correlated with an increased risk of death.Actin-binding proteins,including cofilin(CFL1),profilin 1(PFN1),and adenylate cyclase-associated protein 1(CAP1),are thought to be involved in tumor cell motility and metastasis,specifically in head and neck squamous cell carcinoma(HNSCC).However,currently,there are no published studies on CFL1,PFN1,and CAP1 in CTCs and leukocytes in HNSCC patients.We assessed serum levels of CFL1,PFN1,and CAP1 and the number of CTCs and leukocytes containing these proteins in blood from 31 HNSCC patients(T1-4N0-2M0).The analysis used flow cytometry and an enzyme-linked immunosorbent assay kit.We found that CAP1+CTCs and CAP1+leukocyte subpopulations were prevalent in these HNSCC patient samples,while the prevalence rates of CFL1+and PFN1+CTCs were relatively low.Patients with stage T2-4N1-2M0 had CFL1+and PFN1+CTCs with an elevated PFN1 serum level,compared with the T1-3N0M0 group.In summary,the PFN1 serum level and the relative number of PFN1+CD326+CTCs could be valuable prognostic markers for HNSCC metastases.The current study is the first to obtain data regarding the contents of actin-binding proteins(ABPs)in CTCs,and leukocytes in blood from HNSCC patients.This is also the first to assess the relationship between the number of CTCs subgroups and disease characteristics.
基金supported by a core fund from Tel Aviv University and the Department of Oral and Maxillofacial Surgery,Baruch Padeh Medical Center,Poriya,Israel。
文摘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.
基金supported by grants from the Guangdong Science and Technology Development Fund(Grant No.2019A1515110662).
文摘5-Methylcytosine(m5C)methylation contributes to the development and progression of various malignant tumors.This study aimed to explore the potential role of m5C methylation regulators(m5CMRs)in head and neck squamous cell carcinoma(HNSCC).Methods:The transcription data of HNSCC samples were obtained from The Cancer Genome Atlas(TCGA)and the Gene Expression Omnibus(GEO)databases.Subsequently,the m5C patterns in HNSCC were evaluated based on 14 m5CMRs.Then,the m5Cscore was developed to quantify m5C patterns by using principal component analysis(PCA)algorithms.Two single-cell RNA sequencing datasets and various methods were employed to assess the prognostic value and sensitivity to immunotherapy.Finally,key prognostic m5CMRs were identified using univariate COX regression analysis,and their clinical significance was validated based on the Human Protein Atlas(HPA)database and by using immunohistochemistry.Results:Two distinct m5C clusters were identified.m5C cluster A is characterized by an immune-activated microenvironment and is associated with a favorable prognosis.Notable differences were observed in prognosis,immune infiltration,and immunotherapy response between the high-and low-m5Cscore groups.Patients in the high-m5Cscore group exhibited high TMB,which is correlated with poor prognosis.The m5Cscore of epithelial cells in HNSCC was higher than that in other cells.Key prognostic m5CMRs,including NSUN2,DNMT3B,ALKBH1,and Y-Box Binding Protein 1(YBX1),were associated with poor prognosis.Conclusion:Our research indicates that in head and neck squamous cell carcinoma,the m5C modification profoundly affects the TME’s diversity and complexity,influencing prognosis and the success of immunotherapy.Targeting m5C regulatory elements may be a new method for enhancing the efficacy of immunotherapy in HNSCC.
基金Supported by Natural Science Foundation of China(82160386)Guangxi Natural Science Foundation(2023GXNSFAA0261892021GXNSFAA075042)。
文摘[Objectives] To optimize the culture medium for head and neck squamous cell carcinoma patient-derived organoid and screen suitable cytokines;compare the transfection efficiency of direct transfection and short-term suspension transfection for organoid in matrigel. [Methods] Advanced DMEM/F12 medium, GlutaMax and HEPES buffer, nicotinamide, N-acetylcysteine, B27, A83-01, EGF, Y-27632 and Primocin primary cell antibiotics were prepared. On this basis, fibroblast growth factor 10(FGF10), Neuregulin 1, Noggin and R-spondin-1 were added in turn to prepare the selection medium, and the organoid diameter was used as the evaluation index to evaluate the effect of organoid medium. Using lentivirus, mCherry red fluorescent protein was transfected into HNSCC—PDO in different ways, and the transfection effect was evaluated by the fluorescence intensity of organoid sphere. [Results] Nrg1 Noggin and R-Spondin-1 promoted the growth of head and neck squamous cell carcinoma sphere(P<0.05) while FGF10 did not significantly promote the growth of head and neck squamous cell carcinoma sphere(P>0.05). Compared with direct transfection, short-term suspension transfection had higher transfection efficiency for HNSCC—PDO in matrigel. [Conclusions] R-Spondin-1 Nrg1 and Noggin may be the key cytokines in culture of HNSCC—PDO whereas FGF10 played an insignificant role in this study. Short-term suspension transfection could improve the transfection efficiency of lentivirus to HNSCC—PDO.
