Development Of Head And Neck Squamous Cell Carcinoma Research Articles

Human papilloma virus and tobacco-associated modulation of NOTCH1 pathway during development of head and neck squamous cell carcinoma: Clinical importance

Background: Modulation of NOTCH1 pathway during development of head and neck squamous cell carcinoma (HNSCC) was evaluated with human papillomavirus (HPV) infection and/or tobacco habit to define the molecular mechanism of transformation of normal oral epithelium into neoplastic tissue. Materials and Methods: Comprehensive messenger RNA (mRNA) expression profile of NOTCH1 pathway genes (NOTCH1, JAG1/2, HES1, HEY1, and FBXW7) in HNSCC samples was mined from five different datasets followed by validation at genetic/expression level (RNA/protein). Results: Differential expression pattern of the NOTCH1 pathway genes was seen in different datasets. In our HNSCC samples, high mRNA expression of NOTCH1, JAG1/2, HES1, HEY1 was seen with a significant increase particularly in NOTCH1 and HES1 expression in HPV+ ve (H+) samples. However, no such change in mRNA expression of FBXW7 was noted. In immunohistochemical analysis, high/medium expressions of activated NOTCH1 (NICD)/FBXW7/HES1 proteins were seen in basal/parabasal layers of adjacent normal oral epithelium than in the spinous layers with prevalent expression in H+ samples, followed by increased expression with the progression of the disease. A similar trend was seen in the H+ and/or tobacco+ve (T+) samples, except H-T- group. Infrequent copy number variation was seen in NOTCH1/JAG1/JAG2 loci in HNSCC samples. High/medium expression of NICD/HES1 protein showed overall poor patient outcome, though patients under H+ T– group showed better survival. Conclusion: Our data showed that activated NOTCH1 pathway in basal/parabasal layers of the oral epithelium was gradually aggravated during the development of HNSCC with a distinct association with HPV infection and tobacco habit.

Identification and verification of aging-related lncRNAs for prognosis prediction and immune microenvironment in patients with head and neck squamous carcinoma.

Aging is highly associated with tumor formation and progression. However, little research has explored the association of aging-related lncRNAs (ARLs) with the prognosis and tumor immune microenvironment (TIME) of head and neck squamous cell carcinoma (HNSCC). RNA sequences and clinicopathological data of HNSCC patients and normal subjects were downloaded from The Cancer Genome Atlas. In the training group, we used Pearson correlation, univariate Cox regression, least absolute shrinkage/selection operator regression analyses, and multivariate Cox regression to build a prognostic model. In the test group, we evaluated the model. Multivariate Cox regression was done to screen out independent prognostic factors, with which we constructed a nomogram. Afterward, we demonstrated the predictive value of the risk scores based on the model and the nomogram using time-dependent receiver operating characteristics. Gene set enrichment analysis, 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. The most important LINC00861 in the model was examined in HNE1, CNE1, and CNE2 nasopharyngeal carcinoma cell lines and transfected into the cell lines CNE1 and CNE2 using the LINC00861-pcDNA3.1 construct plasmid. In addition, CCK-8, Edu, and SA-β-gal staining assays were conducted to test the biofunction of LINC00861 in the CNE1 and CNE2 cells. The signature based on nine ARLs has a good predictive value in survival time, immune infiltration, immune checkpoint expression, and sensitivity to multiple drugs. LINC00861 expression in CNE2 was significantly lower than in the HNE1 and CNE1 cells, and LINC00861 overexpression significantly inhibited the proliferation and increased the senescence of nasopharyngeal carcinoma cell lines. This work built and verified a new prognostic model for HNSCC based on ARLs and mapped the immune landscape in HNSCC. LINC00861 is a protective factor for the development of HNSCC.

PLAU and LAMC2 can predict a poor prognosis in patients with HNSCC.

