Head And Neck Squamous Cell Carcinoma Progression Research Articles

FAT1 knockdown enhances the CSC properties of HNSCC through p-CaMKII-mediated inactivation of the IFN pathway.

FAT atypical cadherin 1 (FAT1), which encodes an atypical cadherin-coding protein, has a high mutation rate and is commonly regarded as a tumor suppressor gene in head and neck squamous cell carcinoma (HNSCC). Nonetheless, the potential regulatory mechanisms by which FAT1 influences the progression of HNSCC remain unresolved. In this context, we reported that FAT1 was downregulated in tumor tissues/cells compared with normal tissues/cells and that it was correlated with the clinicopathological features and prognosis of HNSCC. Knockdown of FAT1 enhanced cancer stem cell (CSC) properties and decreased the percentage of apoptotic tumor cells. Mechanistically, FAT1 knockdown increased the phosphorylation levels of Ca2+/calmodulin-dependent protein kinase II (CaMKII), subsequently resulting in diminished interaction between phosphorylated STAT1 and interferon regulatory factor 9 (IRF9), which inactivated the interferon pathway and facilitated the adoption of the malignant phenotype of HNSCC cells. The overexpression of STAT1 and IRF9 alleviated the malignant behavior caused by FAT1 inhibition. In summary, our study reveals the role of FAT1 in suppressing the CSC properties of HNSCC via the CaMKII/STAT1/IRF9 pathway, and that targeting FAT1 might be a promising treatment for HNSCC.

MiR-15a-5p Knockdown up-Regulated ABCB1 Expression and Abated HNSCC Progression via the NF-κB Signaling Pathway

Background The high invasion and heterogeneity of head and neck squamous cell carcinoma (HNSCC) commonly leads to poor clinical outcomes. Identification of reliable biomarkers for HNSCC is imperative. Methods The targeted gene with the highest mutation was screened out in cBioPortal database, and the interactive microRNAs (miRNAs) were identified by miRNA-mRNA co-expression analysis. CCK-8 and transwell assays were used to explore the proliferative, migrative, and invasive behaviors of HNSCC cells. The dual-luciferase reporter assay and cell transfection experiment were conducted. The role of miR-15a-5p was investigated in the in vivo xenograft mouse model. Results ATP binding cassette transporter 1 (ABCB1) had the highest mutation frequency and multiple mutation types in HNSCC, and the decreased ABCB1 was significantly related to better prognosis of HNSCC patients. MiR-15a-5p was a regulator for ABCB1, which was up-regulated after miR-15a-5p inhibition in vitro. Furthermore, the miR-15a-5p knockdown significantly suppressed HNSCC cell proliferation, migration, and invasion in vitro, and reduced the HNSCC tumor growth and migration capabilities in vivo, possibly through NF-κB signaling pathway. Conclusion Collectively, miR-15a-5p knockdown increased the ABCB1 level and abated the HNSCC progression via the NF-κB signaling pathway. ABCB1 and miR-15a-5p were underlying predictors for HNSCC therapeutic biomarkers.

ETS1 Promotes Aerobic Glycolysis and Growth in Head and Neck Squamous Cell Carcinoma by Targeting RRAS2.

Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy with a five-year survival rate below 50%, highlighting the urgent need for novel therapeutic targets. This study explores the role of the small GTPase RRAS2 in HNSCC progression and its regulation of glycolysis. Analysis of data from the TCGA and GTEx databases revealed that RRAS2 is significantly upregulated in HNSCC tissues and is associated with poorer overall patient survival. Functional experiments demonstrated that silencing RRAS2 in HNSCC cell lines inhibits glycolytic activity and cell proliferation while promoting apoptosis, whereas overexpression of RRAS2 enhances glycolysis and cell growth. Additionally, bioinformatics and experimental approaches identified the transcription factor ETS1 as an upstream regulator of RRAS2. ETS1 binds to the RRAS2 promoter, facilitating its transcription and contributing to metabolic reprogramming in HNSCC cells. Rescue experiments confirmed that the ETS1-RRAS2 axis is crucial for maintaining the glycolytic phenotype and proliferative capacity of HNSCC cells. These findings suggest that the ETS1-RRAS2 pathway plays a critical role in HNSCC progression and metabolic adaptation, positioning RRAS2 as a potential therapeutic target for improving patient outcomes.

