Infiltration Of Cervical Cancer Research Articles

Reduced 2,4-dienoyl-CoA reductase 1 is served as an unfavorable biomarker and is related to immune infiltration in cervical cancer.

Worldwide, cervical cancer (CC) remains the most prevalent malignancy of the female reproductive system, posing a threat to women's life and health, and increasing the medical and economic burden on society. Therefore, the search for tumor biomarkers for CC remains an important research direction. Immunotherapy has significantly improved patient outcomes, and genes related to tumor immune infiltration have been clinically relevant and highly reproducible biomarkers that affect the prognosis and response to treatment of CC. 2,4-dienoyl-CoA reductase 1 (DECR1) was considered to be an oncogene in a previous study, but relationship between DECR1 and immune infiltration was not mentioned. Our study aimed to reveal the clinical value of DECR1 in CC and to investigate its relationship with immune infiltration. Human Protein Atlas was used to identify the localization of DECR1. The Ualcan database, TCGA, and IHC were used to assess the prognostic value of DECR1. GSEA was used to assess the possible signaling pathways of DECR1 in CC. The TIMER database was applied to reveal the relevance between DECR1 and immune infiltration. GEPIA was conducted to detect the co-relationship among DECR1, immune markers, and typical molecules of apoptosis. DECR1 was mainly distributed in the cytoplasm and overlapped with the endoplasmic reticulum. DECR1 was downregulated in CC compared to adjacent tissue. Survival analysis showed that patients with lower expression of DECR1 have a worse prognosis in CC. GSEA suggested that DECR1 was closely related to apoptosis signaling. TIMER showed that DECR1 was positively correlated with CD8+ T cell and CD4+ T cell but not with B cell in CC. DECR1 may be a potential cancer suppressor in CC and may be involved in apoptotic pathways and associated with immune infiltration.

Lymph node metastasis-related gene signature shows good performance in predicting prognosis and immune infiltration in cervical cancer.

This study aimed to construct a lymph node metastasis-related gene signature to predict prognosis and immune infiltration in patients with cervical cancer. Clinical and RNA sequencing data of 193 patients with cervical cancer, which were divided into lymph node metastasis (N1) and non-lymph node metastasis (N0) groups, were acquired from TCGA. Differentially expressed genes (DEGs) between the N1 and N0 groups were detected, and protein-protein interaction combined with LASSO analysis was conducted to further screen lymph node metastasis-related genes. Univariate and multivariate Cox regression analyses were performed to establish a predictive signature. The genetic features, potential biological behavior, and immune infiltration characteristics of the predictive signature were explored. Furthermore, the sensitivity of patients to chemotherapy drugs was estimated based on the predictive signature and the expression of TEKT2 and RPGR was investigated in the cervical cancer tissue samples. A total of 271 lymph node metastasis-related DEGs, including 100 upregulated and 171 downregulated genes, were identified. Two genes, TEKT2 and RPGR, were associated with lymph node metastasis and prognosis in cervical cancer, and were used to construct a lymph node metastasis-related predictive signature. Based on the predictive signature, patients with cervical cancer were divided into high- and low-risk groups. The high-risk group, characterized by a higher tumor mutation burden and somatic mutation rate, indicated a poor overall survival. The activation of immune infiltration and increased expression of checkpoint genes were observed in the high-risk group, indicating that they might benefit from immunotherapy. Cytarabine, FH535, and procaspase-activating compound-1 were estimated as reasonable chemotherapy options for patients in the high-risk group, whereas two taxanes and five tyrosine kinase inhibitors, including etoposide and vinorelbine, had therapeutic significance for patients in the low-risk group. The expression of TEKT2 and RPGR was significantly downregulated in cervical cancer tissues, especially in metastatic lymph node tissues. The lymph node metastasis-related predictive signature based on TEKT2 and RPGR showed good performance in predicting the survival outcomes of patients with cervical cancer. The risk score of the predictive signature was related to genetic variation and immune infiltration, which could guide immunotherapy and chemotherapy strategies.