Objectives: Head and neck squamous cell carcinoma (HNSCC) is the most common malignancy of the head and neck. However, the molecular mechanisms governing the development of HNSCC have not been fully elucidated. Materials and Methods: Differentially expressed genes (DEGs) were screened out from The Cancer Genome Atlas (TCGA) and GSE23036 datasets. Weighted gene coexpression network analysis (WGCNA) was used to reveal the correlations among genes and to search for significantly correlated gene modules. The expression levels of genes in HNSCC and normal samples according to antibody-based detected methods was assessed by utilizing the Human Protein Atlas (HPA). The impact of the selected hub genes on the prognosis of HNSCC patients was assessed by analysing immunohistochemistry (IHC) and immunofluorescence (IF) expression levels and clinical data. Results: Twenty-four genes positively correlated with tumour status and 15 genes negatively correlated with tumour status were screened out by WGCNA. PLAU and LAMC2 were associated with a poor prognosis in patients with HNSCC and were finally screened out and verified by GEPIA and HPA database analysis. Immunohistochemistry of samples collected from 175 patients with HNSCC and subsequent statistical analysis also showed that PLAU and LAMC2 were associated with a poor prognosis in patients with HNSCC, and the levels of these two factors were positively correlated. The expression and co-localization of PLAU and LAMC2 in HNSCC tissues were confirmed by double immunofluorescence labeling. Conclusions: There was a positive correlation between PLAU and LAMC2 expression in HNSCC samples, and PLAU and LAMC2 might be independent prognostic biomarkers for HNSCC.

Gene polymorphisms and risk of head and neck squamous cell carcinoma: a systematic review.

Exposure to the same environmental factors in different people have resulted in different susceptibility to head and neck squamous cell carcinoma (HNSCC), which suggests genetic variation may be a risk factor for the development of HNSCC. So, the aim was to review literatures on the association between gene polymorphisms and risk of HNSCCs. This systematic review included all articles on the impact of gene polymorphisms on risk and susceptibility to HNSCC published till September 2021 using PubMed, Web of science, SCOPUS, Google Scholar and Cochrane library databases. Of 1163 initial searched articles, 77 articles were eligible to include in this review. Studies were categorized based on gene functions. In each category, studied gene polymorphisms related to growth control genes, cell cycle control, apoptosis, DNA repair genes, carcinogen-metabolizing enzymes, alcohol-metabolizing genes, antioxidant gene, inflammatory cytokine, transcription factor, tumor immunity, folate metabolism, and tumor suppressor gene were discussed separately. Among the polymorphisms that are often significantly associated with HNSCC risk are: GSTM1 null, GSTT1 null, CYP2D6 *4, XRCC1 Arg194Trp and Arg399Gln, ERCC1 C8092A, XPD Lys751Gln, XRCC3 Thr241Met, P53 codon 72 and MTHFR C677T polymorphisms. Varied and contradictory results have been reported in different studies regarding the association of gene polymorphisms with HNSCC risk. To conclude about this association and to overcome these contradictions, it is necessary to use the results of existing meta-analyses or to perform new or updated meta-analyses.

The XRCC1 Arg194Trp polymorphism was associated with the risk of head and neck squamous cell carcinoma development: Results from a systematic review and meta-analysis.