CircRNA_036186 mediates HNSCC progression by regulating 14-3-3ζ.

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal malignancy, accounting for 95% of head and neck cancers. Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activating protein ZETA (14-3-3ζ) is central to various signalling pathways and is pivotal in tumour progression. Cancerous and corresponding non-cancerous tissue samples were collected from five patients diagnosed with HNSCC. circRNA and mRNA expression profiles were analyzed using high-throughput sequencing techniques. Potential circRNA-microRNA (miRNA)-mRNA interactions were predicted using bioinformatics tools. The study found that CircRNA_036186 regulates the expression of 14-3-3ζ in HNSCC through miR-193b-5p. These findings suggest that CircRNA_036186 has the potential to be a biomarker and therapeutic target for HNSCC and provide some theoretical basis for further research on the role of circRNA in HNSCC.

Single-nucleus CUT&RUN elucidates the function of intrinsic and genomics-driven epigenetic heterogeneity in head and neck cancer progression.

Interrogating regulatory epigenetic alterations during tumor progression at the resolution of single cells has remained an understudied area of research. Here we developed a highly sensitive single-nucleus CUT&RUN (snCUT&RUN) assay to profile histone modifications in isogenic primary, metastatic, and cisplatin-resistant head and neck squamous cell carcinoma (HNSCC) patient-derived tumor cell lines. We find that the epigenome can be involved in diverse modes to contribute toward HNSCC progression. First, we demonstrate that gene expression changes during HNSCC progression can be comodulated by alterations in both copy number and chromatin activity, driving epigenetic rewiring of cell states. Furthermore, intratumor epigenetic heterogeneity (ITeH) may predispose subclonal populations within the primary tumor to adapt to selective pressures and foster the acquisition of malignant characteristics. In conclusion, snCUT&RUN serves as a valuable addition to the existing toolkit of single-cell epigenomic assays and can be used to dissect the functionality of the epigenome during cancer progression.

Massive parallel sequencing of head and neck conventional squamous cell carcinomas: A comprehensive review.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is a cause of significant mortality and morbidity. The epidemiology of this cancer varies worldwide due to either genetic differences in populations or differences in carcinogen exposure. The application of massive parallel sequencing-based techniques in HNSCC should provide a helpful understanding of the genetic alterations that eventually lead to HNSCC development and progression, and ideally, could be used for personalized therapy. In this review, the reader will find an overview of the mutational profile of conventional HNSCC according to published results on massive parallel sequencing data that confirm the pivotal role of TP53 and the frequent involvement of CDKN2A and PIK3CA. The reader will also find a more detailed description of the genes, such as NOTCH1 and FBXW7, that were not identified in HNSCCs before the development of these techniques, the differences that can be site-specific, such as the different mutational signatures that indicate specific carcinogens for various subsites of the head and neck, and finally, the actionability of these findings that should allow more personalized therapy for patients.

ULBP2 promotes progression of head and neck squamous cell carcinoma by modulating MAPK signaling pathway.

UL16-binding protein 2 (ULBP2) is significantly overexpressed in diverse cancers, it may also serve as a potential prognostic factor. Nonetheless, the mechanism of action and functions associated with ULBP2 in head and neck squamous cell carcinoma(HNSCC) are unexplored. This study aims to clarify the role and mechanism of ULBP2 in HNSCC and determine whether this molecule promotes tumor progression through modulation multiple downstream MAPK signaling. The Cancer Genome Atlas (TCGA) database was used to find out the mRNA transcript levels of ULBP2 in people with HNSCC. Here, the impact of ULBP2 on proliferation, migration and invasion abilities was evaluated in HNSCC cell lines using multi-methods. To understand the effect of ULBP2 on tumor-related signaling pathways, Genomic Enrichment Analysis (GSEA) was performed. We did an in vivo cancer study to learn more about the part ULBP2 plays in the growth of tumors. Moreover, Western blot was used to determine the signaling pathways influenced by ULBP2. ULBP2 is highly expressed in HNSCC cells. In addition, we saw that HNSCC patients who had high levels of ULBP2 had a poor prognosis. Silencing ULBP2 expression reduces invasive and metastatic abilities of HNSCC cells Mechanistic experiments showed the function of ULBP2 in vitro and in vivo tumorigenic assays potentially associated with MAPK pathway. We validated that ULBP2 promotes HNSCC cell progression by regulating the MAPK pathway. These findings are crucial for understanding the process of HNSCC pathogenesis and progression caused by ULBP2.

