Development Of Head And Neck Squamous Cell Carcinoma Research Articles

The Role of MicroRNA in Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) include epithelial tumors arising in the structures of aerodigestive tract such as oral and nasal cavity, pharynx, larynx, paranasal sinuses, and local lymph nodes. HNSCC is the sixth most common cancer worldwide, and its prognosis is very poor. MicroRNAs (miRNAs) are small single stranded noncoding RNAs which are about 19-25 nucleotides involved in cell proliferation, development, differentiation and metastasis. It is believed that miRNA alterations correlate with initiation and progression of cancer cell proliferation or inhibition of tumorigenesis especially in development, progression, and metastasis of HNSCC. Altered expression of miRNAs could be novel molecular biomarkers for the diagnosis and prognosis of HNSCC. Despite the advances in cancer treatment, the mortality rate of HNSCC is still high. The potential application of miRNAs for cancer therapy has been demonstrated in many studies. In this review, we discuss the very recent studies on different aspects of miRNA dysregulation with their clinical significance and miRNA-based therapy.

Aberrant translation regulated by METTL1/WDR4-mediated tRNA N7-methylguanosine modification drives head and neck squamous cell carcinoma progression.

BackgroundCancer cells selectively promote the translation of oncogenic transcripts to stimulate cancer progression. Although growing evidence has revealed that tRNA modifications and related genes participate in this process, their roles in head and neck squamous cell carcinoma (HNSCC) remain largely uncharacterized. Here, we sought to investigate the function and mechanisms of the transfer RNA (tRNA) N7‐methylguanosine (m7G) modification in regulating the occurrence and development of HNSCC.MethodsCell lost‐of‐function and gain‐of‐function assays, xenograft models, conditional knockout and knockin mouse models were used to study the physiological functions of tRNA m7G modification in HNSCC tumorigenesis. tRNA modification and expression profiling, mRNA translation profiling and rescue assays were performed to uncover the underlying molecular mechanisms. Single‐cell RNA sequencing (scRNA‐seq) was conducted to explore the tumor microenvironment changes.ResultsThe tRNA m7G methyltransferase complex components Methyltransferase‐like 1 (METTL1)/WD repeat domain 4 (WDR4) were upregulated in HNSCC and associated with a poor prognosis. Functionally, METTL1/WDR4 promoted HNSCC progression and metastasis in cell‐based and transgenic mouse models. Mechanistically, ablation of METTL1 reduced the m7G levels of 16 tRNAs, inhibiting the translation of a subset of oncogenic transcripts, including genes related to the phosphatidylinositol‐3‐kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. In addition, chemical modulators of the PI3K/Akt/mTOR signaling pathway reversed the effects of Mettl1 in mouse HNSCC. Furthermore, scRNA‐seq results revealed that Mettl1 knockout in mouse tumor cells altered the immune landscape and cell‐cell interaction between the tumor and stromal compartment.ConclusionsThe tRNA m7G methyltransferase METTL1 was found to promote the development and malignancy of HNSCC through regulating global mRNA translation, including the PI3K/AKT/mTOR signaling pathway, and found to alter immune landscape. METTL1 could be a promising treatment target for HNSCC patients.

ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development

BackgroundTargeting mitochondrial oncoproteins presents a new concept in the development of effective cancer therapeutics. ATAD3A is a nuclear-encoded mitochondrial enzyme contributing to mitochondrial dynamics, cholesterol metabolism, and signal transduction. However, its impact and underlying regulatory mechanisms in cancers remain ill-defined.MethodsWe used head and neck squamous cell carcinoma (HNSCC) as a research platform and achieved gene depletion by lentiviral shRNA and CRISPR/Cas9. Molecular alterations were examined by RNA-sequencing, phospho-kinase profiling, Western blotting, RT-qPCR, immunohistochemistry, and immunoprecipitation. Cancer cell growth was assessed by MTT, colony formation, soft agar, and 3D cultures. The therapeutic efficacy in tumor development was evaluated in orthotopic tongue tumor NSG mice.ResultsATAD3A is highly expressed in HNSCC tissues and cell lines. Loss of ATAD3A expression suppresses HNSCC cell growth and elicits tumor regression in orthotopic tumor-bearing mice, whereas gain of ATAD3A expression produces the opposite effects. From a mechanistic perspective, the tumor suppression induced by the overexpression of the Walker A dead mutant of ATAD3A (K358) produces a potent dominant-negative effect due to defective ATP-binding. Moreover, ATAD3A binds to ERK1/2 in the mitochondria of HNSCC cells 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 drives HNSCC development in a RAS-independent fashion and, thus, tumor suppression is more effectively achieved when ATAD3A knockout is combined with RAS inhibitor treatment.ConclusionsThese findings highlight the novel function of ATAD3A in regulating mitochondrial ERK1/2 activation that favors HNSCC development. Combined targeting of ATAD3A and RAS signaling may potentiate anticancer activity for HNSCC therapeutics.

Investigation of miR-21-5p Key Target Genes and Pathways in Head and Neck Squamous Cell Carcinoma Based on TCGA Database and Bioinformatics Analysis.

Aim: Head and neck squamous cell carcinoma (HNSCC) is the sixth most commonly diagnosed malignancy worldwide. Overexpressed of microRNA-21-5p (miR-21-5p) has been reported to be involved in the development of HNSCC. However, the role of miR-21-5p in HNSCC is still not fully elucidated. The purpose of this study was to explore the underlying molecular mechanisms of miR-21-5p in HNSCC. Methods: RT-qPCR was used to determine the differential expression levels of miR-21-5p in tissue samples of HNSCC patients. Meta-analysis was performed based on miRNA expression data collected from the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA), and published articles to evaluate the expression of miR-21-5p in HNSCC. We investigated the biological function of miR-21-5P by gene ontology enrichment and target prediction analysis. Furthermore, RT-qPCR and IHC were conducted to verify the expression of target genes. Finally, Kaplan–Meier survival analysis was performed to assessed the prognostic value of the putative miR-21-5p target genes. Results: MiR-21-5p was significantly overexpressed in HNSCC compared to healthy tissues (P < .05) and showed potent predictive power with a summary receiver operating characteristic of 0.90. Meanwhile, the expression of miR-21-5p was significantly correlated with tumor stage, T stage and smoking in HNSCC (P < .05). A total of 71 down-regulated genes, both HNSCC-related and miR-21-p5-related, were obtained from the analytical integration. Two predicted genes (ADH7, RDH12) were down-regulated in HNSCC, and significantly negatively correlated with miR-21-5p. IHC and RT-qPCR demonstrated that the expression of ADH7 and RDH12 in HNSCC samples was significantly lower than control. And high expression of ADH7 was associated with better DFS of HNSCC patients. Conclusions: miR-21-5p may target at ADH7, RDH12 and participate in regulation of retinol metabolism, which might affect the prognosis of HNSCC. High expression of ADH7 may indicate better prognosis in HNSCC patients.

Clinical applications of liquid biopsy in HPV-negative and HPV-positive head and neck squamous cell carcinoma: advances and challenges.

Head and neck squamous cell carcinomas (HNSCCs) represent the most common epithelial tumors that arise from mucosa of the oral cavity, pharynx, and larynx. The development of HNSCCs is usually associated with tobacco use, alcohol consumption, and human papillomavirus (HPV) infection. Most HNSCCs are diagnosed in advanced states, leading to a worse clinical outcome. Screening tests based on potential biomarkers associated with HNSCCs could improve this scenario. Liquid biopsy has emerged as a promising area of cancer investigation, offering a minimally invasive approach to track circulating biomarkers in body fluids that could potentially contribute to the diagnosis, predict prognosis, and monitor response to treatment. This review will discuss translational studies describing the clinical applications of liquid biopsy in HPV-negative and HPV-positive HNSCCs focused on circulating nucleic acids [cell-free DNA (cfDNA) and cell-free RNA (cfRNA)], circulating tumor cells (CTCs), and extracellular vesicles (EVs), which can be found in plasma, serum, and saliva.

