Prognosis Of Cervical Squamous Cell Carcinoma Research Articles

The immune landscape and prognostic analysis of CXCL8 immune-related genes in cervical squamous cell carcinoma.

Cervical squamous cell carcinoma (CESC), one of the most common malignancies in women, imposes a significant burden on women's health worldwide. Despite extensive research, the molecular and pathogenic mechanisms of cervical squamous cell carcinoma and CESC remain unclear. This study aimed to explore the immune-related genes, immune microenvironment infiltration, and prognosis of CESC, providing a theoretical basis for guiding clinical treatment. Initially, by mining four gene sets and immune-related gene sets from public databases, 14 immune-related genes associated with CESC were identified. Through univariate and multivariate COX regression analyses, as well as lasso regression analysis, four CESC-independent prognostic genes were identified, and a prognostic model was constructed, dividing them into high and low-risk groups. The correlation between these genes and immune cells and immune functions were explored through ssGSEA enrichment analysis, revealing a close association between the high-risk group and processes such as angiogenesis and epithelial-mesenchymal transition. Furthermore, using public databases and qRT-PCR experiments, significant differences in CXCL8 expression between normal cervical cells and cervical cancer cells were discovered. Subsequently, a CXCL8 knockdown plasmid was constructed, and the efficiency of CXCL8 knockdown was validated in two CESC cell lines, MEG-01 and HCE-1. Through CCK-8, scratch, and Transwell assays, it was confirmed that CXCL8 knockdown could inhibit the proliferation, invasion, and migration abilities of CESC cells. Targeting CXCL8 holds promise for personalized therapy for CESC, providing a strong theoretical basis for achieving clinical translation.

Prognostic value of APOBEC3A in patients with cervical squamous cell carcinoma in a major urban center in China: a retrospective study.

APOBEC3A (A3A) has been implicated to have vital prognostic value in several common cancers. This study aimed to investigate the prognostic value of A3A expression in cervical squamous cell carcinoma (CESC). This retrospective study enrolled 59 patients with CESC or cervical squamous intraepithelial neoplasia from January 2014 to January 2017 in Changhai Hospital, Naval Medical University. Then, A3A histoscores (H-scores) using immunohistochemistry (IHC) were analyzed in formalin-fixed paraffin-embedded archival tissue blocks. Moreover, overall survival was analyzed by the Kaplan-Meier method. The H-score of A3A protein expression was relatively higher in CESC than in squamous intraepithelial neoplasia, and the relative expression level of normal cervical tissues was lower than that of cervical squamous intraepithelial neoplasia (P<0.001). Moreover, the H-score of poorly differentiated cases was 6, which was higher than that of moderately differentiated cases (H-score =3), while the H-score of well-differentiated cases was 2, which was lower than that of moderately differentiated cases. Moreover, patients in the A3A low expression group had higher overall survival rates by prognostic analysis (P=0.027). A3A protein expression was increased during CESC progression. Moreover, A3A expression was tightly related to poor prognosis in CESC. Thus, these results showed that A3A overexpression may provide a marker for poor prognosis in CESC.

Identification of ferroptosis-related molecular subtypes and a methylation-related ferroptosis gene prognostic signature in cervical squamous cell carcinoma.

We aimed to investigate the molecular characteristics of cervical squamous cell carcinoma (CESC) by analyzing ferroptosis-related gene (FRG) expression data to predict prognosis. Gene expression and clinicopathological data of patients with CESC were collected from the Cancer Genome Atlas and the Genotype-Tissue Expression databases. Using Cox regression analysis, we identified 21 FRGs associated with prognosis. Cluster analysis categorized patients into subgroups based on these genes and compared their clinicopathological, biological, and immune infiltration features. FRG methylation levels were examined, and a risk model based on such FRG methylation levels was constructed using LASSO and Cox regression analyses. The model's predictive capacity was validated, and the relationships between the risk score and immune infiltration, tumor microenvironment, and drug sensitivity were explored. FRG methylation in CESC tissues was validated by immunohistochemistry. We identified 21 FRGs associated with CESC prognosis. Patients were stratified into two subtypes based on these genes, they showed differences in prognosis, immune cell types, and immune checkpoint expression. A three-gene risk score (including AQP3, MGST1, and TFRC) was generated, and the low-risk group showed better overall survival. The high-risk and low-risk groups differed in terms of immune infiltration, gene mutations, and drug sensitivity. Experimental validation confirmed the upregulation of AQP3 and TFRC, whereas MGST1 expression was not significantly altered in CESC tissues compared with that in normal cervical tissues. This study highlights the potential role of FRG methylation in predicting CESC prognosis and provides a personalized assessment of immune responses in patients with CESC.