The X-ray repair cross complementing group 1 (XRCC1) is a DNA repair gene. Various studies have examined the association between XRCC1 Arg194Trp polymorphism and head and neck squamous cell carcinoma (HNSCC) susceptibility with contradictory results. So, this systematic review and meta-analysis aimed to assess whether variants of this polymorphism increase the HNSCC risk or not. Thirty three studies consisting of 14282 subjects (6012 cases and 8270 controls) were included in this meta-analysis. Variants of XRCC1 Arg194Trp polymorphism were associated with increased HNSCC risk and the associations were significant based on heterozygous and dominant models (heterozygous model: OR = 1.182, 95%CI = 1.015-1.377, P = 0.032; homozygous model: OR = 1.274, 95%CI = 0.940-1.727, P = 0.119; dominant model: OR = 1.194, 95%CI = 1.027-1.388, P = 0.021; recessive model: OR = 1.181, 95%CI = 0.885-1.576, P = 0.119). There were significant associations between variants of this polymorphism and HNSCC risk based on Asian ethnicity under dominant model, hospital control source under different genetic models, PCR-RFLP genotyping method under dominant model and oral cavity tumor site under heterozygous and dominant models. The X-ray repair cross complementing group 1 (XRCC1) is a DNA repair gene. Various studies have examined the association between XRCC1 Arg194Trp polymorphism and head and neck squamous cell carcinoma (HNSCC) susceptibility with contradictory results. So, this systematic review and meta-analysis aimed to assess whether variants of this polymorphism increase the HNSCC risk or not. A systematic search of the literatures published till April 2022 was conducted using Google Scholar, Scopus, PubMed, Web of Science, Cochrane Library and Embase databases. The heterogeneity was assessed with the I-Square statistic. A random effects model or fixed effects model was used to analyze the data. Data were reported by odds ratio (OR) and 95% confidence interval (CI). The p value was considered significant if p < .05. Thirty three studies consisting of 14 282 subjects (6012 cases and 8270 controls) were included in this meta-analysis. Variants of XRCC1 Arg194Trp polymorphism were associated with increased HNSCC risk and the associations were significant based on heterozygous and dominant models (heterozygous model: OR=1.182, 95%CI=1.015-1.377, p=.032; homozygous model: OR=1.274, 95%CI=0.940-1.727, p=.119; dominant model: OR=1.194, 95%CI=1.027-1.388, p=.021; recessive model: OR=1.181, 95%CI=0.885-1.576, p=.119). There were significant associations between variants of this polymorphism and HNSCC risk based on Asian ethnicity under dominant model, hospital control source under different genetic models, PCR-RFLP genotyping method under dominant model and oral cavity tumor site under heterozygous and dominant models. Variants of XRCC1 Arg194Trp polymorphism were significantly associated with increased risk of HNSCC development based on heterozygous and dominant genetic models.

GOLM1 and FAM49B: Potential Biomarkers in HNSCC Based on Bioinformatics and Immunohistochemical Analysis.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide. We aimed to identify potential genetic markers that could predict the prognosis of HNSCC. A total of 44 samples of GSE83519 from Gene Expression Omnibus (GEO) datasets and 546 samples of HNSCC from The Cancer Genome Atlas (TCGA) were adopted. The differently expressed genes (DEGs) of the samples were screened by GEO2R. We integrated the expression information of DEGs with clinical data from GES42743 using the weighted gene co-expression network analysis (WGCNA). A total of 17 hub genes were selected by the module membership (|MM| > 0.8), and the gene significance (|GS| > 0.3) was selected from the turquoise module. GOLM1 and FAM49B genes were chosen based on single-gene analysis results. Survival analysis showed that the higher expression of GOLM1 and FAM49B genes was correlated with a worse prognosis of HNSCC patients. Immunohistochemistry and multiplex immunofluorescence techniques verified that GOLM1 and FAM49B genes were highly expressed in HNSCC cells, and high expressions of GOLM1 were associated with the pathological grades of HNSCC. In conclusion, our study illustrated a new insight that GOLM1 and FAM49B genes might be used as potential biomarkers to determine the development of HNSCC, while GOLM1 and FAM49B have the possibility to be prognostic indicators for HNSCC.

NUTF2 as a Prognostic Indicator and Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma.

Aim: To identify genes associated with the prognosis of head and neck squamous cell carcinoma (HNSC) and potential molecular targets for therapy. Materials and Methods: Gene Expression Profiling Interactive Analysis, Human Protein Atlas, University of ALabama at Birmingham CANcer, LinkedOmics, cBioPortal, Cell Counting Kit 8, and polymerase chain reaction were used in this study. Results: The expression level of nuclear transport factor 2 (NUTF2) was elevated in HNSC tissues and was associated with poor prognosis in HNSC patients. NUTF2-targeted intervention inhibited the proliferation of HNSC cells. SEC61G, which was positively correlated with NUTF2, was decreased in HNSC cells with NUTF2 suppression. Conclusions: NUTF2 may be correlated with the prognosis and development of HNSC, laying the foundation for future studies on the potential role of NUTF2 in HNSC.