Identification of key biomarkers and related immune cell infiltration in cervical cancer tissue based on bioinformatics analysis

Cervical cancer (CC) is the most common gynecological malignant tumor. Immunotherapy has become a new model for the treatment of CC, especially advanced and recurrent cancer. At present, many studies are exploring the safety and efficacy of immunotherapy for advanced or recurrent CC. In this study, CIBERSORT was used to analyze the immune cell infiltration in CC patients, to evaluate the proportion of immune cell types in CC samples, to quantify the cell composition of the immune response, and to analyze its prognostic value. The expression profile datasets of CC were downloaded from the GEO. The differentially expressed genes (DEGs) between CC and normal cervical tissues were identified via R software (version 4.1.1), and their functions and pathways were enriched and analyzed. A protein–protein interaction network was constructed to screen the hub gene. Immune cell infiltration in CC was analyzed via scientific reverse convolution algorithm (CIBERSORT), and the hub gene was analyzed via survival analysis to screen the diagnostic biomarkers of CC. A total of 144 DEGs and 12 hub genes were identified. DEGs are mainly involved in molecular functions such as serine-peptidase activity, serine-hydrolase activity, and chemokine activity. The enrichment pathway is closely related to the interaction between viral proteins and cytokines and cytokine receptors, the interleukin 17 signaling pathway, and chemokine signaling pathway. The immune cell infiltration analysis showed that T cells were the main infiltrating immune cells in CC, especially T cells CD8+ and CD4+ . The survival analysis of the hub gene showed that CEP55, MCM2, RFC4, and RRM2 had high diagnostic value. CEP55, MCM2, RFC4, and RRM2 can be used as diagnostic markers for CC. CD8+ and CD4+ T cells are closely related to the occurrence and development of CC.

CD48 suppresses proliferation and migration as an immune-related prognostic signature in the cervical cancer immune microenvironment.

Cervical cancer (CC) is one of the most common malignant tumors in gynecology. Immunotherapy and targeted therapy are two particularly effective treatments. In this study, weighted gene co-expression network analysis and CIBERSORT algorithm that quantifies the composition of immune cells were used to analyze CC expression data based on the GEO database and identify modules related to T cells. Five candidate hub genes were identified by tumor-infiltrating immune cells estimation and Kaplan-Meier survival analysis according to CC data from The Cancer Genome Atlas (TCGA). Chemotherapeutic response, methylation, and gene mutation analyses were implemented so that the five candidate hub genes identified may be the potential biomarkers and therapeutic targets which were related to T cell infiltration. Moreover, the results of RT-qPCR revealed that CD48 was a tumor suppressor gene, which was negatively correlated with CC stages, lymph node metastasis, and differentiation. Furthermore, the functional study verified that the interference of CD48 was able to boost the proliferation and migration ability in vitro and the growth of transplanted tumors in vivo. Overall, we identified molecular targets related to immune infiltration and prognosis, regarded CD48 as a key molecule involved in the progression of CC, thus providing new insights into the development of molecular therapy and immunotherapeutics against CC.

TMEM33 as a Prognostic Biomarker of Cervical Cancer and Its Correlation with Immune Infiltration.

In women all over the world, cervical cancer (CC) ranks as the fourth most common form of cancer to be diagnosed. It was previously reported that transmembrane protein 33(TMEM33) could report a poor prognosis in several cancers. The current study is aimed at investigating the potential prognostic value of TMEM33 and its relevance to the tumor microenvironment in CC in a comprehensive manner. In this study, CC specimens presented noticeably higher TMEM33 expression level in comparison to nontumor specimens. In pan-cancer assays, it was found that TMEM33 was present at a high level in many different kinds of tumors. We found that patients with CC patients who had a high TMEM33 expression presented worse overall survival (OS) and disease-free survival (DFS) relative to patients who had a low TMEM33 expression. According to the results of a multivariate analysis, a high level of TMEM33 expression can significantly and independently predict the prognosis of CC. The levels of TMEM33 were found to have a negative correlation with resting dendritic cells, resting mast cells, plasma cells, T cells CD8, T cells regulatory, and regulatory T cells. Finally, we confirmed that TMEM33 was overexpressed in CC cells, and its knockdown distinctly suppressed the proliferation and invasion of CC cells. Overall, we provided evidences that TMEM33 could be used as a potential biomarker to assess the prognosis and the level of immune infiltration in CC.

