Cervical Cancer Tissues Research Articles

CircVIRMA enhances cell malignant behavior by governing the miR-452-5p/CREBRF pathway in cervical cancer.

Our current study aimed to investigate the role and mechanism of circVIRMA in cervical cancer (CC) progression. CircVIRMA, microRNA-452-5p (miR-452-5p) and CREB3 regulatory factor (CREBRF) mRNA levels were examined in CC via quantitative real-time PCR (qRT-PCR). The protein level of CREBRF in CC was checked by Western blot. Cell Counting Kit-8 (CCK-8), colony formation, 5-Ethynyl-2'-deoxyuridine (EdU) staining, cell cycle, flow cytometry and transwell assays were conducted to estimate the effects of circVIRMA on malignant phenotypes of CC tumors. Western blot was used to measure related marker protein levels. The interaction between miR-452-5p and circVIRMA or CREBRF was predicted by bioinformatics analysis and verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. Xenograft assay was used to assess the effect of circVIRMA on tumor growth in vivo. Immunohistochemistry (IHC) assay was performed to detect Ki-67 expression in tissues of mice. CircVIRMA and CREBRF levels were upregulated, while miR-452-5p was downregulated in CC tissues and cells. CircVIRMA silencing restrained CC cell proliferation, migration and invasion whereas induced apoptosis in vitro. In addition circVIRMA knockdown markedly attenuated xenograft tumor growth in vivo. circVIRMA was an efficient molecular sponge for miR-452-5p, and negatively regulated miR-452-5p expression. circVIRMA regulated CREBRF expression to modulate CC progression via miR-452-5p. MiR-452-5p downregulation reversed the effects of circVIRMA knockdown on CC progression. MiR-452-5p directly targeted CREBRF, and CREBRF overexpression partly restored the impact of miR-452-5p mimics on CC progression. circVIRMA mediated CC progression via regulating miR-452-5p/CREBRF axis, providing a novel therapeutic target for CC treatment.

METTL3 facilitates the progression of cervical cancer by m6A modification-mediated up-regulation of NEK2.

N6-methyladenosine (m6A) is the most prevalent modification found in eukaryotic RNA and played a significant role in various cancers. However, the mechanism by which m6A modification influences cervical cancer (CC) tumorigenesis remains unclear. Therefore, we aim to elucidate the role and mechanism of METTL3 in CC progression. In the present study, we observed a significant upregulation of METTL3 in CC tissues and cell lines. Knockdown of METTL3 resulted in reduced growth, migration, and invasion of CC cells, as well as affected apoptosis, while overexpression of METTL3 reversed these effects. Through a combined analysis of meRIP-seq and Ribo-seq data following METTL3 knockdown, NEK2 was identified as a key target of METTL3 in CC cells. Correlation analysis, MeRIP-qPCR, and luciferase reporter assay suggested that METTL3 regulates NEK2 expression through m6A modification. NEK2 synergized with METTL3 to mediate the malignant phenotype of CC cells. The METTL3-NEK2 axis promoted CC progression by activating the Wnt/β-catenin pathway and inhibiting the apoptosis pathway. In conclusion, METTL3 facilitated the malignant progression of CC and contributed to the formation of the METTL3-NEK2 regulatory axis in an m6A-dependent manner, which represented a potential target for CC therapy.

Exploring MPC1 as a potential ferroptosis-linked biomarker in the cervical cancer tumor microenvironment: a comprehensive analysis

BackgroundThe increasing problems of drug and radiotherapy resistance in cervical cancer underscores the need for novel methods for its management. Reports indicate that the expression of MPC1 may be associated with the tumor microenvironment and the occurrence of ferroptosis in cervical cancer. The objective of this study was to visually illustrate the prognostic significance and immunological characterization of MPC1 in cervical cancer.MethodsThe expression profile and prognostic significance of MPC1 were analyzed using various databases, including UALCAN, TIMER2, GEPIA2, and Kaplan–Meier Plotter. TISIDB, TIMER2, and immunohistochemical analysis were used to investigate the correlation between MPC1 expression and immune infiltration. GO enrichment analysis, KEGG analysis, Reactome analysis, ConsensusPathDB, and GeneMANIA were used to visualize the functional enrichment of MPC1 and signaling pathways related to MPC1. The correlation analysis was carried out to examine the relationship between MPC1 and Ferroptosis gene in TIMER 2.0, ncFO, GEPIA Database and Kaplan–Meier Plotter.ResultsWe demonstrated that the expression levels of MPC1 in cervical cancer tissues were lower than those in normal cervical tissues. Kaplan–Meier survival curves showed shorter overall survival in cervical cancer patients with low levels of MPC1 expression. The expression of MPC1 was related to the infiltrating levels of tumor-infiltrating immune cells in cervical cancer. Moreover, MPC1 expression was associated with the iron-mediated cell death pathway, and several important ferroptosis genes were upregulated in cervical cancer cells. Furthermore, after knocking down MPC1 in HeLa cells, the expression of these genes decreased.ConclusionThese findings indicate that MPC1 functions as a prognostic indicator and plays a role in the regulation of the ferroptosis pathway in cervical cancer.