Abstract IA020: Targeting mTOR signaling in oral premalignant lesions: From bench to clinic and back

Abstract Despite encouraging recent results from novel treatment options, such as immunotherapy, for head and neck squamous cell carcinoma (HNSCC), limited progress has been made in improving outcomes for most patients. Prevention and early detection are key to improving the prognosis of HNSCC. Our team has focused on decoding the oncogenic signaling circuitries driving HNSCC initiation and progression, aimed at identifying novel druggable targets to treat and prevent this aggressive malignancy. These efforts led to the early discovery that persistent activation of PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in HNSCC, and that in turn, the overreliance on PI3K/mTOR for HNSCC initiation and progression can be exploited for therapeutic purposes. Evidence will presented that mTOR inhibition exerts a potent antitumor activity in HNSCC patients in a recently reported window of opportunity clinical trial (NCT01195922). Thus, mTOR inhibitors can be considered for the prevention of HNSCC development and for the treatment of existing HNSCC lesions. However, their safety profile and tolerability may hamper their potential long-term use for HNSCC prevention. In this regard, we have shown that the repurposed drug metformin, which is safely used by millions of type 2 diabetes patients, decreases mTOR signaling in HNSCC and displays potent chemopreventive activity in experimental oral premalignancy models. Based on these findings, we have conducted a Phase IIa Clinical Trial using metformin for HNSCC prevention (NCT02581137) in patients with oral premalignant lesions (OPL), which was recently completed. Metformin administration resulted in mTOR inhibition, and improvement in the histological severity of 60% of the OPLs, including a subset (17%) of patients that exhibited complete responses. Ongoing experimental and planned clinical studies will be presented, which may provide a mechanistic framework for the use of metformin as a precision preventive agent for HNSCC. Citation Format: J. Silvio Gutkind. Targeting mTOR signaling in oral premalignant lesions: From bench to clinic and back [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA020.

Construction and clinical evaluation of N6-methyladenosine risk signature of YTHDC2, IGF2BP2, and HNRNPC in head and neck squamous cell carcinoma.

This work aimed to construct N6-methyladenosine (m6A) regulator-based prognostic signature and evaluate the prognostic value and the intervention on tumor immune microenvironment of this m6A risk signature. Using transcriptome and clinical data of head and neck squamous cell carcinoma (HNSCC) from The Cancer Genome Atlas (TCGA), we profiled m6A regulators and constructed an m6A risk signature. The relationship between m6A modulation and immune function was studied by differential gene expression, cell type enrichment, and correlation analyses. Fifteen m6A regulators had aberrant expression in HNSCC. A three-gene m6A prognostic signature (i.e., YTHDC2, IGF2BP2, and HNRNPC) was constructed and identified as an independent prognostic indicator for HNSCC. The m6A regulator signature-based high-risk group revealed pro-tumoral immune microenvironment due to the dysregulation of immune-related gene expression, abnormal enrichment of multiple immunocytes, and production of immunoregulatory factors. This comprehensive analysis of m6A regulators and tumor immune landscape in HNSCC revealed that the m6A signature of YTHDC2, IGF2BP2, and HNRNPC could serve as a promising biomarker for monitoring HNSCC development and may be a potential target for tumor therapy in the future.

Identification of a Prognostic Pyroptostic-Related Model for Head and Neck Squamous Cell Carcinoma Based on LASSO-Cox Regression Analysis.

Pyroptosis is associated with the biological behavior of the tumor and with tumor immunity. We investigated the effect of pyroptosis on the tumor microenvironment and tumor immunity in head and neck squamous cell carcinoma (HNSCC). RNA sequencing data and clinical information of HNSCC were downloaded from TCGA. Differentially expressed pyroptosis-related genes in HNSCC were identified between HNSCC and normal tissue. Pyroptosis-related classification of HNSCC was conducted based on consensus clustering analysis. LASSO-Cox regression analysis was used to construct a prognostic risk model-based pyroptosis-related gene. Evaluation of the immune microenvironment was conducted in prognostic risk signature based on pyroptosis-related genes. Total 22 differentially expressed pyroptosis-related genes were identified in HNSCC. Six prognostic-related genes were included to construct a LASSO regression model with a prognostic risk score = (0.133 ∗ GSDME (DFNA5) + 0.084 ∗ NOD1 + 0.039 ∗ IL6 + 0.003 ∗ IL1B + 0.084 ∗ CASP3 + 0.028 ∗ NLRP2). Higher fraction of resting memory CD4+ T cells and macrophages M1 was infiltrated in the high-risk group compared with the low-risk group in HNSCC. Furthermore, the PI3K-Akt signaling pathway and the IL-17 signaling pathways were identified to be involved in the development of high-risk HNSCC. Our study constructed a prognostic risk signature based on pyroptosis-related genes, which emphasizes the critical importance of pyroptosis in HNSCC and provided a novel perspective of HNSCC therapy.