Identification of key immune cell-related genes involved in tumorigenesis and prognosis of cervical squamous cell carcinoma

ABSTRACT The infiltration of immune cells can significantly affect the prognosis and immune therapy of patients with cervical squamous cell carcinoma (CSCC). This study aimed to explore key immune cell-related genes in the tumorigenesis and prognosis of CSCC. The module significantly related to immunity was screened by weighted gene co-expression network analysis (WGCNA) and ESTIMATE analysis, followed by correlation analysis with clinical traits. Key candidate genes were intersected with the protein–protein interaction (PPI) network genes for immune-related genes. The relationship between immune cell infiltration and key genes was analyzed. Tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS) predicted the response to immunotherapy in CSCC patients. Clinically, quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry were manipulated for analyzing the changes in mRNA and protein expression of key genes in cancer. Western blot was conducted to assess the correlation between key genes and immune infiltration. The brown module was notably associated with the immune microenvironment of CSCC, from which three immune-related key genes (TYROBP, CCL5, and HLA-DRA) were obtained. High expression of these genes was significantly positively associated with the infiltration abundance of T cells, B cells, and other immune cells. High expression levels of three key genes were confirmed in para-cancer tissue and correlated with the abundance of immune cells. The high-expression group of key genes was more sensitive to immunotherapy. We provide a theoretical basis for searching for potential targets for effective treatment and diagnosis of CSCC and provide new ideas for developing novel immunotherapy strategies.

Clinicopathological and prognosis significance of RIPK1 in patients with cervical squamous cell carcinoma: a retrospective cohort study.

Cervical cancer is one of the most common types of carcinoma in women and has high morbidity and mortality rates worldwide. Recurrent and metastatic disease remains difficult to treat. Receptor interacting protein kinase 1 (RIPK1) is a key molecule in mediating apoptosis, necroptosis, and inflammatory pathways downstream of death receptors and pattern recognition receptors. This study sought to explore the clinicopathological and prognosis significance of RIPK1 expression in cervical squamous cell carcinoma (CSCC). The data of 100 CSCC patients who underwent curative surgery from 2019 to 2020 were retrospectively included in this study. We collected the clinicopathological information of the patients and detected RIPK1 protein expression using immunohistochemistry. The Chi-square test and a 1-way analysis of variance were used to make comparisons between groups stratified by RIPK1 expression. A Pearson linear correlation analysis was used to evaluate the association between RIPK1 expression and the clinicopathological characteristics of the patients. A Cox regression analysis and Kaplan-Meier curves were used to analyze overall survival (OS) and progression-free survival (PFS). A multivariable regression analysis was conducted to identify the risk factors for an impaired prognosis in CSCC. RIPK1 was found to be overexpressed in the CSCC tissues. RIPK1 expression was significantly associated with age, the preoperative serum squamous cell carcinoma antigen (SCC-Ag) level, lymph node metastasis, invasion depth, International Federation of Gynecology and Obstetrics (FIGO) stage, tumor size, PFS, and OS (P<0.05). The PFS and OS differed significantly among patients with RIPK1 expression (P<0.05). The multivariate analysis showed that RIPK1 was not independent risk factors for PFS and OS in CSCC patients (P>0.05). The expression of RIPK1 was significantly upregulated in CSCC and was associated with the clinicopathological features of CSCC. RIPK1 might serve as a novel marker that can be used to predict the prognosis of CSCC patients and as a biological target for the treatment of CSCC.

Fatty acid synthase (FASN) inhibits the cervical squamous cell carcinoma (CESC) progression through the Akt/mTOR signaling pathway

