Identification of Three Autophagy-Related Long Non-Coding RNAs as a Novel Head and Neck Squamous Cell Carcinoma Prognostic Signature

Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis. Considerable evidence indicates that autophagy and non-coding RNA play essential roles in the biological processes involved in cancers, but associations between autophagy-related long non-coding RNAs (lncRNAs) and HNSCC remain unclear. In the present study, HNSCC RNA sequences and autophagy-related gene data were extracted from The Cancer Genome Atlas database and the Human Autophagy Database. A total of 1,153 autophagy-related lncRNAs were selected via calculating Pearson’s correlation coefficient. Three prognosis-related autophagy lncRNAs were identified via univariate Cox regression, least absolute shrinkage and selection operator analysis, and multivariate Cox regression analysis. We also constructed a prognostic model based on these autophagy-related lncRNAs and evaluated its ability to accurately and independently predict the prognosis of HNSCC patients. The area under the curve (AUC) was 0.864 (3-year) and 0.836 (5-year), and our model can independently predict the prognosis of HNSCC. The prognostic value of the three autophagy lncRNAs was confirmed via analysis of samples from five databases. To further identify the functions of the three lncRNAs, a co-expression network was constructed and pathway analysis was performed. In that analysis the lncRNAs were correlated with 189 related genes and 20 autophagy-related genes, and these lncRNAs mainly involved homologous recombination, the Fanconi anemia pathway, the autophagy-related pathway, and immune-related pathways. In addition, we validated the expression levels of three lncRNAs and autophagy markers (ATG12, BECN1, and MAP1LC3B) based on TIMER, Oncomine, and HPA database analysis. Our results indicated that TTTY15 was increased in HPV positive and HPV negative HNSCC patients, and three autophagy markers were up-regulated in all HNSCCC patients. Lastly, association between three lncRNAs and autophagy markers was performed, and our results showed that TTTY15 and MIF-AS1 were associated with autophagy markers. Collectively, these results suggested that three autophagy-related lncRNAs have prognostic value in HNSCC patients.

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Data Mining Identifies Six Proteins that Can Act as Prognostic Markers for Head and Neck Squamous Cell Carcinoma

Cell Transplantation ◽

10.1177/0963689720929308 ◽

2020 ◽

Vol 29 ◽

pp. 096368972092930

Author(s):

Zeng-hong Wu ◽

Yun-Tang ◽

Qing Cheng

Keyword(s):

Squamous Cell Carcinoma ◽

Regression Analysis ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

High Throughput Sequencing ◽

Cox Regression ◽

Neck Squamous Cell Carcinoma ◽

The Cancer Genome Atlas ◽

Cox Regression Analysis

Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor of the upper aerodigestive tract affecting the oral cavity, lips, paranasal sinuses, larynx, and nasopharynx. Proteogenomics combines proteomics and genomics and employs mass spectrometry and high-throughput sequencing technologies to identify novel peptides. The aim of this study was to identify potential protein biomarkers for clinical treatment of HNSCC. To achieve this, we utilized two sets of data, one on proteins from The Cancer Proteome Atlas (TCPA) and the other on gene expression from The Cancer Genome Atlas (TCGA) database, to evaluate dysfunctional proteogenomics microenvironment. Univariate Cox regression analysis was performed to examine the relationship between protein signatures and prognosis. A total of 19 proteins were significantly associated with overall survival (OS) of patients, of which E2F transcription factor 1 (E2F1; HR = 4.557, 95% CI = 1.810 to 11.469) and enhancer of zeste homolog 2 (EZH2; HR = 0.430, 95% CI = 0.187 to 0.984) were the most differentially expressed between patients with longer and shorter OS, respectively. Furthermore, multivariate Cox regression analysis on six proteins (ERALPHA, HER3, BRAF, P27, RAPTOR, and E2F1) was performed to build the prognostic model. The receiver operating characteristic curves were used to determine whether the expression pattern of survival-related proteins could provide an early prediction of the occurrence of HNSCC. Herein, we found an AUC of 0.720. Based on an online database, we identified novel protein markers for the prognosis of HNSCC. The findings of the present study may provide new insights into the development of new and reliable tools for precise cancer intervention.