Targeting DNA damage response as a potential therapeutic strategy for head and neck squamous cell carcinoma.

Cells experience both endogenous and exogenous DNA damage daily. To maintain genome integrity and suppress tumorigenesis, individuals have evolutionarily acquired a series of repair functions, termed DNA damage response (DDR), to repair DNA damage and ensure the accurate transmission of genetic information. Defects in DNA damage repair pathways may lead to various diseases, including tumors. Accumulating evidence suggests that alterations in DDR-related genes, such as somatic or germline mutations, single nucleotide polymorphisms (SNPs), and promoter methylation, are closely related to the occurrence, development, and treatment of head and neck squamous cell carcinoma (HNSCC). Despite recent advances in surgery combined with radiotherapy, chemotherapy, or immunotherapy, there has been no substantial improvement in the survival rate of patients with HNSCC. Therefore, targeting DNA repair pathways may be a promising treatment for HNSCC. In this review, we summarized the sources of DNA damage and DNA damage repair pathways. Further, the role of DNA damage repair pathways in the development of HNSCC and the application of small molecule inhibitors targeting these pathways in the treatment of HNSCC were focused.

The prognostic impact of the immune signature in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that retain their poor prognosis despite recent advances in their standard of care. As the involvement of the immune system against HNSCC development is well-recognized, characterization of the immune signature and the complex interplay between HNSCC and the immune system could lead to the identification of novel therapeutic targets that are required now more than ever. In this study, we investigated RNA sequencing data of 530 HNSCC patients from The Cancer Genome Atlas (TCGA) for which the immune composition (CIBERSORT) was defined by the relative fractions of 10 immune-cell types and expression data of 45 immune checkpoint ligands were quantified. This initial investigation was followed by immunohistochemical (IHC) staining for a curated selection of immune cell types and checkpoint ligands markers in tissue samples of 50 advanced stage HNSCC patients. The outcome of both analyses was correlated with clinicopathological parameters and patient overall survival. Our results indicated that HNSCC tumors are in close contact with both cytotoxic and immunosuppressive immune cells. TCGA data showed prognostic relevance of dendritic cells, M2 macrophages and neutrophils, while IHC analysis associated T cells and natural killer cells with better/worse prognostic outcome. HNSCC tumors in our TCGA cohort showed differential RNA over- and underexpression of 28 immune inhibitory and activating checkpoint ligands compared to healthy tissue. Of these, CD73, CD276 and CD155 gene expression were negative prognostic factors, while CD40L, CEACAM1 and Gal-9 expression were associated with significantly better outcomes. Our IHC analyses confirmed the relevance of CD155 and CD276 protein expression, and in addition PD-L1 expression, as independent negative prognostic factors, while HLA-E overexpression was associated with better outcomes. Lastly, the co-presence of both (i) CD155 positive cells with intratumoral NK cells; and (ii) PD-L1 expression with regulatory T cell infiltration may hold prognostic value for these cohorts. Based on our data, we propose that CD155 and CD276 are promising novel targets for HNSCC, possibly in combination with the current standard of care or novel immunotherapies to come.

Role of IGF2BPs in head and neck squamous cell carcinoma.