Inhibiting SNX10 induces autophagy to suppress invasion and EMT and inhibits the PI3K/AKT pathway in cervical cancer.

Cervical cancer (CC) is a prevalent malignancy among women with high morbidity and poor prognosis. Sorting nexin 10 (SNX10) is a newly recognized cancer regulatory factor, while its action on CC progression remains elusive. Hence, this study studied the effect of SNX10 on CC development and investigated the mechanism. The SNX10 level in CC and the overall survival of CC cases with different SNX10 expressions were determined by bioinformatics analysis in GEPIA. The SNX10 expression in tumor tissues and clinical significance were studied in 64 CC cases. The overall survival was assessed using Kaplan-Meier analysis. The formation of LC3 was evaluated using immunofluorescence. Cell invasion was measured using the Transwell assay. Epithelial-to-mesenchymal transition (EMT) was determined by observing cell morphology and assessing EMT marker levels. A xenograft tumor was constructed to evaluate tumor growth. SNX10 was elevated in CC tissues and cells, and the CC cases with high SNX10 levels exhibited poor overall survival. Besides, SNX10 correlated with the FIGO stage, lymph node invasion, and stromal invasion of CC. SNX10 silencing induced CC cell autophagy and suppressed CC cell invasion and EMT. Meanwhile, silenced SNX10 could suppress invasion and EMT via inducing autophagy. Furthermore, SNX10 inhibition suppressed the PI3K/AKT pathway. Moreover, silenced SNX10 restrained the tumor growth, autophagy, and EMT of CC in vivo. SNX10 was enhanced in CC and correlated with poor prognosis. Silenced SNX10 induced autophagy to suppress invasion and EMT and inhibited the PI3K/AKT pathway in CC, making SNX10 a valuable molecule for CC therapy.

Identification of 10 differentially expressed genes involved in the tumorigenesis of cervical cancer via next-generation sequencing.

The incidence and mortality of cervical cancer remain high in female malignant tumors worldwide. There is still a lack of diagnostic and prognostic markers for cervical carcinoma. This study aimed to screen differentially expressed genes (DEGs) between normal and cervical cancer tissues to identify candidate genes for further research. Uterine cervical specimens were resected from our clinical patients after radical hysterectomy. Three patients' transcriptomic datasets were built by the next generation sequencing (NGS) results. DEGs were selected through the edgeR and DESeq2 packages in the R environment. Functional enrichment analysis, including GO/DisGeNET/KEGG/Reactome enrichment analysis, was performed. Normal and cervical cancer tissue data from the public databases TCGA and GTEx were collected to compare the expression levels of 10 selected DEGs in tumor and normal tissues. ROC curve and survival analysis were performed to compare the diagnostic and prognostic values of each gene. The expression levels of candidate genes were verified in 15 paired clinical specimens via quantitative real-time polymerase chain reaction. There were 875 up-regulated and 1,482 down-regulated genes in cervical cancer samples compared with the paired adjacent normal cervical tissues according to the NGS analysis. The top 10 DEGs included APOD, MASP1, ACKR1, C1QTNF7, SFRP4, HSPB6, GSTM5, IGFBP6, F10 and DCN. GO, DisGeNET and Reactome analyses revealed that the DEGs were related to extracellular matrix and angiogenesis which might influence tumorigenesis. KEGG enrichment showed that PI3K-Akt signaling pathway might be involved in cervical cancer tumorigenesis and progression. The expression levels of selected genes were decreased in tumors in both the public database and our experimental clinical specimens. All the candidate genes showed excellent diagnostic value, and the AUC values exceeded 0.90. Additionally, APOD, ACKR1 and SFRP4 expression levels could help predict the prognosis of patients with cervical cancer. In this study, we selected the top 10 DEGs which were down-regulated in cervical cancer tissues. All of them had dramatically diagnostic value. APOD, ACKR1 and SFRP4 were associated with the survivals of cervical cancer. C1QTNF7, HSPB6, GSTM5, IGFBP6 and F10 were first reported to be candidate genes of cervical carcinoma.