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A 8-gene-methylation-based Signature for Head and Neck Squamous Cell Carcinoma Prognosis

10.21203/rs.3.rs-735108/v1 ◽

2021 ◽

Author(s):

Zihui Wang ◽

Jingrun Yang ◽

Lihong Liu

Keyword(s):

Gene Expression ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Cox Regression ◽

Neck Squamous Cell Carcinoma ◽

The Cancer Genome Atlas ◽

Gene Methylation ◽

Cox Regression Analysis

Abstract Background Head and neck squamous cell carcinoma (HNSCC), accounting for 6% of systemic malignant tumors, has an increasing incidence rate year by year worldwide. A large number of studies have investigated the tumor markers to determine clinical stage, prognosis, treatment evaluation, predict relapses, and overall survival of HNSCC patients, with controversial results. Methods In this paper, we comprehensively analyzed gene expression and DNA methylation data sets of HNSCC and adjacent non-tumor samples from The Cancer Genome Atlas (TCGA). Univariate cox regression analysis followed by sure independence screening (SIS) were used for identifying differential methylation signatures to stratify patients with significantly different prognosis. Results We identified methylation levels of HS3ST1，TOMM34，RPL26L1，MTHFD2，ORC1，MYOSLID，UHRF1 and AL357033.3 as potential HNSCC prognosis signatures, and verified the correlation between their gene expression and the corresponding methylation. Their reliability for predicting the prognosis of HNSCC was confirmed in an independent dataset. Conclusions In conclusion, we built a 8-gene-methylation-based signature which can well assess the prognosis of HNSCC patients.

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The Prognostic Significance of Immune-Related Metabolic Enzyme MTHFD2 in Head and Neck Squamous Cell Carcinoma

Diagnostics ◽

10.3390/diagnostics10090689 ◽

2020 ◽

Vol 10 (9) ◽

pp. 689

Author(s):

Li Cui ◽

Huan Chen ◽

Xinyuan Zhao

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Cox Regression ◽

Prognostic Significance ◽

Neck Squamous Cell Carcinoma ◽

The Cancer Genome Atlas ◽

Metabolic Enzyme ◽

Cox Regression Analysis

Metabolic dysregulation has emerged as a crucial determinant of the clinical responses to immunotherapy. The aim of this study was to determine the clinical significance of the candidate immune-related metabolic enzymes (IRMEs) methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2 (MTHFD2) in head and neck squamous cell carcinoma (HNSCC). The gene expression profile of HNSCC cohort and the corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA). The differentially expressed IRMEs were identified, and then, the prognosis-associated IRMEs were revealed by univariate cox regression analysis. The prognostic significance of MTHFD2 in HNSCC as well as the association between MTHFD2 and immune cell infiltration were further analyzed. A total of 121 significantly altered IRMEs were identified between HNSCC and normal tissues, and 21 IRMEs were found to be strongly associated with overall survival of HNSCC. Upregulation of MTHFD2 was positively correlated with adverse clinicopathological factors in TCGA HNSCC cohort, which was further validated with our own cohort using immunohistochemical analysis. Interestingly, bioinformatic analysis further revealed that increased MTHFD2 expression was negatively associated with NK cells activation, while positively correlated with mast cells activation. In conclusion, MTHFD2 overexpression is closely correlated with unfavorable prognosis of HNSCC, and it might play an important role in modulating the tumor immune microenvironment.