Transcriptome Analysis of HNSCC by Aggregatibacter actinomycetemcomitans Extracellular Vesicles.

The role of extracellular vesicles (EVs), also known as outer membrane vesicles (OMVs), secreted by oral bacteria in the progression of head and neck squamous cell carcinomas (HNSCCs), is largely unexplored. This study aimed to investigate the influence of bacterial EVs, specifically those derived from Aggregatibacter actinomycetemcomitans (Aa), on the progression of HNSCC. FaDu and UMSCC1 cell lines were treated with Aa-derived EVs, and oncogenic activities were assessed. Comprehensive cellular and RNA-sequencing transcriptome analyses were conducted to assess the impact of these EVs on cell cycle progression and gene expression. Our findings reveal that Aa-derived EVs accelerate cell cycle progression through the S and G2 phases and enhance invasion in HNSCC cell lines. RNA-sequencing analysis showed that Aa-derived EVs exert a more significant effect on general transcript expression than on microRNA profiles, except for miR-146a, which is recognized as a key factor in both carcinogenesis and immune modulation. Bacterial EVs, particularly from periodontal pathogens like Aa, are significant modulators within the oral cancer environment, potentially affecting cellular behavior and gene expression profiles. This study highlights the complex relationship between periodontal health and oral carcinogenesis, emphasizing the significant role of bacterial EVs in HNSCC progression.

Survival prediction in patients with head and neck squamous cell carcinoma and novel mechanistic insights of S100A8/A9

BackgroundS100A8/A9, an innate immune protein, significantly regulates inflammatory processes and immune responses. While S100A8/A9 has been linked to various diseases, its association with head and neck squamous cell carcinoma (HNSCC) remains unclear. MethodsSamples from the Cancer Genome Atlas (TCGA) were categorized into groups with low and high expression of S100A8/A9. R software, Sangerbox, UALCAN, GEPIA2, STRING, Cytoscape, TCGC Data Portal, miRcode, OncomiR and ENCORI databases were used to comprehensively study the expression, interactome and mutational profiles of S100A8/A9 and associated mechanism in HNSCC. ResultsThe proteins S100A8/A9 were found to be associated with processes of ‘epithelium development’, ‘regulating pluripotency of stem cells’ and ‘regulation of immune system’. The most frequent mutation observed in the S100A8 protein was E93K (3/37, MU4401889), while for the S100A9 protein, it was R10C (4/37, MU4633862). Furthermore, the group expressing high levels of S100A8/A9 showed increased infiltration by dendritic cells and neutrophils, but decreased infiltration by M2 macrophages, compared to the group with low S100A8/A9 expression. S100A8/A9 was also found to interact with a variety of mRNA transcripts, several of which were involved in initiation and progression of HNSCC. Through LASSO-Cox method, 20 genes (CALML5, MSX1, FZD3, STC2, SLC2A3, TMEM198B, DYNC1I1, SPHK2, ALMS1.IT1, SPPL2B, PDGFA, BCORL1, TEX101, SGCE, DNAJC12, RRN3P1, HOXB9, TMEM150C, METTL7B and PSPN) were screening to construct a prognostic model to distinguish favorable and poor prognosis of HNSCC patients. Besides, our prognostic model was also validated in GSE41613 cohort. ConclusionsS100A8/A9 may be a promising marker for the diagnostic and prognostic assessment of the HNSCC patients. Based on these insights, we have devised a new classification model for HNSCC, which has the potential to enhance the management and personalized treatment of HNSCC patients. The model should also be further optimized through the expansion of sample size and implemented experimental studies in future research.