Abstract P042: Chemokine dysregulation creates the immunosuppressive tumor microenvironment and promotes human papillomavirus-associated head and neck cancer

Abstract Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is a fast-growing health problem in the United States. By analyzing the transcriptomes of HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC patient tissues, we previously revealed that expression of CXCL14, constitutively expressed in basal epithelial cells, is downregulated in HPV-positive HNSCC. In contrast, the expression of proinflammatory chemokines, particularly CXCL1, CXCL2, and CXCL8, are significantly upregulated in both HPV+ and HPV- HNSCCs. We further showed that restored expression of CXCL14 in HPV+ HNSCC cells leads to tumor-free survival in vivo by increasing MHC-I antigen presentation on the cancer cell surface and CD8+ T cell activation. Interestingly, high CXCL1, CXCL2, and CXCL8 expression levels significantly correlate to poor HNSCC patient survival, showing an exact opposite pattern of the clinical outcomes associated with the CXCL14 expression levels. To determine the roles of these chemokines in HPV+ HNSCC development, CXCL1 and CXCL2 genes (no murine CXCL8 ortholog) were deleted using a CRISPR-Cas9 knockout system in HPV+ murine HNSCC cells. Using these stably engineered HNSCC cells, we investigated tumor growth, immune cell infiltration, and metastasis in immunocompetent syngeneic mice. Interestingly, the deletion of CXCL1 and CXCL2 significantly delays in vivo tumor growth, decreases myeloid-derived suppressor cell (MDSC) infiltration in the tumor, and decreases lung metastasis. However, the numbers of natural killer (NK), CD4+, and CD8+ T cells in the tumor microenvironment were not affected by CXCL1 and CXCL2 knockout. Next, mice injected with the murine HNSCC cells were treated twice daily with AZD5068, a selective inhibitor of CXCR2, which is a common receptor of CXCL1, CXCL2, and CXCL8 expressed on myeloid cells. Our result showed that the treatment of CXCR2 suppresses in vivo tumor growth in a similar pattern with CXCL1 and CXCL2 knockout. These results suggest that the dysregulation of chemokine expression in HPV-infected cells plays an important role in regulating tumor growth, antitumor immune responses, and metastasis of HPV+ HNSCC. Our findings may provide promising strategies to develop novel immunotherapies for HPV+ HNSCC patients which can likely be extended to other non-viral cancers with immunosuppressive phenotypes. Citation Format: Daniel Vermeer, Joseph Westrich, Paul Colbert, Craig Welbon, John H. Lee, David Raben, William C. Spanos, Dohun Pyeon. Chemokine dysregulation creates the immunosuppressive tumor microenvironment and promotes human papillomavirus-associated head and neck cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P042.

Influence of standardization of human papillomavirus diagnosis in head and neck cancer treatment

The presence of human papillomavirus (HPV) in patients with head and neck squamous cell carcinoma (HNSCC) can guide medical management. The aim of this study was to highlight the importance of HPV diagnosis, verifying which diagnostic techniques are most used in identifying HPV and the differences between these techniques, in the research aimed at establishing a consensus on the gold standard method. We verify that HPV infection is associated with the development of HNSCC. The techniques most commonly used for diagnosis of HPV are immunohistochemistry (IHC), polymerase chain reaction (PCR), reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization (ISH). Our study concludes that detection of E6/E7 DNA by PCR is the most accepted method of diagnosis. The standardization of an accurate HPV diagnostic method can reduce morbidity and mortality in HNSCC, especially in emerging countries, where few screenings are performed, in addition to improving the social and economic impact of the disease.