文摘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.
文摘AIM To evaluate the clinical impact of surveillance for head and neck(HN) region with narrow band imaging(NBI) in patients with esophageal squamous cell carcinoma(ESCC).METHODS Since 2006, we introduced the surveillance for HN region using NBI for all patients with ESCC beforetreatment, and each follow-up. The patients with newly diagnosed stage Ⅰ to Ⅲ ESCC were enrolled and classified into two groups as follows: Group A(no surveillance for HN region); between 1992 and 2000), and Group B (surveillance for HN region with NBI; between 2006 and 2008). We comparatively evaluated the detection rate of superficial head and neck squamous cell carcinoma (HNSCC), and the serious events due to metachronous advanced HNSCC during the follow-up.RESULTS A total 561 patients(group A: 254, group B: 307) were enrolled. Synchronous superficial HNSCC was detected in 1 patient (0.3%) in group A, and in 12 (3.9%) in group B (P=0.008). During the follow up period, metachronous HNSCC were detected in 10 patients(3.9%) in group A and in 30 patients(9.8%) in group B(P = 0.008). All metachronous lesions in group B were early stage, and 26 patients underwent local resection, however, 6 of 10 patients (60%) in group A lost their laryngeal function and died with metachronous HNSCC.CONCLUSION Surveillance for the HN region by using NBI endoscopy increase the detection rate of early HNSCC in patients with ESCC, and led to decrease serious events related to advanced metachronous HNSCC.
基金supported by ACTREC PhD fellowshipfunded by TMC-IRB (3542)ACTREC annual funds。
文摘Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates.Amongst oral cavity cancers,tongue carcinoma is a very common and aggressive oral cavity carcinoma.Despite the implementation of a multimodality treatment regime including surgical intervention,chemo-radiation as well as targeted therapy,tongue carcinoma shows a poor overall 5-year survival pattern,which is attributed to therapy resistance and recurrence of the disease.The presence of a rare population,i.e.,cancer stem cells(CSCs)within the tumor,are involved in therapy resistance,recurrence,and distant metastasis that results in poor survival patterns.Therapeutic agents targeting CSCs have been in clinical trials,although they are unable to reach into therapy stage which is due to their failure in trials.A more detailed understanding of the CSCs is essential for identifying efficient targets.Molecular signaling pathways,which are differentially regulated in the CSCs,are one of the promising targets to manipulate the CSCs that would provide an improved outcome.In this review,we summarize the current understanding of molecular signaling associated with the maintenance and regulation of CSCs in tongue squamous cell carcinoma in order to emphasize the need of the hour to get a deeper understanding to unravel novel targets.
基金Supported by University of Michigan,School of Dentistry startup
文摘Head and neck squamous cell carcinoma(HNSCC) is the sixth most common cancer worldwide, and is responsible for a quarter of a million deaths annually. The survival rate for HNSCC patients is poor, showing only minor improvement in the last three decades. Despite new surgical techniques and chemotherapy protocols, tumor resistance to chemotherapy remains a significant challenge for HNSCC patients. Numerous mechanisms underlie chemoresistance, including genetic and epigenetic alterations in cancer cells that may be acquired during treatment and activation of mitogenic signaling pathways, such as nuclear factor kappa-light-chain-enhancer-of activated B cell, that cause reduced apoptosis. In addition to dysfunctional molecular signaling, emerging evidence reveals involvement of cancer stem cells(CSCs) in tumor development and in tumor resistance to chemotherapy and radiotherapy. These observations have sparked interest in understanding the mechanisms involved in the control of CSC function and fate. Post-translational modifications of histones dynamically influence gene expression independent of alterations to the DNA sequence. Recent findings from our group have shown that pharmacological induction of posttranslational modifications of tumor histones dynamically modulates CSC plasticity. These findings suggest that a better understanding of the biology of CSCs in response to epigenetic switches and pharmacological inhibitors of histone function may directly translate to the development of a mechanism-based strategy to disrupt CSCs. In this review, we present and discuss current knowledge on epigenetic modifications of HNSCC and CSC response to DNA methylation and histone modifications. In addition, we discuss chromatin modifications and their role in tumor resistance to therapy.