Downregulation of circSTX6 suppresses tumor progression while facilitating radiosensitivity in cervical squamous cell carcinoma

Backgroundcervical squamous cell carcinoma (CSCC) is the second gynecological tumors that seriously threaten women’s life quality. Circular RNA (circRNA) is related with cervical cancer carcinogenesis and radiosensitivity. AimTo investigate the performance of hsa_circ_0007905 (circSTX6) on regulating cellular activities and radiosensitivity in CSCC. MethodsThe relative expression of circSTX6 in different tissue samples was detected by RT-qPCR. The cellular activity influence of circSTX6 in cervical cancer cells was measured by CCK-8 and Transwell assays. The survival fractions of cancer cells were detected after the radiation treatment to explore the relationship between circSTX6 and radiosensitivity of cervical cancer. The downstream miRNAs were predicted and analyzed. Rescue experiments confirmed their targeting relationship. Bioinformatic analysis was performed to identify the potential targets of miR-203a-3p. ResultscircSTX6 was increased and miR-203a-3p was decreased in cervical cancer tissues and radio-resistant tissues. CircSTX6 expression was related to the patient’s survival rates. CircSTX6 absence decreased cervical cancer cell proliferation and invasion while enhancing the sensitivity of cervical cancer cells to radiotherapy by regulating miR-203a-3p. RAB27B may be a target of miR-203a-3p. ConclusioncircSTX6 may be a clinical prognostic biomarker in CSCC. The absence of circSTX6 inhibits cellular behaviors and increases the sensitivity of cervical cancer cells to radiation by modulating miR-203a-3p/RAB27B axis.

Serinc2 Drives the Progression of Cervical Cancer Through Regulating Myc Pathway.

As one of the most common malignancies, cervical cancer (CC) seriously affects women's health. This study aimed to investigate the biological function of Serinc2 in CC. Serinc2 expression was surveyed utilizing immunohistochemistry, western blot, and qRT-PCR. CC cell viability, invasion, proliferation, migration, and apoptosis, were detected via CCK-8, Transwell assay, colony formation, wound healing assay, and flow cytometry. Glucose consumption, lactate production, and ATP levels were determined by the corresponding kit. The protein expression of c-Myc, PDK1, HK2, PFKP, LDHA, Snail, Vimentin, N-cadherin, and E-cadherin was detected via western blot. The interaction between the promoter of PFKP and Myc was confirmed through luciferase reporter assay and Chip assay. Invivo, to evaluate the function of Serinc2 on tumor growth, a xenograft mouse model was used. In CC tissues and cells, Serinc2 was upregulated. In CC cells, knockdown of Serinc2 suppressed cell invasion, proliferation, migration, decreased the expression of Snail, Vimentin, N-cadherin, HK2, PFKP, LDHA, and PDK1, increased E-cadherin expression, reduced glucose consumption and the production of lactate and ATP, and induced cell apoptosis; Serinc2 overexpression led to the opposite results. Mechanically, Serinc2 promoted Myc expression, and Myc induced PFKP expression. Furthermore, overexpressed Myc abolished the inhibitive influences of Serinc2 knockdown on the malignant behaviors of CC cells. Additionally, knockdown of Serinc2 inhibited tumor growth and reduced the protein expression of c-Myc, PFKP, LDHA, and PDK1 invivo. Knockdown of Serinc2 inhibited the malignant progression of CC, which was achieved via Myc pathway. Our study provides novel insight into CC pathogenesis.

Dissecting the Single-Cell Diversity and Heterogeneity Underlying Cervical Precancerous Lesions and Cancer Tissues.