The hsa_circ_0000276-ceRNA regulatory network and immune infiltration in cervical cancer

BackgroundOur previous studies have confirmed that miR-154-5p can regulate pRb expression, and thus, play a tumor suppressor role in HPV16 E7-induced cervical cancer. However, its upstream molecules have not been elucidated in the progression of cervical cancer. This study aimed to explore the role of the miR-154-5p upstream molecule, hsa_circ_0000276 in cervical cancer development and its possible mechanisms of action.MethodsWe detected differences in whole transcriptome expression profiles of cervical squamous carcinoma and tissues adjacent to cervical cancer tissues from patients using microarray technology to predict circular RNAs (circRNAs) with binding sites to miR-154-5p. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of hsa_circ_0000276 (which had the strongest binding capacity to miR-154 and was selected as the target molecule) in cervical cancer tissues, followed by in vitro functional assays. Downstream microRNAs (miRNAs) and mRNAs of hsa_circ_0000276 were identified using transcriptome microarray data and databases, while the protein–protein interaction networks were obtained using STRING. A competing endogenous RNA (ceRNA) network centered on hsa_circ_0000276 was constructed using Cytoscape and GO and KEGG databases. Abnormal expression and prognosis of critical downstream molecules were analyzed using gene databases and molecular experiments. qRT-PCR and western blot analysis was performed to verify the expression of candidate genes.ResultsWe identified 4,001 differentially expressed circRNAs between HPV16-positive cervical squamous carcinoma and benign cervical tissues and 760 circRNAs targeting miR-154-5p, including hsa_circ_0000276. hsa_circ_0000276 and miR-154-5p directly bound, and hsa_circ_0000276 was upregulated, in cervical precancerous lesions and cervical cancer tissues and cells. Silencing hsa_circ_0000276 inhibited G1/S transition and cell proliferation and promoted apoptosis in SiHa and CaSki cells. Bioinformatics analysis showed that the hsa_circ_0000276 ceRNA network included 17 miRNAs and seven mRNAs, and downstream molecules of hsa_circ_0000276 were upregulated in cervical cancer tissues. These downstream molecules were associated with a poor prognosis and affected cervical cancer-associated immune infiltration. Of these, expression of CD47, LDHA, PDIA3, and SLC16A1 was downregulated in sh_hsa_circ_0000276 cells.ConclusionsOur findings show that hsa_circ_0000276 exerts cancer-promoting effects in cervical cancer and is an underlying biomarker for cervical squamous cell carcinoma.

Construction of an immune-related ceRNA network in cervical cancer based on HPV E6 splicing.

Cervical cancer is one of the leading causes of cancer-related deaths worldwide. The unspliced human papillomavirus (HPV) E6 plays an important role in tumor progression and immune regulation. Improved immunotherapy implementation might benefit from a better knowledge of HPV E6 splicing-related immune gene expressions and immunocyte infiltration in cervical cancer. This study aimed to identify the potential therapeutic and prognostic roles of unspliced/spliced E6 ratio (E6 ratio) in cervical cancer. Data from the TCGA were used to analyze the E6 condition and clinical information. Nomogram and K-M analysis were used to analyze assess the prognostic significance, IOBR was used to investigate immunological infiltrates. Functions and pathway enrichment analysis of DEGs were investigated through GO analysis and KEGG pathway analysis, respectively. A core module was taken from the competitive endogenous RNA (ceRNA) network and used to build a lncRNA-miRNA-mRNA network. QT-qPCR was used to detect the expression of genes. CCK-8, colony formation, wound healing and migration assays were used to detect cell functions. Our study found that HPV E6 ratio had significantly correlation with overall survival. In cervical cancer, a high E6 ratio was adversely linked with infiltrating levels of aDC, M1 macrophages, monocytes, NKT, and Tgd. High E6 ratio phenotypes were shown to be implicated in immune response regulation, cell adhesion, and Wnt signaling pathways, according to functional enrichment analysis. Subsequently, we constructed an immune-related ceRNA network based on E6 splicing in cervical cancer, including three lncRNA (LINC00943, LIFR-AS1, DANT2, and RASSF8-AS1), four miRNA (miR-205-5p, miR-181d-5p, miR-222-3p, and miR-221-3p), and seven mRNA (FGFR1, PRLR, CXCL2, ISG20, ISG15, SDC1, and NR2F2). Among them, CXCL2, SDC1, and miR-221-3p were associated with survival and immune cell infiltration. These data imply that a high E6 ratio in cervical cancer contributes to the immune-related ceRNA network, resulting in a low amount of infiltrating effector immune cells and tumor growth. As a result, the E6 ratio might be employed as a biomarker in cervical cancer to determine prognosis and treatment success.