文摘Lymphatic metastasis is a continuous and complicated process. The detailed mechanisms of lymphatic metastasis are still not very clear, despite considerable research efforts in recent years. Previously, it was commonly accepted that there were no lymphatic vessels in the primary tumor. However, recent studies have demonstrated that lymphatic vessels are detectable in certain types of cancer, and more and more evidence has shown that cancer cells invade into local lymph nodes mainly via peritumoral lymphatic vessels, Moreover, activated endothelial cells may also be important, having an influence on lymphatic metastasis of cancer cells. This article, based on recent research findings, provides an in-depth discussion of the relationship between lymphangiogenesis, tumor-derived lymphatic endothelial cells and lymphatic metastasis in head and neck cancer.
文摘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.
基金supported in part by Grants from the National Natural Science Foundation of China(Nos.81473048 and 81302361)Priority Academic Program Development of Jiangsu Higher Education Institutions(Public Health and Preventive Medicine)+2 种基金Specialized Research Fund for the Doctoral Program of Higher Education of China(No.20133234120013)China Postdoctoral Science Foundation(No.2013M540457)Jiangsu Planned Projects for Postdoctoral Research Funds(No.1301018A)
文摘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.
基金supported by Funding for the Basic Research of the Ministry of Sciences and Technology,Sichuan Province(2015JY0090)the National Natural Science Foundation of China(81972546,81602373)。
文摘Background:p53 and DIRAS3 are tumor suppressors that are frequently silenced in tumors.In this study,we sought to determine whether the concurrent re-expression of p53 and DIRAS3 could effectively induce head and neck squamous cell carcinoma(HNSCC)cell death.Methods:CAL-27 and SCC-25 cells were treated with Ad-DIRAS3 and rAd-p53 to induce re-expression of DIRAS3 and p53 respectively.The effects of DIRAS3 and p53 re-expression on the growth and apoptosis of HNSCC cells were examined by TUNEL assay,flow cytometric analysis and MTT.The effects of DIRAS3 and p53 re-expression on Akt phosphorylation,oncogene expression,and the interaction of 4 E-BP1 with eIF4 E were determined by real-time PCR,Western blotting and immunoprecipitation analysis.The ability of DIRAS3 and p53 re-expression to induce autophagy was evaluated by transmission electron microscopy,LC3 fluorescence microscopy and Western blotting.The effects of DIRAS3 and p53 re-expression on HNSCC growth were evaluated by using an orthotopic xenograft mouse model.Results:TUNEL assay and flow cytometric analysis showed that the concurrent re-expression of DIRAS3 and p53 significantly induced apoptosis(P<0.001).MTT and flow cytometric analysis revealed that DIRAS3 and p53 reexpression significantly inhibited proliferation and induced cell cycle arrest(P<0.001).Mechanistically,the concurrent re-expression of DIRAS3 and p53 down-regulated signal transducer and activation of transcription 3(STAT3)and upregulated p21WAF1/CIP1 and Bax(P<0.001).DIRAS3 and p53 re-expression also inhibited Akt phosphorylation,increased the interaction of eIF4 E with 4 E-BP1,and reduced the expression of c-Myc,cyclin D1,vascular endothelial growth factor(VEGF),fibroblast growth factor(FGF),epidermal growth factor receptor(EGFR)and Bcl-2(P<0.001).Moreover,the concurrent re-expression of DIRAS3 and p53 increased the percentage of cells with GFP-LC3 puncta compared with that in cells treated with control adenovirus(50.00%±4.55%vs.4.67%±1.25%,P<0.001).LC3 fluorescence microscopy and Western blotting further showed that DIRAS3 and p53 re-expression significantly promoted autophagic activity but also inhibited autophagic flux,resulting in overall impaired autophagy.Finally,the concurrent re-expression of DIRAS3 and p53 significantly decreased the tumor volume compared with the control group in a HNSCC xenograft mouse model[(3.12±0.75)mm^(3) vs.(189.02±17.54)mm^(3),P<0.001].Conclusions:The concurrent re-expression of DIRAS3 and p53 is a more effective approach to HNSCC treatment than current treatment strategies.
文摘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.
文摘Locally recurrent head and neck squamous cell carcinoma(HNSCC)is often unresectable,and a repeat course of radiotherapy is associated with incremental toxicities.Boron neutron capture therapy(BNCT)is a novel targeted radiotherapy modality that can achieve a high dose gradient between cancerous and adjacent normal tissues.However,the relationships among the dose resulting from BNCT,tumor response to BNCT,and survival are not completely understood.Recently,a study published in Radiotherapy and Oncology investigated the efficacy of BNCT in the treatment of patients with locally recurrent HNSCC and the factors associated with favorable treatment response and survival.In this article,the findings,strengths and limitations of this study are discussed in depth,and the significance of the study and motivations for future research are highlighted.