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Significance of TP53 mutation in treatment and prognosis in head and neck squamous cell carcinoma

Biomarkers in Medicine ◽

10.2217/bmm-2020-0400 ◽

2021 ◽

Vol 15 (1) ◽

pp. 15-28

Author(s):

Yu Jin ◽

Xing Qin

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Tp53 Mutation ◽

Cox Regression ◽

Cancer Genome ◽

Neck Squamous Cell Carcinoma ◽

The Cancer Genome Atlas ◽

Cox Regression Analysis

Background: TP53 is ranked as the most common mutated gene in head and neck squamous cell carcinoma (HNSCC). Results: The status of TP53 mutation was investigated on International Cancer Genome Consortium and The Cancer Genome Atlas database and TP53-related differentially expressed genes were screened out from transcriptome data and mutation information. A TP53-related prognostic gene signature ( TIMP4, ONECUT2, CGNL1, DMRTA2 and NKX2.3) was constructed based on Cox regression analysis and LASSO algorithm. Univariate and multivariate analyses were carried out to identify promising prognosticators for HNSCC. Conclusion: Our findings provide a well-rounded landscape of TP53 mutation in HNSCC and pave the groundwork for developing innovative and effective cancer treatment methods for HNSCC.

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A Novel Ferroptosis-Related Gene Signature to Predict Prognosis in Patients with Head and Neck Squamous Cell Carcinoma

Disease Markers ◽

10.1155/2021/5759927 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Li Xu ◽

Ying-ying Li ◽

Yang-chun Zhang ◽

Yong-xu Wu ◽

Dan-dan Guo ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Cox Regression ◽

Risk Group ◽

Tnm Staging ◽

Neck Squamous Cell Carcinoma ◽

The Cancer Genome Atlas ◽

Cox Regression Analysis

The clinical TNM staging system is currently used to evaluate the prognosis of head and neck squamous cell carcinoma (HNSCC). The 5-year survival rate for patients with HNSCC is less than 50%, which is attributed to the lack of reliable prognostic biomarkers. Ferroptosis-related genes (FRGs) regulate cancer initiation and progression. Therefore, we analyzed the correlation between FRGs and the clinical outcomes of patients with HNSCC. A typical prognostic model of FRGs for HNSCC was constructed using bioinformatics tools and data from public databases, including The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and GeneCards. The model was generated based on the following six FRGs: ATG5, PRDX6, OTUB1, FTH1, SOCS1, and MAP3K5. The accuracy of model prediction was analyzed systematically. The overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group. The AUC for 1-year, 3-year, and 5-year survival were 0.645, 0.721, and 0.737, respectively, in the training set (TCGA cohort) and 0.726, 0.620, and 0.584, respectively, in the validation set (GSE65858). The multivariate Cox regression analysis revealed that the risk score was an independent prognostic factor for HNSCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that six FRGs were enriched in the ferroptosis pathway. A novel FRG prognostic signature model was established for HNSCC. The findings of this study reveal that FRGs are potential biomarkers for HNSCC.

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Six Glycolysis-Related Genes as Prognostic Risk Markers Can Predict the Prognosis of Patients with Head and Neck Squamous Cell Carcinoma

BioMed Research International ◽

10.1155/2021/8824195 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

LangXiong Chen ◽

XiaoSong He ◽

ShiJiang Yi ◽

GuanCheng Liu ◽

Yi Liu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Regression Analysis ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Cox Regression ◽

Neck Squamous Cell Carcinoma ◽

Risk Markers ◽

Cox Regression Analysis ◽

Normal Head

Objective. Head and neck squamous cell carcinoma (HNSCC) is one of the worst-prognosis malignant tumors. This study used bioinformatic analysis of the transcriptome sequencing data of HNSCC and the patients’ survival and clinical data to construct a prediction signature of glycolysis-related genes as the prognostic risk markers. Methods. Gene expression profile data about HNSCC tissues ( n = 498 ) and normal tissues in the head and neck ( n = 44 ) were got from The Cancer Genome Atlas (TCGA), as well as patients’ survival and clinical data. Then, we obtained core genes; their expression in head and neck squamous cell carcinoma tissues is significantly different from that in normal head and neck tissues. The predicted glycolysis-related genes are screened through univariate Cox regression analysis, and then, the prognostic risk markers were constructed through further correction of multivariate Cox regression analysis. The Kaplan-Meier curve and receiver operating characteristic curve are used to analyze the potential value of these risk markers in diagnosis and prognosis. We also evaluated that the glycolysis-related prognostic risk markers composed of 6 oncogenes are correlated with clinical features, such as age, gender, grade, and clinical stage of the tumor, by univariate and multivariate Cox regression analyses. Results. Differentially expressed glycolytic genes in HNSCC tissues and normal head and neck tissues were screened from TCGA databases using the bioinformatic method. We confirmed a set of six glycolytic genes that were significantly associated with OS in the test series. According to our analysis, the prognostic risk markers composed of HPRT1, STC2, PLCB3, GPR87, PYGL, and SLC5A12 may be an independent risk factor for the prognosis of HNSCC. Conclusions. Through this analysis, we constructed new prognostic risk markers related to glycolysis as a prognostic risk marker for patients with HNSCC and provided new ideas and molecular targets for the research and individualized treatment of HNSCC.