The underlying cellular diversity and heterogeneity from cervix precancerous lesions to cervical squamous cell carcinoma (CSCC) is investigated. Four single-cell datasets including normal tissues, normal adjacent tissues, precancerous lesions, and cervical tumors were integrated to perform disease stage analysis. Single-cell compositional data analysis (scCODA) was utilized to reveal the compositional changes of each cell type. Differentially expressed genes (DEGs) among cell types were annotated using BioCarta. An assay for transposase-accessible chromatin sequencing (ATAC-seq) analysis was performed to correlate epigenetic alterations with gene expression profiles. Lastly, a logistic regression model was used to assess the similarity between the original and new cohort data (HRA001742). After global annotation, seven distinct cell types were categorized. Eight consensus-upregulated DEGs were identified in B cells among different disease statuses, which could be utilized to predict the overall survival of CSCC patients. Inferred copy number variation (CNV) analysis of epithelial cells guided disease progression classification. Trajectory and ATAC-seq integration analysis identified 95 key transcription factors (TF) and one immunohistochemistry (IHC) testified key-node TF (YY1) involved in epithelial cells from CSCC initiation to progression. The consistency of epithelial cell subpopulation markers was revealed with single-cell sequencing, bulk sequencing, and RT-qPCR detection. KRT8 and KRT15, markers of Epi6, showed progressively higher expression with disease progression as revealed by IHC detection. The logistic regression model testified the robustness of the resemblance of clusters among the various datasets utilized in this study. Valuable insights into CSCC cellular diversity and heterogeneity provide a foundation for future targeted therapy.

Study on the Role of EPHB6 in Inhibiting the Malignant Progression of Cervical Cancer C33A Cells by Binding to CBX7.

Cervical cancer stands as the most frequently diagnosed malignancy affecting the female reproductive. The erythropoietin-producing hepatocyte (Eph) family tyrosine kinases play important roles in tumorigenesis and cancer aggression. However, the exact role of EPHB6 in cervical cancer remains unknown. The present study investigated the role of EPHB6 in the malignant process of cervical cancer. GEPIA, tnmplot and kmplot database was used to study the expression of EPHB6 in cervical cancer tissues. western blotting was used to detect the expression of EPHB6, CyclinD, CDK4, CDK6, CBX7, MMP2 and MMP9. CCK8 and EDU staining were used to detect cell proliferation. Wound healing and transwell were used to detect cell proliferation and migration. Flow cytometry was used to detect cell cycle level. The linkedomics database was used to predict the correlation of EPHB6 and CBX7 in cervical cancer. Subsequently, HDOCK server was used to predict the combination of EPHB6 and CBX7. Our current results suggested that the expression of EPHB6 is reduced in cervical cancer tissues and cell lines, and the lower the expression, the worse the prognosis. Moreover, overexpression of EPHB6 inhibits cell proliferation, invasion and migration and cycle acceleration of C33A cells. Furthermore, EPHB6 and CBX7 bind to each other in C33A cells, and EPHB6 inhibits cell proliferation, invasion, migration and cell cycle acceleration in cervical cancer by binding to CBX7. EPHB6 expression is reduced in cervical cancer tissues and cells. Its overexpression inhibits proliferation, invasion, migration, and cell cycle acceleration in C33A cells, exhibiting synergy when bound to CBX7.

Role of HPV E7/miR-143-3p/SH2D3A pathway in regulating the occurrence and development of cervical cancer.

This study aims to explore the role of SH2D3A in cervical cancer, as well as its potential interaction with human papillomavirus (HPV) E7 and microRNA (miRNA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were used to compare the expressions of SH2D3A in tissues. To assess the effects of SH2D3A on cervical cancer cell phenotypes, SH2D3A was knocked down in SiHa and HeLa cells, followed by cell proliferation (Cell Counting Kit-8 assay), apoptosis (flow cytometry), and invasion (Transwell assay) analyses. A transplantation tumor model was established to compare the tumorigenic ability of cervical cancer cells before and after SH2D3A silencing. Bioinformatics analysis predicted and dual-luciferase reporter assays verified the sponge adsorption effect of SH2D3A on miRNA. Western blot and qRT-PCR analyses were conducted to examine the impact on target genes following the downregulation of HPV E7 and SH2D3A. SH2D3A expression was significantly elevated in cervical cancer tissues. SH2D3A silencing inhibited cell proliferation and invasion, induced apoptosis, and reduced tumorigenesis in nude mice. Bioinformatics tools identified a binding relationship between SH2D3A and miR-143-3p, confirmed by the luciferase reporter assays. Western blot analysis revealed that SH2D3A knockdown led to decreased levels of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) proteins. Additionally, qRT-PCR showed that SH2D3A mRNA levels decreased after HPV E7 silencing, whereas miR-143-3p levels significantly increased. HPV E7 influences SH2D3A expression through miR-143-3p, thereby regulating the JAK1/STAT3 pathway. This mechanism promotes the occurrence and development of cervical cancer.