Construction of prognosis model of pyroptosis gene and characterization of tumor microenvironment infiltration in cervical cancer.

Pyroptosis has been demonstrated in recent years to be an inflammatory form of programmed cell death. However, the prognostic evaluation of cervical cancer (CESC) to pyroptosis is insufficient and their correlations with prognosis remain unclear. In this study, we identified 15 differentially expressed pyroptosis-related genes between tumor samples and normal samples. By using Cox regression analysis, a 3-gene risk signature was built and classified all CESC patients in the cancer genome atlas cohort into a low-risk or high-risk group. CESC patients in the low-risk group showed significantly higher survival probabilities than those in the high-risk group (P < .05). And the risk score was found to be an independent factor for predicting the overall survival of CESC patients. Besides, based on 33 pyroptosis-related genes, all CESC cases could be divided into 3 clusters with consensus clustering analysis. We characterized and analyzed the characteristics of tumor microenvironment infiltration in different clusters. Our findings provide a foundation for future research targeting pyroptosis and its immune microenvironment to improve prognosis in CESC patients.

Identification of CD8+ T cell infiltration-related genes and their prognostic values in cervical cancer

Cervical cancer is a female-specific cancer with relatively high morbidity and mortality. As known to all, immune cell infiltrations in the cancer microenvironment are closely related to the cancer diagnosis and prognosis. Here we revealed that the CD8+ T cell infiltration was significantly upregulated in cervical cancer versus normal cervix uteri samples. Through univariate and multivariate cox analyses, we discovered that the CD8+ T cell infiltration was the only independent beneficial factor for the prognosis of cervical cancer. To explore the genes associated with the CD8+ T cell infiltration in cervical cancer, we performed the WGCNA analysis on the differentially expressed genes (DEGs) of cervical cancer versus normal cervix uteri tissues. As a result, 231 DEGs were found to be associated with CD8+ T cell infiltration in cervical cancer. Subsequently, with the Cytoscape analysis, we identified 105 hub genes out of the 231 DEGs. To further explore the genes that might be responsible for the prognosis of cervical cancer, we performed a univariate cox analysis followed by a LASSO assay on the 105 hub genes and located four genes (IGSF6, TLR10, FCRL3, and IFI30) finally. The four genes could be applied to the prediction of the prognosis of cervical cancer, and relatively higher expression of these four genes predicted a better prognosis. These findings contributed to our understanding of the prognostic values of CD8+ T cell infiltration and its associated genes in cervical cancer and thus might benefit future immune-related therapies.

Comprehensive characterization of tumor microenvironment and m6A RNA methylation regulators and its effects on PD-L1 and immune infiltrates in cervical cancer.

Understanding the role of N6-adenosine methylation (m6A) in the tumor microenvironment (TME) is important since it can contribute to tumor development. However, the research investigating the association between m6A and TME and cervical cancer is still in its early stages. The aim of this study was to discover the possible relationship between m6A RNA methylation regulators, TME, PD-L1 expression levels, and immune infiltration in cervical cancer. We gathered RNA-seq transcriptome data and clinical information from cervical cancer patients using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. To begin, researchers assessed the differences in m6A regulatory factor expression levels between cervical cancer and normal tissues. Clustering analysis was adapted to assess PD-L1 expression, immunological score, immune cell infiltration, TME, and probable pathways in cervical cancer samples. The majority of m6A regulators were found to be considerably overexpressed in cervical cancer tissues. Using consensus clustering of 21 m6A regulators, we identified two subtypes (clusters 1/2) of cervical cancer, and we found that WHO stage and grade were associated with the subtypes. PD-L1 expression increased dramatically in cervical cancer tissues and was significantly linked to ALKBH5, FTO, METTL3, RBM15B, YTHDF1, YTHDF3, and ZC3H13 expression levels. Plasma cells and regulatory T cells (Tregs) were considerably elevated in cluster 2. Cluster 1 is involved in numerous signature pathways, including basal transcription factors, cell cycle, RNA degradation, and the spliceosome. The prognostic signature-based riskscore (METTL16, YTHDF1, and ZC3H13) was found to be an independent prognostic indicator of cervical cancer. The tumor immune microenvironment (TIME) was linked to m6A methylation regulators, and changes in their copy number will affect the quantity of tumor-infiltrating immune cells dynamically. Overall, our research discovered a powerful predictive signature based on m6A RNA methylation regulators. This signature correctly predicted the prognosis of cervical cancer patients. The m6A methylation regulator could be a critical mediator of PD-L1 expression and immune cell infiltration, and it could have a significant impact on the TIME of cervical cancer.