BackgroundCervical cancer is a malignant tumor that affects females and remains the cause of the highest morbidity and mortality among women worldwide. Currently, gene-targeted therapy is a novel treatment option for clinicians. Furthermore, fatty acid synthase (FASN) plays a therapeutic role in various cancers. Nonetheless, the mechanism of action of this enzyme in cervical squamous cell carcinoma and cervical duct adenocarcinoma (CESC) has not yet been reported. MethodsRNA (ribonucleic acid) sequencing data and clinical information were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). The expression levels of FASN were obtained from Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and Human Protein Atlas (HPA). Univariate and multivariate Cox regression analyses were utilized to assess independent prognostic factors associated with survival. A nomogram and receiver operating characteristic curve (ROC) were employed to evaluate survival and predictive power. In vitro experiments and real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) were conducted to identify cell interference efficiency. MTS, monoclonal formation, and EDU assays were used to determine cell viability. Wound healing and invasion assays (transwell assay) were used to evaluate cell migration and invasion. Finally, Hoechst 33342, propidium iodide (PI) staining and Annexin V-FITC staining were used to assess apoptosis and the cell cycle, while western blotting was utilized to determine the protein expression levels. ResultsFASN was aberrantly expressed in various cancers, including CESC, where it was highly expressed. Kaplan-Meier, univariate, multivariate Cox regression analyses and ROC curve indicated that FASN is a potential key indicator of survival prognosis among CESC patients and demonstrated good predictive ability and efficacy. Complementary in vitro experiments confirmed that FASN is an important target for CESC therapy. ConclusionThe current study validated the biological and clinical significance of FASN in CESC prognosis, suggesting that FASN knockdown may exert antitumor activity against cervical cancer through the Akt/mTOR signaling pathway.

Identification of Oxidative Stress-Associated Molecular Subtypes and Signature for Predicting Survival Outcome of Cervical Squamous Cell Carcinoma.

Background Cervical squamous cell carcinoma (CESC) is the gynecologic malignancy with high incidence rate and high mortality rate. Oxidative stress participates in gene regulation and malignant tumor progression, including CESC. Methods RNA-seq, clinical information, and genomic mutation were from The Cancer Genome Atlas- (TCGA-) CESC and GSE44001 datasets. Oxidative stress-related genes were obtained from the gene set enrichment analysis (GSEA) website. ConsensusClusterPlus was used for clustering, which was assessed by the Kaplan-Meier (KM) survival curve analysis, mutation analysis, immunocharacteristic analysis, and therapy. Prognostic signatures were built by combining weighted correlation network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) algorithm, and stepAIC. The prognostic power of this model was evaluated using the KM survival curve analysis, receiver operating characteristic (ROC) curve analysis, nomogram, and decision curve analysis (DCA). Results 218 of the 291 CESC cases (74.91%) presented oxidative stress-related gene mutation, especially FBXW7. Three clusters were determined based on oxidative stress-related genes, among which cluster 3 (C3) presented low-frequency mutation and hyperimmune state and was sensitive to immunotherapy. This research developed a 5-gene oxidative stress-related prognostic signature and a RiskScore model. As shown by ROC analysis, in the TCGA and GSE44001 datasets, the RiskScore model showed a high prediction accuracy for 1-, 3-, and 5-year CESC overall survival. High RiskScore was associated with enhanced immune status. The nomogram model was greatly predictive of the overall survival of CESC patients. Conclusion Our prognostic model was based on oxidative stress-related genes in CESC, potentially aids in CESC prognosis, and provides potential targets against CESC.

Uncovering of potential molecular markers for cervical squamous cell carcinoma (CESC) based on analysis of methylated-differentially expressed genes

ObjectiveCervical squamous cell carcinoma (CESC) is a cancer with high mortality caused by human papillomavirus. The aim of this study was to uncover potential CESC biomarkers to help early diagnosis and treatment. Materials and methodsThe mRNA transcriptome data and DNA methylation data were downloaded from database for the identification of differentially expressed mRNAs (DEmRNAs) and DNA methylation analysis. Functional analysis was used to reveal the molecular functions. Then, the association between differential methylation and DEmRNA was analyzed. Protein–protein interaction (PPI) network analysis was performed on the selected differentially methylated genes (DEGs). Subsequently, we analyzed the prognosis and constructed a prognostic risk model. We also performed diagnostic analyses of risk model genes. In addition, we verified the protein expression level of identified DEGs. Results1438 DEmRNAs, 1669 differentially methylated sites (DMSs), 46 differentially methylated CpG islands and 53 differential methylation genes (DMGs) were obtained. In PPI, the highest interaction scores were MX2 and IRF8, and their interaction score was 0.928. Interestingly, 5 DMGs were found to be associated with CESC prognosis. In addition, our results demonstrated that high risk score was associated with poor prognosis of CESC. Furthermore, it was found that ZIK1, ZNRF2, HHEX, VCAM1 could be diagnostic molecular markers for CESC. ConclusionAnalysis of methylated-differentially expressed genes may contribute to the identification of early diagnosis and therapeutic targets of CESC. In addition, a prognostic model based on 5 DMGs can be used to predict the prognosis of CESC.