MiR-154 Influences HNSCC Development and Progression through Regulation of the Epithelial-to-Mesenchymal Transition Process and Could Be Used as a Potential Biomarker

MicroRNAs and their role in cancer have been extensively studied for the past decade. Here, we analyzed the biological role and diagnostic potential of miR-154-5p and miR-154-3p in head and neck squamous cell carcinoma (HNSCC). miRNA expression analyses were performed using The Cancer Genome Atlas (TCGA) data accessed from cBioPortal, UALCAN, Santa Cruz University, and Gene Expression Omnibus (GEO). The expression data were correlated with clinicopathological parameters. The functional enrichment was assessed with Gene Set Enrichment Analysis (GSEA). The immunological profiles were assessed using the ESTIMATE tool and RNAseq data from TCGA. All statistical analyses were performed with GraphPad Prism and Statistica. The study showed that both miR-154-5p and miR-154-3p were downregulated in the HNSCC samples and their expression levels correlated with tumor localization, overall survival, cancer stage, tumor grade, and HPV p16 status. GSEA indicated that individuals with the increased levels of miR-154 had upregulated AKT-MTOR, CYCLIN D1, KRAS, EIF4E, RB, ATM, and EMT gene sets. Finally, the elevated miR-154 expression correlated with better immune response. This study showed that miR-154 is highly involved in HNSCC pathogenesis, invasion, and immune response. The implementation of miR-154 as a biomarker may improve the effectiveness of HNSCC treatment.

Roles of Major RNA Adenosine Modifications in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer malignancy worldwide and is known to have poor prognosis. The pathogenesis behind the development of HNSCC is not fully understood. Modifications on RNA are involved in many pathophysiological processes, such as tumor development and inflammation. Adenosine-related RNA modifications have shown to be linked to cancer and may play a role in cancer occurrence and development. To date, there are at least 170 different chemical RNA modifications that modify coding and non-coding RNAs (ncRNAs). These modifications affect RNA stability and transcription efficiency. In this review, we focus on the current understanding of the four major RNA adenosine modifications (N6-Methyladenosine, N1-Methyladenosine, Alternative Polyadenylation Modification and A-to-I RNA editing) and their potential molecular mechanisms related to HNSCC development and progression. We also touch on how these RNA modifications affect treatment of HNSCCs.

Genotype Distribution and Prevalence of Human Papillomavirus in Head and Neck Cancer Samples from Istanbul, Turkey.

Human papillomavirus (HPV)-associated tumors account for a significant proportion of head and neck squamous cell carcinomas (HNSCC) in developed countries. In recent years, there has been a rise of HPV infections associated with HNSCC, especially HPV16, which is the most commonly detected type in oral and oropharyngeal cancers. To investigate the frequency of HPV-driven HNSCC among patients living in Turkey, HPV DNA positivity and p16INK4A expression were assessed in primary tumor biopsies (n = 106). Eighteen out of one hundred and six (19%) HNSCC tumors showed p16INK4A overexpression, and 26/106 cases (24.5%) were positive for HPV DNA. Sixteen out of twenty-six samples were positive for both HPV DNA and p16INK4A staining. HPV16 could be isolated from 22/26 samples (84.6%) and was found to be the most frequently detected HPV type. This study represents the largest cohort of Turkish patients with HNSCC characterized according to HPV status and p16INK4A expression. Our data suggest that HPV16 infection, along with smoking, contribute to the development of HNSCC.

Head and Neck Cancers Are Not Alike When Tarred with the Same Brush: An Epigenetic Perspective from the Cancerization Field to Prognosis.