The significance of m6A RNA methylation modification in prognosis and tumor microenvironment immune infiltration of cervical cancer.

Recent studies have highlighted that N6-methyladenosine (m6A) plays a significant role in tumorigenicity and progression. However, the mechanism of m6A modifications in the tumor microenvironment (TME) immune cell infiltration in cervical cancer (CC) remains unclear.Clinical and RNA sequencing data of 25 m6A RNA methylation regulators were acquired from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. LASSO Cox regression analysis was used to generate a prognostic risk signature. m6A modification patterns were identified based on the expression of 25 m6A regulators, and their correlation with TME immune cell-infiltrating characterization was analyzed. Principal component analysis was used to construct an m6A-scoring signature (m6A score) to evaluate the m6A modification patterns of individual CC samples and guide the selection of more effective immunotherapeutic strategies.Genetic and expression alterations of 25 m6A regulators were highly heterogeneous between CC and normal tissues. METTL14 and IGF2BP1 were selected to conduct the prognostic risk signature. Three m6A modification patterns were identified in 659 CC samples, which were associated with distinct clinical outcomes and biological pathways. The TME immune cell-infiltrating characterization of the three m6A modification patterns was highly consistent with 3 tumor immune phenotypes, including immune-excluded, immune-inflamed, and immune-desert phenotypes. Due to the heterogeneity of m6A modification patterns, an m6A scoring signature was established to evaluate the m6A modification patterns of individual CC samples. Univariate and multivariate Cox regression analyses revealed that the m6A score is a robust and independent prognostic biomarker for assessing the prognosis of CC patients. A low m6A score, characterized by higher somatic mutation and higher expression of proliferation-related and DNA repair-related genes, indicated poor overall survival. Activation of immune infiltration was exhibited by the high m6A score, which was likely to have a good response and clinical benefits to antiPD-1/L1 immunotherapy.This study highlights the prognostic value of 25 m6A regulators in CC. The m6A modification is related to immune regulation and the formation of TME heterogeneity and complexity. An m6A scoring signature to clarify the individual m6A modification pattern could enhance our understanding of TME immune cell-infiltrating characterization and guide immunotherapy strategies.

SPI1‐related protein inhibits cervical cancer cell progression and prevents macrophage cell migration

The functions and molecular mechanisms of SPI1-related protein (SPIB) were examined in cervical cancer (CC) cells. Genes related to miscarriage and prognosis in CC were identified by Kaplan-Meier and differential expression analysis, respectively. Cell proliferation, apoptosis, migration, and invasion were examined by cell counting kit-8, flow cytometry, transwell migration, and transwell invasion assays, respectively. The potential functions and molecular mechanisms of SPIB in CC were speculated by gene set enrichment analysis (GSEA) analysis. The mRNA and protein levels of genes were examined by RT-qPCR and western blot assays, respectively. The effect of SPIB on macrophage cells was tested by macrophage recruitment assay and bioinformatics analysis. A total of 753 dysregulated genes were identified in 88 TCGA CC samples with a history of one or more miscarriages versus 208 CC samples with no miscarriage history. Also, 91 genes related to CC prognosis were identified. SPIB, a gene related to both miscarriage and CC prognosis, inhibited Hela cell proliferation, migration, and invasion, and facilitated Hela cell apoptosis. GSEA analysis disclosed that SPIB might play vital roles in immunity, chemokine signaling pathway, and macrophage chemotaxis/activation in CC. Moreover, SPIB inhibited C-X-C motif chemokine ligand 8 (CXCL8), C-C motif chemokine ligand 17 (CCL17), and C-C motif chemokine ligand 25 (CCL25) expression in Hela cells, and SPIB overexpression in Hela cells hampered THP-1 cell migration. Higher SPIB expression was associated with less M2 macrophage infiltration in CC. SPIB inhibited CC-cell progression and hindered macrophage cell migration in CC.