Exploring Potential Regulatory Anesthetic Drugs Based on RNA Binding Protein and Constructing CESC Prognosis Model: A Study Based on TCGA Database.

ObjectiveTo investigate the differential expression of RBPs in cervical squamous cell carcinoma (CESC), analyze the regulatory effect of narcotic drugs on RBPs, and establish the prognostic risk model of CESC patients.MethodsRNA-SEQ data and clinical case data of cancer and normal samples from CESC patients were obtained from the Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) database. Differentially expressed RBPs were screened by R language and enriched. The CMAP database is used to predict the anesthetic drugs that regulate the differential expression of RBPs. The prognostic risk score model was constructed by COX regression analysis. Risk score of each CESC patient was calculated and divided into high-risk group and low-risk group according to the median risk score. The prediction efficiency of prognostic risk model was evaluated by Kaplan-Meier (KM) analysis and receiver operating characteristic (ROC) curve, and the correlation between prognostic risk model and clinical characteristics was analyzed. Immunohistochemistry was used to detect the expression of RNASEH2A and HENMT1 in tissues.ResultsThere were 65 differentially expressed RBPs in CESC. Five anesthetics, including benzocaine, procaine, pentoxyverine, and tetracaine were obtained to regulate RBPs. Survival analysis showed that seven genes were related to the prognosis of patients, and the CESC risk score model was constructed by COX regression. The risk score can be used as an independent prognostic factor. RNASEH2A and HENMT1 are up-regulated in tumors, which can effectively distinguish normal tissues from tumor tissues.ConclusionIt is found that different anesthetic drugs have different regulatory effects on the differential expression of RBPs. Based on the differentially expressed RBPs, the prognostic risk score model of CESC patients was constructed. To provide ideas for the formulation of individualized precise anesthesia scheme and cancer pain analgesia scheme, which is helpful to improve the perioperative survival rate of cancer patients.

Increased expression of SRPK1 (serine/arginine-rich protein-specific kinase 1) is associated with progression and unfavorable prognosis in cervical squamous cell carcinoma

ABSTRACT Previous studies suggest that SRPK1 (serine/arginine-rich protein-specific kinase 1) is involved in tumorigenesis and closely related to unfavorable outcomes. However, its expression pattern in cervical squamous cell carcinoma (CESC) remains uncovered. In this study, we initially investigated the clinical significance and function of SRPK1 in human CESC. Data mining and analysis on SRPK1 mRNA expression in CESC samples were conducted using TCGA database, which indicated that SRPK1 mRNA was significantly upregulated in CESC samples. Protein expression of SRPK1 was tested by immunohistochemistry in a retrospective cohort (n = 122), revealing a higher SRPK1 protein abundance in CESC specimens whose aberrant up-regulation was obviously related to worse survival. Cox proportional hazards regression analysis further confirmed the role of SRPK1 as an independent prognostic factor of CESC. Cellular experiments validated that SRPK1 may function through enhancing CESC proliferation, migration, and invasion. In conclusion, aberrant up-regulation of SRPK1 is remarkably related to progression and unfavorable prognosis of CESC, which can serve as a novel prognostic biomarker and therapeutic target for CESC.

Screening of genes related to survival prognosis of cervical squamous cell carcinoma and construction of prognosis prediction model.

We aimed to screen for the genes related to survival prognosis of cervical squamous cell carcinoma (CSCC) and then constructed a prognosis prediction model. The GSE63514 dataset was obtained from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO). The CSCC gene dataset and the GSE44001 dataset were obtained from The Cancer Genome Atlas and NCBI GEO, respectively. The Kaplan-Meier (KM) curve was used to evaluate the association between high and low prognosis that was with the actual survival prognosis information. The Cox proportional hazards model was used to screen out the optimized prognostic-related signature differentially expressed gene (DEG) combinations. Gene set enrichment analysis was used to perform pathway enrichment annotation analysis for DEGs that were related to risk grouping. In total, 16 399 DEGs were obtained and 23 gene ontology biological processes and 8 Kyoto Encyclopedia of Genes and Genomes pathways were screened. Nine optimized DEG groups related to independent prognosis were selected. The KM curves of pathologic N0 and N1 showed that low-risk group were associated with a better overall survival (p= 1.518e; p= 1.704e-01). The pathways related to risk grouping were cytokine-cytokine receptor interaction, JAK stat signaling pathway, and glycolysis-gluconeogenesis. On the basis of this study, we established a prognostic risk model, which provided a reliable prognostic tool and was of great significance for locating the biomarkers related to survival prognosis in CSCC.