Simple SummarySquamous cell carcinomas affect different head and neck subsites and, although these tumors arise from the same epithelial lining and share risk factors, they differ in terms of clinical behavior and molecular carcinogenesis mechanisms. Differences between HPV-negative and HPV-positive tumors are those most frequently explored, but further data suggest that the molecular heterogeneity observed among head and neck subsites may go beyond HPV infection. In this review, we explore how alterations of DNA methylation and microRNA expression contribute to head and neck squamous cell carcinoma (HNSCC) development and progression. The association of these epigenetic alterations with risk factor exposure, early carcinogenesis steps, transformation risk, and prognosis are described. Finally, we discuss the potential application of the use of epigenetic biomarkers in HNSCC.Head and neck squamous cell carcinomas (HNSCC) are among the ten most frequent types of cancer worldwide and, despite all efforts, are still diagnosed at late stages and show poor overall survival. Furthermore, HNSCC patients often experience relapses and the development of second primary tumors, as a consequence of the field cancerization process. Therefore, a better comprehension of the molecular mechanisms involved in HNSCC development and progression may enable diagnosis anticipation and provide valuable tools for prediction of prognosis and response to therapy. However, the different biological behavior of these tumors depending on the affected anatomical site and risk factor exposure, as well as the high genetic heterogeneity observed in HNSCC are major obstacles in this pursue. In this context, epigenetic alterations have been shown to be common in HNSCC, to discriminate the tumor anatomical subsites, to be responsive to risk factor exposure, and show promising results in biomarker development. Based on this, this review brings together the current knowledge on alterations of DNA methylation and microRNA expression in HNSCC natural history, focusing on how they contribute to each step of the process and on their applicability as biomarkers of exposure, HNSCC development, progression, and response to therapy.

A Ferroptosis-Related Prognostic Signature Based on Antitumor Immunity and Tumor Protein p53 Mutation Exploration for Guiding Treatment in Patients With Head and Neck Squamous Cell Carcinoma.

Background: Due to the lack of accurate guidance of biomarkers, the treatment of head and neck squamous cell carcinoma (HNSCC) has not been ideal. Ferroptosis plays an important role in tumor suppression and treatment of patients. However, tumor protein p53 (TP53) mutation may promote tumor progression through ferroptosis. Therefore, it is particularly important to mine prognostic-related differentially expressed ferroptosis-related genes (PR-DE-FRGs) in HNSCC to construct a prognostic model for accurately guiding clinical treatment.Methods: First, the HNSCC data obtained from The Cancer Genome Atlas (TCGA) was used to identify PR-DE-FRGs for screening candidate genes to construct a prognostic model. We not only used a variety of methods to verify the accuracy of the model for predicting prognosis but also explored the role of ferroptosis in the development of HNSCC from the perspective of the immune microenvironment and mutation. Finally, we explored the correlation between the prognostic model and clinical treatment and drew a high-precision nomogram to predict the prognosis.Results: Seventeen of the 29 PR-DE-FRGs were selected to construct a prognostic model with good predictive performance. Patients in the low-risk group were found to have a greater number of CD8 + T cells, follicular helper T cells, regulatory T cells, mast cells, T-cell costimulations, and type II interferon responses. A higher tumor mutation burden (TMB) was observed in the low-risk group and was associated with a better prognosis. A higher risk score was found in the TP53 mutation group and was associated with a worse prognosis. The risk score is closely related to the expression of immune checkpoint inhibitors (ICIs)-related genes such as PD-L1 and the IC50 of six chemotherapeutic drugs. The nomogram we constructed performs well in predicting prognosis.Conclusion: Ferroptosis may participate in the progression of HNSCC through the immune microenvironment and TP53 mutation. The model we built can be used as an effective predictor of immunotherapy and chemotherapy effects and prognosis of HNSCC patients.

IL-1/IL-1R Signaling in Head and Neck Cancer.

Decades ago, the study of cancer biology was mainly focused on the tumor itself, paying little attention to the tumor microenvironment (TME). Currently, it is well recognized that the TME plays a vital role in cancer development and progression, with emerging treatment strategies focusing on different components of the TME, including tumoral cells, blood vessels, fibroblasts, senescent cells, inflammatory cells, inflammatory factors, among others. There is a well-accepted relationship between chronic inflammation and cancer development. Interleukin-1 (IL-1), a potent pro-inflammatory cytokine commonly found at tumor sites, is considered one of the most important inflammatory factors in cancer, and has been related with carcinogenesis, tumor growth and metastasis. Increasing evidence has linked development of head and neck squamous cell carcinoma (HNSCC) with chronic inflammation, and particularly, with IL-1 signaling. This review focuses on the most important members of the IL-1 family, with emphasis on how their aberrant expression can promote HNSCC development and metastasis, highlighting possible clinical applications.