Identification of Novel Tumor Microenvironment Regulating Factor That Facilitates Tumor Immune Infiltration in Cervical Cancer.

Cervical cancer is one of the most common gynecologic malignancies and one of the leading causes of cancer-related deaths in women worldwide. There are more than 30 categories of human papillomavirus infections in the genital tract. The recently discovered immune checkpoint suppression is a potential approach to improve clinical outcomes in these patients by altering immune cell function. However, many questions remain unanswered in terms of this method. For example, the proportion of responders is limited and the exact mechanism of action is uncertain. The tumor microenvironment (TME) has long been regarded as having nonnegligible influence on effectiveness of immunotherapy. The programmed cell death protein 1 (PD-1) pathway has received much attention due to its involvement in activating T-cell immune checkpoint responses. Since tumor cells may evade immune detection and become highly resistant to conventional treatments, anti-PD-1/PD-L1 antibodies are preferred as a kind of cancer treatment and many have just been licensed. To provide a theoretical basis for the development of new therapies, investigating the effect of tumor microenvironment on the prognosis of cervical cancer is necessary. In this work, immunological scores obtained from the ESTIMATE algorithm were used to differentiate between patients with high and low immune cell infiltration. We identified 11 immunologically significant differentially expressed genes (DEGs). For example, CXCR3 was found to be an important factor in CD8+ T cell recruitment and tumor immunological infiltration in cervical cancer. These results may lead to novel directions of understanding complex interactions between cancer cells and the tumor microenvironment, as well as new treatment options for cervical cancer.

INHBA is a Prognostic Biomarker and Correlated With Immune Cell Infiltration in Cervical Cancer.

Background: Inhibin A (INHBA), a member of the TGF-β superfamily, has been shown to be differentially expressed in various cancer types and is associated with prognosis. However, its role in cervical cancer remains unclear. Methods: We aimed to demonstrate the relationship between INHBA expression and pan-cancer using The Cancer Genome Atlas (TCGA) database. Next, we validated INHBA expression in cervical cancer using the Gene Expression Omnibus (GEO) database, including GSE7803, GSE63514, and GSE9750 datasets. Enrichment analysis of INHBA was performed using the R package “clusterProfiler.” We analyzed the association between immune infiltration level and INHBA expression in cervical cancer using the single-sample gene set enrichment analysis (ssGSEA) method by the R package GSVA. We explored the association between INHBA expression and prognosis using the R package “survival”. Results: Pan-cancer data analysis showed that INHBA expression was elevated in 19 tumor types, including cervical cancer. We further confirmed that INHBA expression was higher in cervical cancer samples from GEO database and cervical cancer cell lines than in normal cervical cells. Survival prognosis analysis indicated that higher INHBA expression was significantly associated with reduced Overall Survival (p = 0.001), disease Specific Survival (p = 0.006), and Progression Free Interval (p = 0.001) in cervical cancer and poorer prognosis in other tumors. GSEA and infiltration analysis showed that INHBA expression was significantly associated with tumor progression and some types of immune infiltrating cells. Conclusion: INHBA was highly expressed in cervical cancer and was significantly associated with poor prognosis. Meanwhile, it was correlated with immune cell infiltration and could be used as a promising prognostic target for cervical cancer.

FANCI may serve as a prognostic biomarker for cervical cancer: A systematic review and meta-analysis.

Background:DNA damage is a fundamental process that plays a considerable role in generating protein diversity. FANCI, loaded on the altered chromatin, plays a vital role in DNA damage. Abnormal FANCI expression is potentially associated with carcinogenesis.However, the biological role of FANCI in cervical cancer is yet to be determined.Methods:We analyzed FANCI expression via multiple gene expression databases. Genes co-expressed with FANCI and its regulators were identified using LinkedOmics. The correlations between FANCI and cancer immune infiltrates were investigated via Tumor Immune Estimation Resource (TIMER).Results:FANCI was found upregulated with amplification in tumor tissues of multiple cervical cancer cohorts. High FANCI expression was associated with poorer overall survival (OS). Functional network analysis suggested that FANCI regulates spliceosome, DNA replication, and cell cycle signaling via pathways involving several cancer-related kinases and the E2F family. In additional, FANCI expression was positively correlated with infiltrating levels of CD4+ T and CD8+ T cells, and neutrophils. FANCI expression also showed strong correlations with diverse immune marker sets in cervical cancer.Conclusion:These findings suggested that FANCI is correlated with prognosis of and immune infiltration in cervical cancer, laying a foundation for further study of the immune regulatory role of FANCI in cervical cancer.