Tumor suppressor ACER1 correlates with prognosis and Immune Infiltration in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is notorious for poor prognoses, and effective biomarkers are urgently needed for early diagnosis of HNSCC patients. We investigate the role of alkaline ceramidase 1 (ACER1) and its relationship with immune infiltration in HNSCC. The differential expression and clinical prognostic significance of ACER1 in HNSCC patients are explored using bioinformatics methods and verified in human HNSCC samples. Genetic mutation, DNA methylation and drug sensitivity linked with ACER1 are examined. The potential biological function of ACER1 co-expression genes is assessed, and a series of functional assays are performed on ACER1in vitro. The results comprehensively reveal a relationship between ACER1 and immune infiltration in HNSCC patients. ACER1 expression is significantly downregulated in HNSCC tissues and closely correlated with better prognoses for HNSCC patients, and this prognostic significance is determined by distinct clinical characteristics. Genetic alteration and promoter hypomethylation of ACER1 are involved in progression of HNSCC, and ACER1 expression is significantly related to several drug sensitivities. Functional analysis shows that ACER1 co-expression genes are mainly enriched in the sphingolipid signaling pathway associated with inhibition of tumorigenesis, leading to better prognoses for HNSCC patients. In vitro, ACER1 overexpression inhibits proliferation and migration, induces apoptosis, and promotes adhesion of Fadu and SCC9 cells. In addition, high ACER1 expression is closely linked with infiltration levels of immune cells, and strongly associated with biomarkers of immune cells in HNSCC, suggesting the important role of ACER1 in regulating tumor immunity in HNSCC patients. In summary, ACER1 may be a useful indicator for diagnosis and prognosis, and may regulate immune infiltration in HNSCC patients, thus promising targeted immunotherapy for HNSCC.

Hypoxia combined with radiation reverses migration and invasion of head and neck squamous cell carcinoma by remodeling extracellular vesicle‐mediated transfer of miR‐23b‐5p from cancer‐associated fibroblasts

AbstractBackgroundCancer‐associated fibroblasts (CAFs), the main matrix components in the tumor microenvironment (TME), play a crucial role in tumor progression. Extracellular vesicles (EVs) as main mediators in intercellular communication can be regulated by hypoxia or radiation.MethodsCAFs were extracted from head and neck squamous cell carcinoma (HNSCC) tissues and CAF‐derived EVs were collected by ultracentrifugation. Bioinformatics analysis determined the role of poly (U)‐specific endonuclease (ENDOU) on HNSCC progression and confirmed that ENDOU inhibited HNSCC progression by overexpressing ENDOU in HNSCC. Dual‐luciferase activity report assay confirmed that miR‐23b‐5p was involved in the regulation of ENDOU expression. The migration and invasion of HNSCC cells were verified by transwell assay. Furthermore, tumor‐bearing mouse models were used to demonstrate the potential of EVs loaded with miR‐23b‐5p in HNSCC to promote tumor progression.ResultsOur results showed that ENDOU was downregulated in HNSCC and inhibited HNSCC migration and invasion. Hypoxia and radiotherapy reversed CAF‐derived EVs to promote migration and invasion of HNSCC. Mechanically, hypoxia and radiation downregulated miR‐23b‐5p in CAF‐derived EVs and then restored ENDOU expression in HNSCC. Finally, CAF‐derived EVs carrying miR‐23b‐5p promoted the progression of HNSCC cells in vivo by regulating ENDOU expression.ConclusionThis study demonstrated that hypoxia combined with radiation reverses the promoting effect of CAFs on HNSCC migration and invasion by reducing the delivery of miR‐23b‐5p by CAF‐derived EVs to decrease the inhibitory effect of ENDOU expression in HNSCC. The results provide a new perspective for better understanding the role of stromal components in TME in tumor regulation. Furthermore, the results provide a strong basis for the possibility of ENDOU as a biomarker for HNSCC.

NSUN2 Promotes Head and Neck Squamous Cell Carcinoma Progression by Targeting EMT-Related Gene LAMC2 in an m5C-YBX1-Dependent Manner.