Abstract C120: Characterization of the inflammatory tumor microenvironment and its association with cancer health disparities

Abstract Black persons have the highest mortality rates of both cervical cancer (CC) and pancreatic ductal adenocarcinoma (PDAC) in the United States. Differences in access to quality healthcare and socioeconomic status contribute to these cancer health disparities as well as ancestry and biology. In other cancer types, differences in the inflammatory tumor landscape across races and ancestral populations have been reported. However, the inflammatory tumor microenvironment (TME) as it relates to CC and PDAC health disparities is not well defined. Black patients are often underrepresented in PDAC studies. Meanwhile, CC health disparities studies primarily investigate socioeconomic status, screening, and vaccination rates. Therefore, we aim to characterize the inflammatory TME in these two cancer types with the long-term goal of informing prevention, prognostic, and therapeutic strategies. Clinicopathological characteristics were compared between Black (n = 144) and White (n = 198) patients with CC who received care at Johns Hopkins Medicine between 1995 and 2019. Surgically resected formalin-fixed paraffin embedded (FFPE) CC tissue samples were obtained from Non-Hispanic Black (n = 10), Non-Hispanic White (n = 10), Hispanic Black (n = 5), and Hispanic White (n = 5) women matched on grade, age, and subtype. Tissue microarrays (TMAs) were constructed using archival surgically resected FFPE PDAC tissues from Black (n = 45) and White (n = 45) patients, matched on sex, age, stage, and time of surgery. Multiplexing immunohistochemistry (mIHC) was used to assess markers for i) T cells (CD3, CD8, CD4, FoxP3), M2 macrophages (CD163), mast cells (Tryptase), and fibroblasts (FAP) in PDAC tissues and ii) B cells (CD79A), T cells (CD3, CD8, CD4, FoxP3), plasma cells (CD138/syndecan-1), programmed death-ligand 1 protein (PD-L1), macrophages (CD68, CD163), natural killer cells (NKP46/CD56/CD16), neutrophils (CD66ce), and mast cells (Tryptase) in CC tissues. HALO Image Analysis Platform (version 3.6.4134.137; Indica Labs) was used to quantify marker expression. GraphPad Prism Software (version 10.0.03), was used for graphing and statistical analysis. Squamous cell CC was the most frequent histological subtype in both Black (68%) and White (44%) women. Progression through treatment was more common among Black women (24%) compared to White women (7%). CD163+ M2 macrophages were significantly increased in PDAC tumors compared to benign tissues among Black patients (p = 0.0435), and in tumors from Black women compared to White women (p = 0.0067). FAP+ fibroblasts were also significantly increased in PDAC tumors compared to benign tissues among Black patients (p = 0.0001) and in tumors from Black women compared to White women (p = 0.0013). CD8+ cytotoxic T cells and FoxP3+ regulatory T cells were comparable between races. We observed differences in macrophage and fibroblast distribution between races supporting the effort for future studies that examine the significance of characterizing the TME to address cancer health disparities. Citation Format: Jelani Jarrett, Jae W Lee, Ali Dbouk, Vahinipriya Manoharan, Kennedy Rains, Terri Mason, Kimberly Levinson, Laura D Wood, Michael G Goggins, Janielle P Maynard. Characterization of the inflammatory tumor microenvironment and its association with cancer health disparities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C120.

AUP1 transcriptionally activated by KDM5B reprograms lipid metabolism to promote the malignant progression of cervical cancer.

Cervical cancer is one of the reproductive malignancies threatening women's lives worldwide. In the present study, it was aimed to explore the role and mechanism of ancient ubiquitous protein 1 (AUP1) in cervical cancer. Through bioinformatics analysis, AUP1 expression in cervical cancer tissues and the correlation between AUP1 and the prognosis of patients were analyzed. AUP1 expression in several cervical cancer cell lines was detected. Following the co‑transfection of short hairpin RNA specific to AUP1 with or without lysine demethylase 5B (KDM5B) overexpression plasmids in SiHa cells, the proliferation and apoptosis of SiHa cells were detected. Additionally, wound healing and Transwell assays were used to detect SiHa cell migration and invasion. Cellular lipid droplets level was detected using the Oil red O staining. Meantime, the levels of triglyceride, cholesterol, oxygen consumption rates and expression of lipid metabolism‑related proteins were detected to assess the lipid metabolism in SiHa cells. Then, the luciferase reporter assay and ChIP assay were used to verify the binding between KDM5B and AUP1. Finally, the effects of AUP1 and KDM5B on the growth and lipid metabolism in SiHa tumor‑bearing mice were measured. AUP1 was significantly upregulated in cervical cancer tissues and cells. AUP1 interference inhibited the malignant biological behaviors and lipid metabolism reprogramming of SiHa cells, which was blocked by KDM5B overexpression. Moreover, KDM5B could transcriptionally activate AUP1 and upregulate AUP1 expression. Furthermore, AUP1 knockdown transcriptionally regulated by KDM5B limited the tumor growth and suppressed the lipid metabolism reprogramming in vivo. Collectively, AUP1 could be transcriptionally activated by KDM5B to reprogram lipid metabolism, thereby promoting the progression of cervical cancer. These findings reveal possible therapeutic strategies in targeting metabolic pathways.