Aryl hydrocarbon receptor is a prognostic biomarker and is correlated with immune responses in cervical cancer

ABSTRACT Aryl hydrocarbon receptor (AHR) plays an important role in tumor development. However, its function in cervical cancer has not been fully elucidated. We evaluated the ten genes that are predicted to associate with AHR protein interaction. The comprehensive scores were: CYP1A1, ARNT2, HSP90AA1, ARNT, AIP, PTGES3, HSP90AB1, CYP1B1, ESR1, MAF, respectively. In addition, we showed that levels of AHR and its related genes were correlated with the immune infiltration and expression of immuno-regulators (immunoinhibitors, immunostimulators, MHC molecules) levels in cervical cancer. High expression of AHR, CYP1A1, HSP90AA1, and HSP90AB1 and low expression of ESR1 were negatively correlated with the prognoses of cervical cancer patients. The Cox multivariate regression showed that high expression of AHR (HR = 1.874, 95% CI = 1.069–3.285, P= 0.028) and CYP1A1 (HR = 1.822, 95%CI = 1.077–3.080, P= 0.025) were risk factors for prognosis in patients with cervical cancer. IHC results indicated that AHR and CYP1A1 were widely expressed in cervical cancer. These findings suggest that AHR and CYP1A1 may serve as prognostic biomarkers for determining prognosis and immune infiltration in cervical cancer.

Clinical value of MRI, serum SCCA, and CA125 levels in the diagnosis of lymph node metastasis and para-uterine infiltration in cervical cancer

BackgroundCervical cancer shows great differences in depth of invasion, metastasis, and other biological behaviors. The location of the lesion is special, so it is usually difficult to determine the clinical stage. This study aimed to explore the clinical value of magnetic resonance imaging (MRI) and tumor serum markers for the preoperative diagnosis of cervical cancer lymph node metastasis and para-uterine invasion.MethodsA total of 200 patients with cervical cancer admitted to our hospital from January 2019 to January 2020 were collected as the research subjects. Comparing the diagnosis results of preoperative MRI scan, serum tumor markers, and postoperative pathological examination using single factor comparison, we determined the MRI scan results, the comprehensive matching rate between serum tumor markers (squamous cell carcinoma antigen (SCCA), carbohydrate antigen 125 (CA125)) and postoperative pathological results, and the differences of sensitivity, specificity, and accuracy in the prediction of lymph node metastasis and para-uterine infiltration of cervical cancer.ResultsThe levels of SCCA and CA125 in patients with para-uterine invasion and lymph node metastasis were higher than those of patients without invasion and metastasis. Among them, the level of SCCA was significantly different (P<0.05). The level of CA125 was not statistically significant (P>0.05), so MRI combined with serum SCCA was selected for combined diagnosis in the later period. The sensitivity, specificity, and accuracy of MRI diagnosis of cervical cancer and para-uterine infiltrating lymph node metastasis and metastasis were 55.2, 91.6, and 89.5% and 55.2, 91.6, and 89.5%, respectively. These data in MRI combined with serum SCCA were 76.3, 95.3, and 94.3% and 63.2, 96.0, and 95.1%, respectively. The accuracy of tumor markers combined with MRI in the diagnosis of cervical cancer lymph node metastasis and para-uterine invasion was higher than that of MRI.ConclusionsMRI combined with serum SCCA can more accurately identify cervical cancer lymph node metastasis and para-uterine invasion compared with MRI alone. Tumor marker combined with MRI diagnosis is an important auxiliary method for cervical cancer treatment and can provide comprehensive and reliable clinical evidence for evaluation before cervical cancer surgery.

Increased Nuclear Transporter Importin 7 Contributes to the Tumor Growth and Correlates With CD8 T Cell Infiltration in Cervical Cancer.