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and aggressive cancer with high rates of metastasis and poor prognosis. Recent research highlights the role of 5-methylcytosine (m5C) in cancer progression. NSUN2, an m5C methyltransferase, has been implicated in various cancers, but its role in HNSCC remains elusive. NSUN2 expression and its impact on HNSCC were analyzed by using clinical samples and bioinformatic analysis. m5C-Bis-Seq was used to assess changes in mRNA m5C modification and identify downstream targets. Both in vitro and vivo studies were performed to evaluate the impact of NSUN2 manipulation on tumor growth and metastasis. Results indicated that NSUN2 was significantly upregulated in HNSCC tissues compared to normal tissues and was associated with poor prognosis. NSUN2 knockdown led to decreased cell proliferation, migration, and invasion in vitro and reduced tumorigenicity and lymph node metastasis in vivo. m5C-Bis-Seq revealed altered m5C-modification patterns upon NSUN2 knockdown, with LAMC2 identified as a key downstream target. NSUN2-mediated m5C-modification enhanced LAMC2 stability, promoting epithelial-mesenchymal transition (EMT) signaling pathways. These findings demonstrate that NSUN2 promotes the initiation and progression of HNSCC by stabilizing the LAMC2 transcript through m5C-dependent mechanisms, offering a promising epitranscriptomic-targeted therapeutic approach for HNSCC.

Small Nucleolar RNAs in Head and Neck Squamous Cell Carcinomas

Small nucleolar RNAs (snoRNAs), a distinct class of noncoding RNAs, encompass highly diverse structures and have a range of 60 to 300 nucleotides in length. About 90% of human snoRNAs are intronic and embedded within introns of their host gene transcripts. Most snoRNAs enriched in specific tissue correlate in abundance with their parental host genes. Advancements in high-throughput sequencing have facilitated the discovery of dysregulated snoRNA expression in numerous human malignancies including head and neck squamous cell carcinoma (HNSCC). Hundreds of differentially expressed snoRNAs have been identified in HNSCC tissues. Among 1,524 snoRNA genes in a 567 HNSCC cohort, 113 snoRNAs were found to be survival related. As for snoRNA’s roles in HNSCC, based on the available evidence, dysregulated snoRNAs are closely associated with the carcinogenesis and development of HNSCC. Upregulated snoRNAs have been shown to augment the expression of other oncogenes or activate the Wnt/β-catenin signaling pathway, thereby promoting tumor cell viability, glycolysis, migration, and the epithelial-mesenchymal transition while inhibiting apoptosis in vitro. In vivo animal studies have further elucidated the functional roles of snoRNAs. Knockdown of host genes of these snoRNAs suppressed the Wnt/β-catenin signaling pathway and restrained tumor proliferation and aggressiveness in mice. The putative mechanisms underlying these observations are associated with the biological functions of snoRNAs, primarily involving microRNA-like functions through the generation of microRNA-like fragments and regulation of alternative splicing to yield diverse transcripts. While most of the snoRNAs are upregulated in HNSCC, 4 downregulated snoRNAs have been identified and annotated. SNORA36B (implicated in the regulation of DNA templates) and U3 (chr17, influencing cell proliferation) may serve as protective factors associated with prolonged overall survival. This review describes the viable structures of snoRNAs, endeavors to refine snoRNA sequencing technology, and summarizes snoRNAs’ expression profile as well as their role in HNSCC progression for potential diagnostic and therapeutic strategies for HNSCC management.

SCG2 Mediates HNSCC Progression With CCL2/TGFβ1high M2 Macrophage Infiltration.

This study aims to unravel the mechanisms underlying M2 macrophage polarization in head and neck squamous cell carcinoma (HNSCC), and identify potential therapeutic targets. We conducted an integrated bioinformatic analysis using HNSCC bulk transcriptomes from TCGA and GEO databases to pinpoint critical factors influencing M2 macrophage polarization and tumor prognosis. The significance of these genes was validated in function analysis, single-cell transcriptome datasets, and invitro experiments. Their mechanisms in modulating M2 macrophage polarization were further explored by gene knockdown, cell coculture, and other assays for quantification. We identified a novel prognostic signature of five genes associated with M2 macrophage infiltration, in which SCG2 emerged as a pivotal factor in M2 macrophage polarization in HNSCC. High expression of SCG2 in tumor patients correlated with poorer prognoses, and knocking down SCG2 reduced the proliferation and migration of HNSCC cells, disrupting M2 macrophage polarization. Furthermore, interference of SCG2 resulted in a significant decrease in the secretion of pro-tumor cytokines such as CCL2 and TGFβ1. Our findings provide deeper insights into the pathogenesis of HNSCC and offer promising therapeutic targets for HNSCC, especially SCG2, to inhibit M2 macrophage polarization and modulate cytokine secretion.