Immunoprognostic analysis of indoleamine 2,3-dioxygenase 1 in patients with cervical cancer.

The incidence of cervical cancer is increasing. Immunotherapies show better patient outcomes than monotherapies; however, the mainstay treatment for cervical cancer remains surgery and chemotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) acts on multiple tryptophan substrates, exhibiting antitumor, immunomodulatory, and antioxidant activities. Despite the association of elevated IDO1 expression with unfavorable outcomes in various cancers, its precise function in cervical cancer remains ambiguous. Here, we explored the prognostic significance of IDO1 in cervical carcinoma. Gene expression datasets were obtained from The Cancer Genome Atlas. Gene Expression Omnibus datasets were used for differential expression and functional correlation analyses. Using Human Protein Atlas alongside Tumor-Immune System Interaction Database, we assessed the association of IDO1 with survival rates. Given the link between cervical cancer prognosis and immune invasion, CIBERSORT was used to assess the connection between immune cells and IDO1, while the percentage of tumor-penetrating immune cells based on IDO1 expression in cervical cancer patients was analyzed using Tumor-Immune System Interaction Database. Incorporating a clinicopathological characteristic-based risk score model with IDO1 risk score, we devised a nomogram to predict cervical cancer patient survival. The effects of IDO1 in immune regulation and its prognostic significance were validated using data from patients with cervical cancer obtained from The Cancer Imaging Archive database. Compared with that in normal cervical tissues, IDO1 expression was significantly upregulated in cervical cancer tissues and significantly correlated with cervical cancer progression and prognosis. IDO1 expression showed a positive association with monocyte and macrophage abundance, while exhibiting a negative correlation with that of endothelial cells and eosinophils. Cox regression analyses highlighted IDO1 as the core immune gene implicated in cervical cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed an association of IDO1 with the metabolic pathways of tryptophan, phenylalanine, and tyrosine. Univariate and multivariate analyses revealed that elevated IDO1 expression correlates markedly with cervical cancer outcomes, suggesting it as a promising therapeutic target. The Cancer Imaging Archive data analysis revealed that the impact of anti-PD1 and CTLA4 therapy is more pronounced in cervical cancer patients exhibiting elevated IDO1 expression. IDO1 is a potential target for immunotherapy for cervical cancer.

Downregulation of RhoB Inhibits Cervical Cancer Progression and Enhances Cisplatin Sensitivity.

RhoB, a member of the Rho GTPase family, has been implicated in the malignant progression of various cancer types. However, its role in cervical cancer (CC) remains unclear. Therefore, this study aims to elucidate the biological function of RhoB in CC and its relationship with cisplatin sensitivity. We analyzed data from the TCGA, GTEx, and GEO databases, revealing that RhoB mRNA expression is downregulated in CC tissues compared to normal cervical tissues. The further analysis of the TCGA database and Tongji samples showed that CC patients with a high RhoB expression had a shorter overall survival (OS). Subsequently, we found that the knockdown of RhoB inhibited the proliferation, migration, and invasion of cancer cells, while increasing apoptosis. Through Western blot (WB) analysis, we found that knocking down RhoB resulted in an increased expression of the epithelial marker E-cadherin, while the levels of N-cadherin, MMP2, MMP9, Vimentin, and Snail1 were reduced. Additionally, RhoB mRNA expression was upregulated in CC tissues after chemotherapy compared to CC tissues before chemotherapy. In CC cells, RhoB expression increased with cisplatin concentration, and the IC50 value decreased following RhoB knockdown. Moreover, the knockdown of RhoB could enhance the cellular apoptosis triggered by cisplatin. This study demonstrated that RhoB plays an oncogenic role in CC and that its knockdown could enhance the sensitivity of CC cells to cisplatin.