Gene Model Related to m6A Predicts the Prognostic Effect of Immune Infiltration on Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive solid tumor. Because most studies have focused on the intrinsic carcinogenic pathways of tumors, we focused on the relationship between N6-methyladenosine (m6A) and the prognosis of HNSCC in the tumor immune microenvironment. We downloaded RNA-seq data from the TCGA dataset and used univariate Cox regression to screen m6A-related lncRNAs. The expression value of LASSO-screened genes was the sum of LASSO regression coefficients. We then evaluated relationships between the risk score and cellular components or cellular immune response. Differences in immune response under various algorithms were visualized with heat maps. The GSVA package in R was used to analyze GO, BP, KEGG, and hallmark gene sets of immune checkpoint clusters and immune checkpoint scores. The GSEA analysis was performed with the cluster profile package, yielding 21 m6A genes. Related lncRNAs were screened with Pearson's correlations, and the resulting 442 lncRNAs were screened using single-factor analysis. Eight lncRNAs closely related to prognosis were identified through survival random forest. Survival analysis showed that patients with a high risk score had a poor prognosis. Low- and high-risk-score groups differed significantly in m6A gene expression. Prognostic scores from different algorithms were significantly correlated with B cells, T cells, and memory cells in the immune microenvironment. Expression of immune checkpoints and signal pathways differed significantly across risk-score groups, suggesting that m6A could mediate lncRNA-induced immune system dysfunction and affect HNSCC development. A comprehensive study of tumor-cell immune characteristics should provide more insight into the complex immune microenvironment, thus contributing to the development of new immunotherapeutic agents.

FOXM1 Promotes Head and Neck Squamous Cell Carcinoma via Activation of the Linc-ROR/LMO4/AKT/PI3K Axis.

Background/AimPrevious literature has implicated the sustained expression of FOXM1 in numerous human cancers, including head and neck squamous cell carcinoma (HNSCC). The current study aimed to elucidate the function and regulatory mechanism of FOXM1 in HNSCC.MethodsWestern blot and RT-qPCR methods were performed to evaluate the expression of Linc-ROR, FOXM1, and LMO4 in HNSCC tissue samples and cells. The binding between FOXM1 and Linc-ROR was analyzed using a ChIP assay. Various cellular processes including proliferation and invasion abilities were assessed following alteration of FOXM1, Linc-ROR and LMO4 expression in HNSCC cells. Xenograft mouse models were established to validate the in vitro findings.ResultsLinc-ROR and FOXM1 were highly expressed in HNSCC tissues and cells. FOXM1 operated as a potential transcription factor to bind to the promoter region of Linc-ROR. Linc-ROR and FOXM1 exhibited high expression levels in both the clinical tissue samples as well as the HNSCC cells, which could facilitate the proliferation and invasion of HNSCC cells. Linc-ROR upregulated the expression of LMO4 and promoted activation of the AKT/PI3K signaling pathway, thus stimulating the proliferation and invasion of HNSCC cells. Silencing of Linc-ROR brought about a contrasting effect relative to that seen when FOXM1 was overexpressed in HNSCC in vivo.ConclusionsOverall, FOXM1 promoted the expression of Linc-ROR and induced the activation of the LMO4-dependent AKT/PI3K signaling pathway, thus facilitating the occurrence and development of HNSCC.