Exploration of a Robust and Prognostic Immune Related Gene Signature for Cervical Squamous Cell Carcinoma.

Background: Cervical squamous cell carcinoma (CESC) is one of the most frequent malignancies in women worldwide. The level of immune cell infiltration and immune-related genes (IRGs) can significantly affect the prognosis and immunotherapy of CESC patients. Thus, this study aimed to identify an immune-related prognostic signature for CESC. Methods: TCGA-CESC cohorts, obtained from TCGA database, were divided into the training group and testing group; while GSE44001 dataset from GEO database was viewed as external validation group. ESTIMATE algorithm was applied to evaluate the infiltration levels of immune cells of CESC patients. IRGs were screened out through weighted gene co-expression network analysis (WGCNA). A multi-gene prognostic signature based on IRGs was constructed using LASSO penalized Cox proportional hazards regression, which was validated through Kaplan–Meier, Cox, and receiver operating characteristic curve (ROC) analyses. The abundance of immune cells was calculated using ssGSEA algorithm in the ImmuCellAI database, and the response to immunotherapy was evaluated using immunophenoscore (IPS) analysis and the TIDE algorithm. Results: In TCGA-CESC cohorts, higher levels of immune cell infiltration were closely associated with better prognoses. Moreover, a prognostic signature was constructed using three IRGs. Based on this given signature, Kaplan–Meier analysis suggested the significant differences in overall survival (OS) and the ROC analysis demonstrated its robust predictive potential for CESC prognosis, further confirmed by internal and external validation. Additionally, multivariate Cox analysis revealed that the three IRGs signature served as an independent prognostic factor for CESC. In the three-IRGs signature low-risk group, the infiltrating immune cells (B cells, CD4/8 + T cells, cytotoxic T cells, macrophages and so on) were much more abundant than that in high-risk group. Ultimately, IPS and TIDE analyses showed that low-risk CESC patients appeared to present with a better response to immunotherapy and a better prognosis than high-risk patients. Conclusion: The present prognostic signature based on three IRGs (CD3E, CD3D, LCK) was not only reliable for survival prediction but efficient to predict the clinical response to immunotherapy for CESC patients, which might assist in guiding more precise individual treatment in the future.

Detection of DKK-1 gene methylation in exfoliated cells of cervical squamous cell carcinoma and its relationship with high risk HPV infection.

To detect the methylation of Dickkopf-associated protein 1 (DKK-1) gene promoter in cervical exfoliated cells and to study its clinical significance in cervical squamous cell carcinoma (CSCC) and its relationship with high-risk HPV infection. Methylation-specific PCR (MSP) was utilized to detect the methylation of DKK-1 gene promoter in cervical exfoliated cells from 40 patients with CSCC and 40 patients with chronic cervicitis in the Affiliated Hospital of Inner Mongolia Medical University. The methylation rate of DKK-1 gene promoter in different clinicopathological factors and its relationship with high-risk HPV infection was compared, and different detection methods were compared. The degree of methylation of DKK-1 gene promoter in CSCC group was significantly higher than that in cervicitis group (P < 0.05). In CSCC group, the degree of methylation was significantly different in high-risk HPV infection, histological differentiation, tumor size, lymph node metastasis and the International Federation of Gynecology and Obstetrics (FIGO) staging (all P < 0.05). The degree of methylation is not related to the type of high-risk HPV infection (P > 0.05). The one-year survival rate of CSCC patients with high-risk HPV positive and DKK-1 gene promoter methylation is relatively low, only 74.1%. The sensitivity, specificity and accuracy of DKK-1 gene methylation combined with high-risk HPV detection were 96.7%, 78.0% and 85.0%, respectively. Methylation of DKK-1 gene promoter in cervical exfoliated cells of patients with CSCC is related to high-risk HPV infection and different clinicopathological factors, but the degree of methylation of DKK-1 gene is not related to the type of high-risk HPV infection. It may become an indicator different from HPV typing detection, which may play a shunt role in suggesting whether further invasive cervical examination is needed and reduce cervical invasive examination and overtreatment. It may be related to the survival rate of patients, which can be used to estimate the development and prognosis of CSCC and may play a good role in early warning in follow-up monitoring of CSCC after treatment. DKK1 gene methylation combined with HPV detection can improve the sensitivity, specificity and accuracy of diagnosis, which may improve the detection rate of early CSCC and make up for the deficiency of HPV and TCT detection. That may become a non-invasive screening method for CSCC.