Background: Importin 7 (IPO7), a karyopherin-β protein, is involved in various tumorigenesis and progression abilities by mediating the nuclear import of oncoproteins. However, the exact biological functions of IPO7 remain to be further elucidated.Materials and Methods: TCGA and GEO datasets were used to identify dysregulated expression of IPO7 in various cancers. Gain-of-function and loss-of-function analyses were used to identify the oncogenic functions of IPO7 in vitro and in vivo. Moreover, LC-MS/MS and parallel reaction monitoring analysis were used to comparatively profiled IPO7-related proteomics and potential molecular machinery.Results: Our works demonstrated that the expression of IPO7 was upregulated and was correlated with a poor prognosis in cervical cancer. In vitro and in vivo experiments demonstrated that knockdown of IPO7 inhibited the proliferation of HeLa and C-4 I cells. LC-MS/MS analysis showed that IPO7-related cargo proteins mainly were enriched in gene transcription regulation. Then independent PRM analysis for the first time demonstrated that 32 novel IPO7 cargo proteins, such as GTF2I, RORC1, PSPC1, and RBM25. Moreover, IPO7 contributed to activating the PI3K/AKT-mTOR pathway by mediating the nuclear import of GTF2I in cervical cancer cells. Intriguingly, we found that the IPO7 expression was negatively correlated with CD8 T cell infiltration via regulating the expression of CD276 in cervical cancer.Conclusion: This study enhances our understanding of IPO7 nuclear-cytoplasmic translocation and might reveal novel potential therapeutic targets. The results of a negative correlation between the IPO7 and CD8 T cell infiltration indicate that the IPO7 might play an important impact on the immune microenvironment of cervical cancer.

PLOD2 Is a Potent Prognostic Marker and Associates with Immune Infiltration in Cervical Cancer.

Background PLOD2 is overexpressed in diverse tumors and plays a vital role in tumorigenesis. However, the prognostic value of PLOD2 in cervical cancer (CESC) remains unclear. Methods PLOD2 expression and CESC patients' survival data were collected from the Oncomine, GEPIA, UALCAN, and Kaplan-Meier Plotter databases; immunohistochemistry (IHC) was used to validate the expression of PLOD2 in CESC; Gene Set Enrichment Analysis was performed using the STRING and DAVID databases; and the correlations between PLOD2 and cancer immune infiltrates were investigated using the TIMER and TISIDB databases. Results We found that the expression level of PLOD2 was increased in various cancers, and meta-analysis in the Oncomine database revealed that PLOD2 was significantly upregulated in CESC compared to that in normal tissues (P < 0.001). In addition, the high expression of PLOD2 was closely related to poor overall survival (OS) and disease-free survival (DFS) in patients with CESC (OS HR = 1.73, P = 0.029; DFS HR = 2.60, P = 0.018). Functional annotations indicated that differentially expressed PLOD2 were primarily related to protein digestion and absorption pathways and to the collagen fibril organization process. Immune infiltration analysis showed that PLOD2 was highly correlated with B cells, CD4+ T cells, T helper type 2 (Th2) cells, and eosinophils in CESC. Conclusion PLOD2 is positively associated with poor prognosis and might be considered a novel diagnostic and prognostic marker for CESC patients.

Magnetic resonance imaging and ultrasound for assessing parametrial infiltration in cervical cancer. A systematic review and meta-analysis.

To provide information on the current evidence regarding the diagnostic performance of ultrasound and MRI for assessing parametrial involvement in cervical cancer using the histological report as the reference standard. Meta-analysis. An extensive search of papers comparing ultrasound and MRI in assessing parametrial infiltration in cervical cancer using pathologic analysis as a reference standard was performed in Medline (Pubmed) and Web of Science from January 1990 to September 2019. Quality was assessed using the QUADAS-2 tool. Our extended search identified 205 citations but after exclusions we finally included 9 articles in the meta-analysis. The risk of bias for most studies was low for four domains were assessed in QUADAS-2. Overall, for ultrasound pooled estimated sensitivity and specificity for diagnosing parametrial infiltration was 78% (95% confidence interval [CI]:48%-93%) and 96% (95% CI=89%-99%), respectively. For MRI these figures were 68% (95% CI=54%-80%) and 91% (95% CI=84%-95%), respectively. No statistical differences were found when comparing both methods (p=0.548). Heterogeneity was low/moderate for MRI and high for ultrasound. Ultrasound and MRI have similar diagnostic performance for detecting parametrial infiltration in women with cervical cancer. This might have relevance from the clinical point of view, since ultrasound is cheaper than MRI.