Inhibition of PNCK inflames tumor microenvironment and sensitizes head and neck squamous cell carcinoma to immune checkpoint inhibitors

BackgroundThe landscape of the tumor microenvironment (TME) is intricately linked to the development of head and neck squamous cell carcinoma (HNSCC) and significantly influences immunotherapy efficacy. Recent research has underscored...

Integrative analysis of FADS3 as a marker for prognosis and immunity in head and neck squamous cell carcinoma

BackgroundLong-chain polyunsaturated fatty acid formation requires fatty acid desaturase (FADS), which is strongly linked to cancer progression. Nevertheless, it's unclear how FADS3 functions in head and neck squamous cell carcinoma (HNSCC). MethodsHNSCC cases were retrieved from TCGA and GEO databases, and FADS members with transcriptionally differential expression were identified. Clinical survival, tumor microenvironment (TME), and potential pathogenic mechanism in HNSCC were also investigated. These results were validated using tissue staining, flow cytometry and functional studies in HNSCC cell lines. ResultsWhen comparing HNSCC to normal epithelial tissues, FADS3 expression was much higher in the former. FADS3 upregulation was correlated with poor clinical outcomes. FADS3 was an independent prognostic factor for poor overall survival in HNSCC patients. KEGG, GO, and GSEA revealed that FADS3 expression correlated with several immune-related pathways and the epithelial-mesenchymal transition (EMT). Knocking down FADS3 restrained HNSCC cell proliferation, migration, invasion, and EMT. Single-cell dataset analysis showed an association between FADS3 and TME features. Further investigation revealed that FADS3high tumor was accompanied with less CD8+ T cells in situ tissue and peripheral blood. FADS3 was positively correlated with immune-related molecules and could predict the adverse efficacy of immunotherapy. Finally, we constructed a CYTOR/hsa-let-7c-5p axis regulating FADS3 expression in HNSCC progression. ConclusionsFADS3 may represent a target for treatment in HNSCC, which is linked to prognosis, EMT, immune infiltration, and ceRNA regulatory network of HNSCC.

NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma

The activation of nuclear factor erythroid 2–related factor 2 (NRF2) has been observed in various cancers. Yet its exact contribution to the development of head and neck squamous cell carcinoma (HNSCC) remains undetermined. We previously found that NRF2 signaling is critical for the differentiation of squamous basal progenitor cells, while disruption of NRF2 causes basal cell hyperplasia. In this study, we revealed a correlation between elevated NRF2 activity and poor outcomes in HNSCC patients. We demonstrated that NRF2 facilitates tumor proliferation, migration, and invasion, as evidenced by both in vitro and in vivo studies. Significantly, NRF2 augments the expression of the antioxidant enzyme GPX2, thereby enhancing the proliferative, migratory, and invasive properties of HNSCC cells. Activation of GPX2 is critical for sustaining cancer stem cells (CSCs) by up-regulating NOTCH3, a key driver of cancer progression. These results elucidate that NRF2 regulates HNSCC progression through the NRF2-GPX2-NOTCH3 axis. Our findings proposed that pharmacological targeting of the NRF2-GPX2-NOTCH3 axis could be a potential therapeutic approach against HNSCC.

The Role of Single Nucleotide Polymorphisms in MicroRNA Genes in Head and Neck Squamous Cell Carcinomas: Susceptibility and Prognosis.

Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent cancers worldwide. The identification of molecular alterations adding to the individual risk of HNSCC development and progression is one of the most important challenges in studies on cancer genetics. MicroRNAs (miRNAs), which belong to the group of important post-transcriptional regulators of human gene expression, seem to be valuable options for consideration as key modifiers of individual cancer risk, and therefore may be helpful in predicting inter-individual differences in cancer risk, response to treatment and prognosis. There have not been many studies focused on the relationship between miRNA variants and HNSCC published in PubMed within the last 15 years. We found and analyzed 30 reviews, meta-analyses and research papers and revealed 14 SNPs which have been reported as significant in the context of HNSCC susceptibility and/or prognosis. These 14 SNPs were located in 13 separate miRNAs. Among them, four were the most frequently studied (miRNA-146, -196, -149 and -499) and have been shown to have the greatest impact on the course of HNSCC. However, the presented results have been conflicting. It must be concluded that, despite the years of studies, there are no conclusive reports demonstrating a significant role of SNPs in miRNAs in the context of the susceptibility to HNSCC or its prognosis.

Epithelial‑derived head and neck squamous tumourigenesis (Review).

Head and neck squamous cell carcinomas (HNSCCs), a heterogeneous group of cancers that arise from the mucosal epithelia cells in the head and neck areas, present great challenges in diagnosis, treatment and prognosis due to their complex aetiology and various clinical manifestations. Several factors, including smoking, alcohol consumption, oncogenic genes, growth factors, Epstein‑Barr virus and human papillomavirus infections can contribute to HNSCC development. The unpredictable tumour microenvironment adds to the complexity of managing HNSCC. Despite significant advances in therapies, the prediction of outcome after treatment for patients with HNSCC remains poor, and the 5‑year overall survival rate is low due to late diagnosis. Early detection greatly increases the chances of successful treatment. The present review aimed to bring together the latest findings related to the molecular mechanisms of HNSCC carcinogenesis and progression. Comprehensive genomic, transcriptomic, metabolomic, microbiome and proteomic analyses allow researchers to identify important biological markers such as genetic alterations, gene expression signatures and protein markers that drive HNSCC tumours. These biomarkers associated with the stages of initiation, progression and metastasis of cancer are useful in the management of patients with cancer in order to improve their life expectancy and quality of life.

Clinical implications of activation of the LIMD1-VHL-HIF1α pathway during head-&-neck squamous cell carcinoma development.

Background & objectives Given the importance of the role of hypoxia induced pathway in different cancers including head-and-neck squamous cell carcinoma (HNSCC), this study delved into elucidating the molecular mechanism of hypoxia-inducible factor-1α (HIF1α) activation in HNSCC. Additionally, it analyzes the alterations of its regulatory genes [von Hippel-Lindau (VHL) and LIM domain containing 1 (LIMD1)] and target gene vascular endothelial growth factor (VEGF) in head-and-neck lesions at different clinical stages in relation with human papillomavirus (HPV) infection. Methods Global mRNA expression profiles of HIF1α, VHL, LIMD1 and VEGF were evaluated from public datasets of HNSCC, followed by validation of their expression (mRNA/protein) in an independent set of HPV+ve/-ve HNSCC samples of different clinical stages. Results A diverse expression pattern of the HIF1α pathway genes was observed, irrespective of HPV infection, in the datasets. In validation in an independent set of HNSCC samples, high mRNA expressions of HIF1α/VEGF were observed particularly in HPV positive samples. However, VHL/LIMD1 mRNA expression was low in tumours regardless of HPV infection status. In immunohistochemical analysis, high/medium (H/M) expression of HIF1α/VEGF was observed in basal/parabasal layers of normal epithelium, with significantly higher expression in tumours, especially in HPV-positive samples. Conversely, high cytoplasmic VHL expression in these layers gradually decreased with the progression of HNSCC, regardless of HPV infection. A similar trend was noted in LIMD1 expression (nuclear/cytoplasmic) during the disease development. The methylation pattern of VHL and LIMD1 promoters in the basal/parabasal layers of normal epithelium correlated with their expression, exhibiting a gradual increase with the progression of HNSCC. The H/M expression of HIF1α/VEGF proteins and reduced VHL expression was associated with poor clinical outcomes. Interpretation & conclusions The results of this study showed differential regulation of the LIMD1-VHL-HIF1α pathway in HPV positive and negative HNSCC samples, illustrating the molecular distinctiveness of these two groups.