Development and Validation of an m6A RNA Methylation Regulator-Based Signature for Prognostic Prediction in Cervical Squamous Cell Carcinoma.

Background: Cervical squamous cell carcinoma (CESC) is one of the most common causes of cancer-related death worldwide. N6-methyladenosine (m6A) plays an important role in various cellular responses by regulating mRNA biology. This study aimed to develop and validate an m6A RNA methylation regulator-based signature for prognostic prediction in CESC.Methods: Clinical and survival data as well as RNA sequencing data of 13 m6A RNA methylation regulators were obtained from The Cancer Genome Atlas (TCGA) CESC database. Consensus clustering was performed to identify different CESC clusters based on the differential expression of the regulators. LASSO Cox regression analysis was used to generate a prognostic signature based on m6A RNA methylation regulator expression. The effect of the signature was further explored by univariate and multivariate Cox analyses.Results: Four regulators (RBM15, METTL3, FTO, and YTHDF2) were identified to be aberrantly expressed in CESC tissues. A prognostic signature that includes ZC3H13, YTHDC1, and YTHDF1 was developed, which can act as an independent prognostic indicator. Significant differences of survival rate and clinicopathological features were found between the high- and low-risk groups. The results of bioinformatics analysis were then validated in the clinical CESC cohort by qRT-PCR and immunohistochemistry staining.Conclusion: In the present study, we developed and validated an m6A RNA methylation regulator-based prognostic signature, which might provide useful insights regarding the development and prognosis of CESC.

Uncovering PD-L1 and CD8+ TILS Expression and Clinical Implication in Cervical Squamous Cell Carcinoma.

Objective To investigate the association between programmed death-ligand 1 (PD-L1) coupled with CD8+ tumor-infiltrating lymphocytes (TILS) and the clinicopathological features, along with prognosis of cervical squamous cell carcinoma (CSCC). Methods 95 patients of CSCC received tumor resection at the Department of Pathology of the First Affiliated Hospital of University of Science and Technology of China (USTC) from 2015 to 2020. Full-automatic immunohistochemistry was applied to measure PD-L1 expression and CD8+ TILS density. Our literature deeply assessed the links between PD-L1 expression, clinicopathological features, and the influences of combination of PD-L1 and CD8+ TILS (PD-L1+/CD8+ TILS) on the prognosis of CSCC. Results 64.21% of CSCC patients (61/95) expressed PD-L1, and PD-L1 expression was related to the Federation of Gynecology and Obstetrics (FIGO) stage, tumor size, invasion depth, differentiation degree, metastasis of lymph node, and vascular invasion (P < 0.05). Dramatic correlation between PD-L1 expression and CD8+ TILS density was illustrated in CSCC patients (r = −0.461, P < 0.001). Obvious differences in differentiation degree, FIGO stage, infiltration depth, and lymph node metastasis were shown between patients with PD-L1 coupled with high-density of CD8+ TILS and those with PD-L1 coupled with low-density of CD8+ TILS (P < 0.05). Patients with PD-L1 negative expression exhibited better prognosis compared with those with PD-L1 positive expression (P < 0.05). Patients with PD-L1 coupled with high-density of CD8+ TILS showed better prognostic status, while those with PD-L1 coupled with low-density of CD8+ TILS had worse prognostic condition (P < 0.05). Differentiation, metastasis of lymph node, and FIGO stage were substantive impact elements of a CSCC patient's overall survival (OS) by Cox multivariate analysis. Conclusions CD8+ TILS density is related to PD-L1 expression in carcinoma. PD-L1/CD8+ TILS density can be regarded as evaluation for the prognosis of patients with CSCC, providing a new therapeutic target in clinical application.

Methylation-driven genes and their prognostic value in cervical squamous cell carcinoma.