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Three Autophagy-Related lncRNA are Prognostic Biomarkers for Patients with Head and Neck Squamous Cell Carcinoma

10.21203/rs.3.rs-892575/v1 ◽

2021 ◽

Author(s):

Haoyue Xu ◽

Xiangpu Wang ◽

Zhien Feng ◽

Renji Chen ◽

Zhengxue Han

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Risk Score ◽

Squamous Cell ◽

Cox Regression ◽

Neck Squamous Cell Carcinoma ◽

Regression Analyses ◽

Good Ability ◽

Non Coding Rnas

Abstract Background: Currently, no systematic analysis has been conducted to assess the potential of multiple autophagy-related long non-coding RNAs (lncRNA) to predict the prognosis of head and neck squamous cell carcinoma (HNSCC). we investigated the prognostic potential of autophagy-related long non-coding RNAs (lncRNA) in HNSCC patients. Methods: Patient information and Autophagy-associated genes were obtained from The Cancer Genome Atlas (TCGA) and Human Autophagy data resource. Autophagy-related lncRNAs were determined through Lasso and Cox regression analyses. Then, on the basis of autophagy- related lncRNAs, a risk score and a nomogram were constructed for estimation of prognostic outcomes for HNSCC patients. These models were verified internally using the TCGA and. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for gene functional analyses. Results: Three autophagy-related lncRNAs (AC002401.4, AC245041.2 and TMEM44-AS1) that are associated with HNSCC were identified. Univariate and multivariate Cox regression analyses revealed that the risk score is an independent prognostic indicator (p ≤ 0.001), with its ability to predict prognosis being higher than that of other clinicopathological indicators (AUC=0.732). Concordance index of the nomogram was 0.712, and AUC values for one-year, three-year and five-year survival rates were 0.730, 0.745 and 0.728, respectively. Internal verifications revealed that this nomogram had a good ability to predict prognosis. Functional analysis showed that the genes were mostly enriched in autophagy and tumor-related cascades. Conclusion: The autophagy-related lncRNAs model can predict the prognosis of patients with HNSCC.Trial registration: Prospective, Observational, Real-world Oral Malignant Tumors Study (POROMS), NCT02395367. Registered 23 March 2015, https://clinicaltrials.gov/ct2/show/NCT02395367

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An Immune-associated lncRNA Signature Predicts the Survival of Patients With Head and Neck Squamous Cell Carcinoma

10.21203/rs.3.rs-446589/v1 ◽

2021 ◽

Author(s):

Jian Wang ◽

Qinjiang Bian ◽

Jialin Liu ◽

Lijuan Du ◽

Adili Moming

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Cox Regression ◽

Characteristic Curve ◽

Area Under The Curve ◽

Neck Squamous Cell Carcinoma ◽

The Cancer Genome Atlas ◽

Data Resource

Abstract Recent researches have established that lncRNAs (long non-coding RNAs) could be exploited as new signatures for head and neck squamous cell carcinoma (HNSCC) diagnosis, prognosis, and treatment. Herein, HNSCC transcriptome data was abstracted from the Cancer Genome Atlas (TCGA) data resource, and uncovered immune linked lncRNAs through co-expression analysis. Besides, univariate along with Lasso penalty regression were employed to determine immune-linked lncRNA pairs with different expressions. We then compared area under the curve, calculated the Akaike information criterion (AIC) value of the receiver operating characteristic curve for 5 years, determined cutoff points, and established an optimal predictive model for identifying high- and low-risk HNSCC patients. Overall, we identified 40 differentially expressed immune-linked lncRNA pairs, 17 of which were incorporated in the Cox regression model. Using this model, we can more effectively stratify patients based on poor survival results, positive clinicopathological features, specific tumor immune invasion status, low chemotherapy responsivity, and high expression of immunosuppressive biomarkers. Our data illustrated that the immune-linked lncRNA pairs signature have clinical prediction value for HNSCC.