IGF2BPs belongs to a family of conserved RNA-bound oncoembryonic proteins that play a crucial part in various aspects of cell function, such as cell migration, morphology, metabolism, proliferation and differentiation. Recent studies have shown that IGF2BPs play a role as a member of m6A reader. m6A is the most abundant modification in RNA epigenetics, which is closely related to a family of RNA-binding proteins. These proteins are fell into three categories—writers, readers and erasers. In the present study, IGF2BPs play an important role in tumor metabolism, especially in head and neck squamous cell carcinoma (HNSCC) metabolism. In this paper, the basic structure of IGF2BPs, its role in the development of HNSCC, molecular mechanism, research progress and research prospect of IGF2BPs in HNSCC are reviewed, which will providing new ideas for further study of IGF2BPs.

Novel prognostic matrisome-related gene signature of head and neck squamous cell carcinoma.

Background: Head and neck squamous cell carcinoma (HNSCC) is a common malignancy of the mucosal epithelium of the oral cavity, pharynx, and larynx. Laryngeal squamous cell carcinoma (LSCC) and oral squamous cell carcinoma are common HNSCC subtypes. Patients with metastatic HNSCC have a poor prognosis. Therefore, identifying molecular markers for the development and progression of HNSCC is essential for improving early diagnosis and predicting patient outcomes. Methods: Gene expression RNA-Seq data and patient clinical traits were obtained from The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma (TCGA-HNSC) and Gene Expression Omnibus databases. Differentially expressed gene (DEG) screening was performed using the TCGA-HNSC dataset. Intersection analysis between the DEGs and a list of core matrisome genes obtained from the Matrisome Project was used to identify differentially expressed matrisome genes. A prognostic model was established using univariate and multivariate Cox regression analyses, least absolute shrinkage, and selection operator (LASSO) regression analysis. Immune landscape analysis was performed based on the single-sample gene set enrichment analysis algorithm, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, prognostic value, receiver operating characteristic curve analysis, and gene mutation analyses. Immunohistochemical results regarding prognostic protein levels were obtained from the Human Protein Atlas. Single-gene RNA-sequencing data were obtained from GSE150321 and GSE172577 datasets. CCK-8 and Transwell assays were used to confirm cell proliferation and migration. Results: A total of 1,779 DEGs, including 939 upregulated and 840 downregulated genes, between tumor and normal samples were identified using the TCGA-HNSC microarray data. Intersection analysis revealed 52 differentially expressed matrisome-related genes. After performing univariate and multivariate Cox regression and LASSO analyses, a novel prognostic model based on six matrisome genes (FN1, LAMB4, LAMB3, DMP1, CHAD, and MMRN1) for HNSCC was established. This risk model can successfully predict HNSCC survival. The high-risk group had worse prognoses and higher enrichment of pathways related to cancer development than the low-risk group. Silencing LAMB4 in HNSCC cell lines promoted cell proliferation and migration. Conclusion: This study provides a novel prognostic model for HNSCC. Thus, FN1, LAMB4, LAMB3, DMP1, CHAD, and MMRN1 may be the promising biomarkers for clinical practice.

S100A10 might be a novel prognostic biomarker for head and neck squamous cell carcinoma based on bioinformatics analysis

Head and neck squamous cell carcinoma (HNSCC) is a frequent malignant tumor of the head and neck with a dismal survival probability due to relapse and metastasis. S100As have been identified as being involved in the tumor procession of various cancer types. However, the expressions of S100As in HNSCC and their prognostic relevance are unknown. Bioinfromatics analysis was conducted to identify the prognostic value and function of S100As in HNSCC patients. In the study, we found that high mRNA expression levels of S100A3, S100A4, S100A7A, S100A9, and low mRNA expression levels of S100A1, S100A10 were related with a good overall survival in HNSCC patients. Importantly, the prognosis model suggested that S100A10 may have a certain impact on the development of HNSCC. Moreover, single-cell RNA sequencing analysis clarified that the specific functions of S100A10 had positive regulatory effects on metastasis, blood vessel generation, EMT, hypoxia, and invasion. Our findings implied that S100A10 might be a new prognostic biomarker for HNSCC, and played a role in promoting the occurrence, and development of HNSCC.