Serum levels of stearic and dihomo-γ-linolenic acids can be used to diagnose cervical cancer and cervical intraepithelial neoplasia

Despite widespread cervical cancer (CC) screening programs, low participation has led to high morbidity and mortality rates, especially in developing countries. Because early-stage CC often has no symptoms, a non-invasive and convenient diagnostic method is needed to improve disease detection. In this study, we developed a new approach for differentiating both CC and cervical intraepithelial neoplasia (CIN)2/3, a precancerous lesion, from healthy individuals by exploring CC fatty acid metabolic reprogramming. Analysis of public datasets suggested that various fatty acid metabolizing enzymes were expressed at higher levels in CC tissues than in normal tissues. Correspondingly, 11 free fatty acids (FFAs) showed significantly different serum levels in CC patient samples compared with healthy donor samples. Nine of these 11 FFAs also displayed significant alterations in CIN2/3 patients. We then generated diagnostic models using combinations of these FFAs, with the optimal model including stearic and dihomo-γ-linolenic acids. Receiver operating characteristic curve analyses suggested that this diagnostic model could detect CC and CIN2/3 more accurately than using serum squamous cell carcinoma antigen level. In addition, the diagnostic model using FFAs was able to detect patients regardless of clinical stage or histological type. Overall, the serum FFA diagnostic model developed in this study could be a powerful new tool for the non-invasive early detection of CC and CIN2/3.

RNF113A as a poor prognostic factor promotes metastasis and invasion of cervical cancer through miR197/PRP19/P38MAPK signaling pathway

It has been discovered that aberrant expression of RNF113A plays a significant role in various diseases, including esophageal cancer, hepatocellular carcinoma, and X-linked trichothiodystrophy syndrome. Nevertheless, its functional implications in cervical cancer (CC) remain unclear. The objective of this study was to investigate the role of RNF113A in both the development and prognosis of CC. To achieve this objective, a total of sixty cases were included in the follow-up investigation. The findings revealed a significant up-regulation of RNF113A protein in CC tissues compared to paired paracancerous tissues, and a high expression level of RNF113A was strongly associated with malignant phenotypes such as lymph node metastasis, differentiation degree, depth of invasion, and FIGO stage. Meanwhile, RNF113A was found to be an independent prognostic risk factor, with its high expression significantly correlating with a reduced overall survival period in patients. To elucidate the underlying cause and mechanism of the unfavorable prognosis associated with RNF113A, comprehensive functional investigations were conducted both in vitro and in vivo.Interestingly, it was revealed that RNF113A promoted migration and invasion while inhibiting apoptosis of CC cells, thereby contributing to a poor prognosis. Mechanistically, RNF113A regulated the progression and prognosis of CC through the miR197/Prp19/p38Mark signaling pathway. Overall, our findings underscore the potential clinical significance of RNF113A as an unfavorable prognostic factor in CC.

METTL3 Regulates the Translation of Oncogene Myc through m6A Modification and Promotes the Occurrence and Development of Cervical Cancer.

Cervical cancer (CC) is one of the major types of gynecological cancer, with a high global incidence and mortality rate. Methyltransferase-like 3 (METTL3), a key constituent of methyltransferase, plays a crucial role in various biological processes. Still, only a rare report has been made on its involvement in the progression of CC. Therefore, this study aims to investigate the impact of METTL3 in CC and its molecular mechanisms. Gene expression datasets about CC were obtained from the Gene Expression Omnibus (GEO) database, and the expression of METTL3 and Myc was analyzed. Cell viability was detected after METTL3 knockdown in HeLa and SiHa cells, followed by cell counting Kit-8 (CCK-8) assays. The relative expression of METTL3 and Myc was detected via real-time quantitative PCR (qPCR) assays, and the protein expression was determined using Western blot. Meanwhile, cell invasion and migration capabilities were assessed utilizing transwell assays, and cell proliferation was detected using the EdU experiment. Furthermore, RNA methylation immunoprecipitation-qPCR detection was performed to determine the expression of Myc after N6-methyladenosine (m6A) modification. Analysis of the GEO database indicated elevated expression of METTL3 and Myc in CC tissues. Patients with high METTL3 expression had shorter disease-free survival, and patients with high Myc expression had shorter overall survival. Following the knockdown of METTL3, there was a significant reduction in the viability, proliferation, invasion, and migration abilities of HeLa and SiHa cells. Besides, the expression of METTL3 and Myc mRNAs and proteins was greatly reduced. The level of m6A Myc decreased significantly after METTL3 knockdown. METTL3 plays an important role in regulating cervical cancer cells. METTL3 promotes CC development through m6A modification to regulate the expression of the oncogene Myc.