Abnormal gene methylation is crucial for tumor progression. This study explored a cluster of methylation-driven genes involved in cervical squamous cell carcinoma (CESC). The data on RNA expression, methylation and clinical outcomes of CESC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Protein-protein interaction (PPI) network was constructed. Gene Ontology (GO) and KEGG analyses were performed to identify the biological functions of methylation-driven genes, and univariable and multivariate Cox analyses to screen out the key prognostic genes. A risk signature was established and its predictive value was evaluated with Kaplan-Meier and ROC curves. The key genes were further investigated by Cox regression analyses, gene set enrichment analysis (GSEA), and methylation site analysis. Additionally, "rms" package was used for establishing nomogram and calibrate curve. We found 144 differentially expressed methylation-driven genes. A risk model was constructed with three key prognostic genes (ITGA5, HHEX and S1PR4). The risk score was an independent risk factor for CESC prognosis. Lowly-expressed and hypermethylated ITGA5, highly-expressed and hypomethylated HHEX and S1PR4 were associated with better CESC prognosis. The methylation sites and biological functions enriched in ITGA5, HHEX and S1PR4 were uncovered. Additionally, the nomogram also validated the performance of risk model. Methylation-driven ITGA5, HHEX and S1PR4 are associated with CESC development. The three genes might serve as potential targets in the treatment of CESC.

Identification of Key Genes in Association with Progression and Prognosis in Cervical Squamous Cell Carcinoma.

Cervical cancer remains a primary cause of female death in developing countries, but its prognosis can be greatly improved if patients are diagnosed earlier. In the present study, we screened the common differentially expressed genes (DEGs) of cervical squamous cell carcinoma (CESC) from dataset GSE7803, Gene Expression Omnibus, and The Cancer Genome Atlas databases. An integrated bioinformatics analysis was performed based on these DEGs for their enrichment in functions and pathways, interaction network, prognostic signature, and candidate molecular drugs. As a result, 164 (114 upregulated and 47 downregulated) DEGs of CESC were identified for further investigation. We then conducted the gene ontology term enrichment and Kyoto Encyclopedia of Genes and Genomes Pathway analyses to reveal the underlying functions and pathways of these DEGs. In the protein-protein interaction network, hub module and hub genes were identified. Five genes of significant prognostic value-DSG2, ITM2A, CENPM, RIBC2, and MEIS2-were identified by prognostic signature analysis and used to construct a risk linear model. Further validation and investigation suggested DSG2 might be a key gene in CESC prognosis. We then identified two candidate small molecules (trichostatin A and tanespimycin) against CESC. Further validation and exploration of these hub genes are warranted for future prospect in clinical applications.

Epigenetic age acceleration of cervical squamous cell carcinoma converged to human papillomavirus 16/18 expression, immunoactivation, and favourable prognosis

BackgroundAgeing-associated molecular changes have been assumed to trigger malignant transformations and the epigenetic clock, and the DNA methylation age has been shown to be highly correlated with chronological age. However, the associations between the epigenetic clock and cervical squamous cell carcinoma (CSCC) prognosis, other molecular characteristics, and clinicopathological features have not been systematically investigated. To this end, we computed the DNA methylation (DNAm) age of 252 CSCC patients and 200 normal samples from TCGA and three external cohorts by using the Horvath clock model. We characterized the differences in human papillomavirus (HPV) 16/18 expression, pathway activity, genomic alteration, and chemosensitivity between two DNAm age subgroups. We then used Cox proportional hazards regression and restricted cubic spline (RCS) analysis to assess the prognostic value of epigenetic acceleration.ResultsDNAm age was significantly associated with chronological age, but it was differentiated between tumour and normal tissue (P < 0.001). Two DNAm age groups, i.e. DNAmAge-ACC and DNAmAge-DEC, were identified; the former had high expression of the E6/E7 oncoproteins of HPV16/18 (P < 0.05), an immunoactive phenotype (all FDRs < 0.05 in enrichment analysis), CpG island hypermethylation (P < 0.001), and lower mutation load (P = 0.011), including for TP53 (P = 0.002). When adjusted for chronological age and tumour stage, every 10-year increase in DNAm age was associated with a 12% decrease in fatality (HR 0.88, 95% CI 0.78–0.99, P = 0.03); DNAmAge-ACC had a 41% lower mortality risk and 47% lower progression rate than DNAmAge-DEC and was more likely to benefit from chemotherapy. RCS revealed a positive non-linear association between DNAm age and both mortality and progression risk (both, P < 0.05).ConclusionsDNAm age is an independent predictor of CSCC prognosis. Better prognosis, overexpression of HPV E6/E7 oncoproteins, and higher enrichment of immune signatures were observed in DNAmAge-ACC tumours.