Single-cell transcriptomics uncover the key ferroptosis regulators contribute to cancer progression in head and neck squamous cell carcinoma.

The mechanism underlying the association between the development of head and neck squamous cell carcinoma (HNSCC) and ferroptosis is unclear. We analyzed the transcriptomes of 5902 single cells from a single-cell RNA-sequencing (scRNA-seq) dataset. They then aggregate into B cells, epithelial cells, fibroblasts, germ cells, mesenchymal cells, cancer stem cells, stem cells, T cells and endometrial cells, respectively. Our study shows that multiple pathways are significantly enriched in HNSCC development including extracellular matrix structural components, humoral immune responses, and muscle contraction. Differentially expressed genes analysis in Pseudotime analysis, pathway and biological function indicated that there was a significant correlation in the ferroptosis pathway. Furthermore, higher ferroptosis potential index (FPI) scores were significantly associated with worse overall survival prognosis in HNSCC patients. Pseudo-temporal, survival analyses and immunohistochemistry identified multiple central genes in HNSCC development, including ACSL1, SLC39A14, TFRC, and PRNP genes, and indicated associated ferroptosis. Overall, our study detected ferroptosis-related features is closely correlated with HNSCC prognosis and development, and deserved candidates suitable for immunotherapy treatment strategies determination for HNSCC patients.

The interplay of cytokine signaling and non-coding RNAs in head and neck squamous cell carcinoma pathobiology.

Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related death worldwide. Despite aggressive treatment approaches, the recurrence of HNSCC remains a challenge. Cytokines play an essential role in HNSCC development and progression. They are not only involved in promoting cancer growth but may also be involved in an anti-tumor immune response. Non-coding RNAs (ncRNAs) have emerged as important transcriptional and post-transcriptional mediators of cytokine function in HNSCC. This review focuses on the complex regulatory network among regulatory ncRNAs and cytokines during HNSCC pathogenesis.

Human Papillomavirus and Risk of Head and Neck Squamous Cell Carcinoma in Iran.

ABSTRACTHuman papillomavirus (HPV) causes a subset of head and neck squamous cell carcinoma (HNSCC). Knowledge of determinants of α-, β-, and γ-HPVs types in the oral cavity is required for a better understanding of HNSCC development. Oral rinse samples of 498 HNSCC cases and 242 controls from the IROPICAN study—a large multicenter case-control study in Iran—were screened for 21 α-HPV, 46 β-HPVs, and 52 γ-HPVs using bead-based HPV genotyping assays. α-HPVs were detected only in 1.2% of the patients and 2.9% of the controls from which HPV16 was the most prevalent type among participants. β-HPVs were detected in 43.8% of the patients and 38.6% of the controls where the lip and oral cavity (45.5%) had the highest positivity. Values for γ-HPV prevalence in patients and controls were 26.1% and 24.7%, respectively. The highest percentage of γ-HPV positivity was found in the larynx (30.4%). Concerning the β genus, HPV23 and HPV38 were the most prevalent types among the patients and controls, respectively. For the γ genus, SD2 in cases and HPV134 in controls were the most prevalent types. Overall, detection of α-HPVs (aOR, 0.40; 95% CI = 0.1 to 1.2; P = 0.11), β-HPVs (aOR, 1.9; 95% CI = 0.9 to 1.6; P = 0.29), and γ-HPVs infections (aOR, 1.04; 95% CI = 0.7 to 1.5; P = 0.83) was not associated with the HNSCC development. Our data did not suggest an HPV-related etiology for HNSCC pathogenesis. Nonetheless, this study provides novel insights into the diversity of β-, and γ-HPVs in different HNSCC anatomical subsites.IMPORTANCE Infection with human papillomavirus (HPV) is responsible for a subset of neck squamous cell carcinoma (HNSCC), but knowledge of the prevalence of and risk factors for oral HPV infection, especially cutaneous types in Iran, remains unknown. In a large retrospective study, the authors used a sensitive assay for the detection of α-, β-, and γ-HPVs in oral rinse samples of HNSCC and matched controls. They find that the α-HPV contribution to HNSCC in Iran is lower than global prevalence. High-risk α-HPVs or cutaneous β- and γ-HPVs were not associated with the HNSCC development. Besides, this study provides novel insights into the diversity of β- and γ-HPVs in different HNSCC anatomical subsites.