Alternatively spliced ANLN isoforms synergistically contribute to the progression of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a common cancer with high mortality. Anilin actin-binding protein (ANLN) has been reported to be associated with carcinogenesis in multiple tumors. However, the expression pattern and functional effects of ANLN in HNSCC remain to be unclear. Clinical data and online databases were used to analyze the expression of ANLN and its relationship with HNSCC patient survival. Expression of two major splice variants of ANLN was assessed in HNSCC tissues and cell lines. The functional effects and related mechanisms of ANLN isoforms were investigated in HNSCC in vitro and in vivo. Our study showed that patients with high expression of ANLN had a poor prognosis. The two primary isoforms of ANLN transcripts ANLN-201 and ANLN-210 were highly expressed in HNSCC tissues and cell lines. Knockout of ANLN restrained cell proliferation, migration, and invasion of SCC-9 cells. Mechanically, ANLN-201 could interact with c-Myc to keep its protein stability, thereby playing a oncogenic role in HNSCC. ANLN-210 could be transferred to macrophages via exosomes by binding to RNA-binding protein hnRNPC. Exosomal ANLN-210 promoted macrophage polarization via PTEN/PI3K/Akt signaling pathway, thus stimulating tumor growth of HNSCC. ANLN was an independent prognostic factor in patients with HNSCC. Alternatively spliced ANLN isoforms collaboratively promote HNSCC tumorigenesis in vitro and in vivo, which might provide the in-depth role and mechanism of ANLN in HNSCC development.

HOXB7 acts as an oncogenic biomarker in head and neck squamous cell carcinoma

BackgroundThe homeobox gene Homeobox B7 (HOXB7) is overexpressed across a range of cancers and promotes tumorigenesis through varying effects on proliferation, survival, migration and invasion. However, its expression pattern and oncogenic role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Here, we aimed to explore the expression pattern of HOXB7, its clinical significance as well as functional roles in HNSCC.MethodsHOXB7 mRNA expression in HNSCC was determined by data mining and analyses from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) datasets. The protein abundance of HOXB7 was measured by immunohistochemistry in 119 primary HNSCC samples and associations between its expression and clinicopathological parameters and patient survival were evaluated. The pro-tumorigenic roles of HOXB7 in HNSCC were further delineated in vitro by loss-of-function assay. And a xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth. Connectivity Map (CMap) analysis was performed to identify bioactive small molecules which might be potential inhibitors for HOXB7.ResultsBioinformatics analyses showed that HOXB7 mRNA was significantly overexpressed in 8 independent HNSCC datasets from TCGA and GEO databases. HOXB7 protein was markedly upregulated in HNSCC samples as compared to normal counterparts and its overexpression significantly associated with high pathological grade, advanced clinical stage, cervical node metastasis (P = 0.0195, 0.0152, 0.0300) and reduced overall and disease-free survival (P = 0.0014, 0.0007). Univariate and multivariate Cox regression analyses further revealed HOXB7 as an independent prognostic factor for patients’ overall survival. Moreover, HOXB7 knockdown significantly inhibited cell proliferation, migration and invasion and induced cell apoptosis in HNSCC cells, and resulted in compromised tumour growth in vivo. Furthermore, CMap (Connectivity map) analysis has identified three potential bioactive small molecule inhibitors (NU-1025, thiamine, vinburnine) for HOXB7 targeted therapy in HNSCC.ConclusionsOur findings revealed that overexpression of HOXB7 was associates with tumour aggressiveness and unfavourable prognosis by serving a novel prognostic biomarker in HNSCC. Moreover, HOXB7 might be involved in the development and progression of HNSCC as an oncogene, and thereby might be a potential therapeutic target for HNSCC.

The Role and Mechanism of MALAT1 Long Non-Coding RNA in the Diagnosis and Treatment of Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor of the head and neck. HNSCC mainly affects the oral cavity and the laryngeal, laryngopharyngeal, and oropharyngeal tracts. The high incidence, hidden onset, low survival rate, and unsatisfactory effects of treatment effect underscore the importance of identify the mechanisms of HNSCC occurrence and development. Although there is a very urgent need for early diagnosis and treatment, there are currently no reliable early HNSCC diagnosis biomarkers or effective treatment targets. Long non-coding RNA (lncRNA) is widely involved in biological processes, especially as a key regulator of tumorigenesis and development. Lung adenocarcinoma metastasis-associated transcript 1 (MALAT1) is an important member of the lncRNA family that can regulate the occurrence and development of a variety of malignant tumors and is anticipated to be an ideal marker for early tumor diagnosis and an effective therapeutic target. Here, we review the research progress into the role of MALAT1 in the diagnosis and treatment of HNSCC and its regulatory mechanism.