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Discovery and Verification of an Immune-Related Gene Pairs Signature for Predicting Prognosis in Head and Neck Squamous Cell Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.654657 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiqiang He ◽

Xinqi Fang ◽

Mingming Han

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Cox Regression ◽

Neck Squamous Cell Carcinoma ◽

Related Gene ◽

Cox Regression Analysis ◽

Gene Pairs ◽

Immune Related Gene

The study of IRGPs to construct the prognostic signature in head and neck squamous cell carcinoma (HNSCC) has not yet elucidated. The objective of this study was to explore a novel model to predict the prognosis of HNSCC patients. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were set as training and validation cohorts, respectively. The least absolute shrinkage and selection operator (LASSO) and time-dependent ROC were employed to screen the highest frequency immune-related gene pairs (IRGPs) and their best cut-off value. Survival analysis, Cox regression analysis were applied to discover the effects of selected IRGPs signature on survival outcomes. The immune cell proportions were deconvoluted by the CIBERSORT method. After a couple of filtering, we obtained 22 highest frequency IRGPs. The overall survival time of HNSCC patients with a high score of IRGPs was shorter as compared to the ones with a low score in two independent datasets (P < 0.001). Six kinds of immune cells were found to be differentially distributed in the two different risk groups of HNSCC patients (P < 0.001). GO and GSEA analysis showed these differentially expressed genes enriched in multiple molecular functions. The new IRGPs signature probably confers a new insight into the prognosis prediction of HNSCC patients.

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JOSD1 promotes proliferation and chemoresistance of head and neck squamous cell carcinoma under the epigenetic regulation of BRD4

Cancer Cell International ◽

10.1186/s12935-021-02060-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chao Jing ◽

Dandan Liu ◽

Qingchuan Lai ◽

Linqi Li ◽

Mengqian Zhou ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Gene Expression Omnibus ◽

Neck Squamous Cell Carcinoma ◽

The Cancer Genome Atlas ◽

In Vivo Experiments

Abstract Background Deubiquitinating enzymes (DUBs) play critical roles in various cancers by modulating functional proteins post-translationally. Previous studies have demonstrated that DUB Josephin Domain Containing 1 (JOSD1) is implicated in tumor progression, however, the role and mechanism of JOSD1 in head and neck squamous cell carcinoma (HNSCC) remain to be explored. In this study, we aimed to identify the clinical significance and function of JOSD1 in HNSCC. Methods The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to find novel DUBs in HNSCC. Immunohistochemistry assay was performed to determine the expression of JOSD1 in our cohort of 42 patients suffered with HNSCC. Kaplan–Meier analysis was used to identify the correlation between JOSD1 and the prognosis of HNSCC patients. The regulation of BRD4 on JOSD1 was determined by using pharmacological inhibition and gene depletion. The in vitro and in vivo experiments were conducted to elucidate the role of JOSD1 in HNSCC. Results The results of IHC showed that JOSD1 was aberrantly expressed in HNSCC specimens, especially in the chemoresistant ones. The overexpression of JOSD1 indicated poor clinical outcome of HNSCC patients. Moreover, JOSD1 depletion dramatically impaired cell proliferation and colony formation, and promoted cisplatin-induced apoptosis of HNSCC cells in vitro. Additionally, JOSD1 suppression inhibited the tumor growth and improved chemosensitivity in vivo. The epigenetic regulator BRD4 contributed to the upregulation of JOSD1 in HNSCC. Conclusions These results demonstrate that JOSD1 functions as an oncogene in HNSCC progression, and provide a promising target for clinical diagnosis and therapy of HNSCC.

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