Abstract 88: ATAD3A enhances head and neck cancer malignancy via mitochondrial ERK1/2 signaling

Abstract Targeting mitochondria as a cancer therapeutic strategy has attracted more and more attention in the recent years. ATAD3A is identified as a nuclear-encoded mitochondrial enzyme that regulates mitochondrial dynamics, cholesterol metabolism, and signal transduction. However, its impact and underlying regulatory mechanisms in cancers remain to be determined. We report here that ATAD3A is highly expressed in head and neck squamous cell carcinoma (HNSCC), where it plays a critical role in favoring tumor progression. Loss of ATAD3A expression dramatically incudes tumor regression in orthotopic tongue tumor-bearing mice, whereas gain of ATAD3A expression produces the opposite effects. Mechanistically, ATAD3A binds to ERK1/2 at HNSCC cell mitochondria in the presence of VDAC1, and this interaction is essential for the activation of mitochondrial ERK1/2 signaling. Most importantly, the ATAD3A-ERK1/2 signaling axis enhances HNSCC development in a Ras-independent manner and, thus, tumor suppression is more effectively achieved when ATAD3A and Ras signaling pathways are co-inhibited. These novel findings highlight the importance of activation of ATAD3A-ERK1/2 axis in cancer progression and suggest that combined targeting of ATAD3A and Ras signaling could potentiate anticancer activity for HNSCC treatment. Citation Format: Liwei Lang, Reid Loveless, Zhaohui Qin, Peng Qiu, Chloe Shay, Yong Teng. ATAD3A enhances head and neck cancer malignancy via mitochondrial ERK1/2 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 88.

Bioinformatics analyses proposed xenotropic and polytropic retrovirus receptor 1 as a potential diagnostic and prognostic biomarker and immunotherapeutic target in head and neck squamous cell carcinoma

ObjectiveThe role of Xenotropic and polytropic retrovirus receptor 1 (XPR1), a cell surface receptor for certain types of murine leukemia viruses, in human cancers has been rarely studied. We aimed to evaluate the values of XPR1 as a biomarker and therapeutic target in head and neck squamous cell carcinoma (HNSCC). MethodsBioinformatics tools and online databases, including R packages, ONCOMINE, The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), UALCAN, MethSurv, cBioPortal, and TIMER2.0 were applied in this study. ResultsThe mRNA and protein expression of XPR1 is significantly up-regulated in HNSCC tissues compared with normal tissues. The receiver operating characteristic (ROC) curve shows XPR1 has high specificity and accuracy in the diagnosis of HNSCC (AUC = 0.883). Patients with high-level expression of XPR1 have poorer overall survival (OS, P = 0.002), disease-specific survival (DSS, P = 0.014), and progress-free interval (PFI, P = 0.017). UALCAN analysis indicates that the methylation of XPR1 promoter in HNSCC is significantly down-regulated. MethSurve was used to investigate the impact of individual CpG islands on the prognosis of HNSCC patients. Low DNA methylation levels of cg11538848 and cg20948051 and high DNA methylation levels of cg23675362, cg18440470, and cg22026687 are significantly related to poor prognosis. The Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicate that XPR1 is involved in various important biological functions and signaling pathways closely related to cancer. The co-expression analysis of XPR1 and N6-methyladenosine (m6A) RNA methylation regulators shows that XPR1 is significantly related to the expression of main m6A regulators. Immune infiltration analysis shows that the expression of XPR1 is related to certain types of immune infiltrating cells and has a positive correlation with the expression of four immune checkpoint genes, PDCD1LG2, CD274, HAVCR2, and SIGLEC15. ConclusionIn summary, these results indicate that XPR1 is a potential diagnostic and prognostic biomarker and immunotherapy target for HNSCC. This study sheds new light on understanding the formation and development of HNSCC and sets the basis for further studying the role of XPR1 in HNSCC and other types of cancers.