High SQLE Expression and Gene Amplification Correlates with Poor Prognosis in Head and Neck Squamous Cell Carcinoma.

ObjectiveSqualene epoxidase (SQLE) is considered a metabolic oncogene, but its biological function and prognostic value in head and neck squamous cell carcinoma (HNSCC) remain unclear. We aimed to evaluate the role of SQLE in the occurrence and development of HNSCC through bioinformatics analysis, and validation experiments.MethodsTranscriptomic, genomic, and clinical data from The Cancer Genome Atlas were used for pan-cancer analysis. SQLE expression in HNSCC was evaluated using Gene Expression Omnibus datasets and immunohistochemistry. The biological significance of SQLE in the tumor microenvironment (TME) of HNSCC was determined using TISCH, HuRI, LinkedOmics, and TIMER 2.0. The prognostic value of SQLE in HNSCC was analyzed using univariate Cox regression and Kaplan–Meier survival curves. Effect of SQLE on the Cal27 HNSCC cell line was evaluated using cell counting kit 8, wound healing, and EdU assays.ResultsSQLE was overexpressed and amplified in various cancers, including HNSCC. High SQLE expression promoted cell proliferation, associated with T stage in HNSCC patients. Copy number amplification and DNA demethylation contributed to high SQLE expression in HNSCC, which was associated with poor prognosis. SQLE was related to HNSCC TME, and its mRNA expression/copy number alterations were negatively correlated with the infiltration of CD8+ T cells, follicular helper T cells, and regulatory T cell infiltration and mast cell activation and positively correlated with the infiltration of M0 macrophages and resting mast cells in HNSCC.ConclusionSQLE was identified as a prognostic biomarker and a potential pharmaceutical target for HNSCC.

Clinicopathological Significance of FOXO4 Expression and Correlation with Prx1 in Head and Neck Squamous Cell Carcinoma.

Objective Forkhead box O 4 (FOXO4), a key albumen in the forkhead box O (FOXOs) family, plays crucial roles as a tumor suppressor in the cancer development. In our previous study, Peroxiredoxin1 (Prx1) promoted the development of oral cancer and was predicted to bind to FOXO4. The aim of this study was to investigate the clinicopathological significance of FOXO4 expression and its potential mechanism in head and neck squamous cell carcinomas (HNSCC). Methods The function of FOXO4 correlation with HNSCC prognosis was analyzed via ONCOMINE, UALCAN, Human Protein Atlas, and cBioPortal. The expression of FOXO4 was detected in Prx1 silenced CaL27 and SCC9 cell lines by Western blot. FOXO4 protein expression was observed via immunohistochemistry (IHC) and the binding of Prx1 to FOXO4 measured by Duolink analysis in a 4-nitro-quinoline-1-oxide- (4NQO-) induced tongue carcinogenesis model in Prx1+/+ and Prx1+/− mice. Results By the analysis of Bioinformation Databases, there was a significant interaction of FOXO4 down expression to clinical tumor stages and pathological grades in the patients with HNSCC. Reduced mRNA and protein expression of FOXO4 were found to be significantly correlated with the poor overall survival (OS) of HNSCC patients. FOXO4 expression is negatively related to Prx1 significantly in HNSCC tissues. By employing a 4NQO-induced oral carcinogenesis mouse model, we confirmed that FOXO4 expression was reduced in 4NQO-induced squamous cell carcinoma (SCC) tongue tissues compared with those in normal tissues. Prx1 knockdown resulted in the upregulation of FOXO4 expression in the SCC tissues and CaL27 and SCC9 cell lines. Furthermore, the interaction of Prx1 with FOXO4 was observed in mouse tongue tissues by Duolink analysis. Conclusion FOXO4 plays an important role in the development of HNSCC. The lower expression of FOXO4 is significantly correlated with the shorter OS in patients with HNSCC. FOXO4 is negatively regulated via interaction with Prx1. FOXO4 could be a potential molecular target for the treatment and prognosis of HNSCC.