High expression of survivin predicts poor prognosis in cervical squamous cell carcinoma treated with paclitaxel and carboplatin.

Lack of effective biomarkers is one of the challenges in current neoadjuvant chemotherapy to predict drug response and sensitivity of cervical squamous cell carcinoma (CSCC). The present study was designed to investigate the correlation of the expression of survivin, an inhibitor of apoptosis with the prognosis of CSCC patients undergoing neoadjuvant chemotherapy.A total of 117 CSCC patients treated with paclitaxel and carboplatin between May 2015 and April 2017 in the Second Hospital of Lanzhou University were retrospectively analyzed. The pathologic diagnosis and classification of CSCC were based on the Guidelines of the International Federation of Gynaecology and Obstetrics (FIGO). The efficacy was defined as complete remission (CR), partial remission (PR), and stability disease (SD). The expressions of survivin, vascular endothelial growth factor (VEGF), and Ki67 were determined with immunohistochemistry. Data were analyzed with SPSS software.Univariate analysis showed that survivin expression had no correlation with ages, FIGO stage, macroscopic type, lymphovascular invasion, depth of lymphovascular invasion, lymph node metastasis, and tumor size among 117 CSCC patients. However, survivin expression was positively correlated with pathological grade (R = 0.691, P < .001). Multivariate analysis revealed that survivin expression was independently correlated with grades (P < .001). In addition, the analysis of correlation indicated that survivin expression is positively correlated with VEGF expression (R = 0.820, P < .001) and Ki67 expression (R = 0.673, P < .001). The numbers (percentages) of complete remission (CR), partial remission (PR), and stability disease (SD) were 11 (9.4%), 91 (77.8%), and 15 (12.8%) respectively after the treatment of paclitaxel and carboplatin. Univariate analysis showed that efficacy of treatment was negatively correlated with pathological grade (R = 0.513, P < .001), Ki67 expression (R = 0.586, P < .001), VEGF expression (R = 0.476, P < .001) and survivin expression (R = 0.519, P < .001). Multivariate analysis revealed that efficacy of treatment was independently correlated with grades (P = .028), Ki67 (P < .001), and survivin expression (P = .015).The results suggested that survivin expression is negatively correlated with the prognosis of CSCC patients treated with paclitaxel and carboplatin. Therefore, survivin expression might be a marker for prognosis in CSCC following neoadjuvant chemotherapy.

Construction and Analysis of lncRNA-Mediated ceRNA Network in Cervical Squamous Cell Carcinoma by Weighted Gene Co-Expression Network Analysis.

BackgroundMore and more recent studies have clearly shown that long non-coding RNA (lncRNA) should be considered as a fundamental part of the ceRNA network, mainly because lncRNA can act as miRNA sponges to regulate the protein-coding gene expression. Nevertheless, it is still not clear how lncRNA-mediated ceRNAs function in cervical squamous cell carcinoma (CESC). Moreover, information about the ceRNA regulatory mechanism is also remarkably limited; thus, prediction of CESC prognosis using ceRNA-related information remains challenging.Material/MethodsWe collected 306 RNA (lncRNA, miRNA, and mRNA) expression profile datasets obtained from cervical squamous cancer tissues plus 3 more from adjacent cervical tissues via the TCGA database. Subsequently, we constructed a lncRNAs-miRNAs-mRNAs CESC ceRNA network, and Gene Ontology (GO) analysis was carried out.ResultsWe identified a total of 30 DElncRNAs, 70 DEmiRNAs, and 1089 DEmRNAs in CESC. Subsequently, to reveal the expression patterns of dysregulated genes, weighted gene co-expression network analysis was carried out, resulting in 3 co-expression modules with significantly related clinical properties. The constructed aberrant lncRNAs-miRNAs-mRNAs CESC ceRNA network was composed of 17 DEmiRNAs, 5 DElncRNAs, and 7 DEmRNAs. Moreover, the survival analysis was performed for DElncRNAs, DEmiRNAs, and DEmRNAs.ConclusionsThe present study shows the involvement of the lncRNA-related ceRNA network in the pathogenesis of CESC. We believe the newly generated ceRNA network will provide more insights into the lncRNA-mediated ceRNA regulatory mechanisms.