Changes in the molecular nodes of the Notch and NRF2 pathways in cervical cancer tissues from the precursor stages to invasive carcinoma.

Cancer is a multifactorial disease characterized by the loss of control in the expression of genes known as cancer driver genes. Cancer driver genes trigger uncontrolled cell replication, which leads to the development of malignant tumors. A cluster of signal transduction pathways that contain cancer driver genes involved in cellular processes, such as cell proliferation, differentiation, apoptosis and dysregulated organ growth, are associated with cancer initiation and progression. In the present study, three signal transduction pathways involved in cervical cancer (CC) development were analyzed: The Hippo pathway (FAT atypical cadherin, yes-associated protein 1, SMAD4 and TEA domain family member 2), the Notch pathway [cellular-MYC, cAMP response element-binding binding protein (CREBBP), E1A-associated cellular p300 transcriptional co-activator protein and F-Box and WD repeat domain containing 7] and the nuclear factor erythroid 2-related factor 2 (NRF2) pathway [NRF2, kelch-like ECH-associated protein 1 (KEAP1), AKT and PIK3-catalytic subunit α]. Tumor samples from patients diagnosed with various stages of CC, including cervical intraepithelial neoplasia (CIN) 1, CIN 2, CIN 3, in situ CC and invasive CC, were analyzed. The mRNA expression levels were analyzed using reverse transcription-quantitative PCR assays, whereas protein expression levels were assessed through immunohistochemical tissue microarrays. High mRNA expression levels of c-MYC and AKT and low expression levels of NRF2 and KEAP1 were associated with a decreased survival time of patients with CC. Additionally, increased expression levels of c-MYC were detected in the invasive CC stage. At the protein level, increased NRF2 expression levels were observed in all five stages of CC samples compared with those in the cancer-free control samples. AKT1 was found to be dysregulated in the CIN 1 and CIN 2 stages, PI3K in the in situ and invasive stages, and CREBBP in the CIN 3 and in situ stages. In summary, the present study demonstrated significant changes in proteins of the Notch and NRF2 pathways in CC. NRF2 was overexpressed in all cervical cancer stages (cervical intraepithelial neoplasia, in situ CC and invasive CC). The present study makes an important contribution to the possible biomarker proteins to be analyzed for the presence of premalignant and malignant lesions in the cervix.

TTYH3 Promotes Cervical Cancer Progression by Activating the Wnt/ β -Catenin Signaling Pathway

The role of tweety homolog 3 (TTYH3) has been studied in several cancers, including hepatocellular carcinoma, cholangiocarcinoma, and gastric cancer. The results showed that TTYH3 is highly expression in cervical cancer tissues and cells and high TTYH3 expression correlates with poor prognosis in patients with cervical cancer. TTYH3 markedly reduced the apoptosis rate and promoted proliferation, migration, and invasion. Silencing of TTYH3 has been shown to have an inhibitory effect on cervical cancer progression. Moreover, TTYH3 enhanced EMT and activated Wnt/β-catenin signaling. Furthermore, TTYH3 knockdown inhibited the tumor growth in vivo. In conclusion, TTYH3 promoted cervical cancer progression by activating the Wnt/β-catenin signaling.

Activation of the G Protein-Coupled Bile Acid Receptor TGR5 Modulates the HCP5/miR-139-5p/DDIT4 Axis to Antagonize Cervical Cancer Progression.

A growing body of evidence indicates that the G protein-coupled bile acid receptor, TGR5, plays a critical role in multiple physiological processes ranging from metabolic disorders to cancers. However, the biological functions of TGR5 in cervical cancer (CC) have not been elucidated. Here, using TGR5 knockout mice, we found that a deficiency of TGR5 leads to greater sensitivity to the progression of cervical inflammation. Activation of TGR5 by its specific ligands significantly attenuated the malignant behavior of CC cells. In addition, we found that TGR5 can negatively modulate the expression of lncRNA HCP5 by blocking its transcription activation when mediated by p65. HCP5 was highly expressed in CC tissues, which was positively correlated with the poor prognosis of CC patients. HCP5 knockdown notably restrained CC cell proliferation, colony formation, and migration in vitro, and inhibited tumor growth in vivo. Furthermore, HCP5 can function as the molecular sponge for miR-139-5p to upregulate DNA damage-induced transcript 4 (DDIT4) in CC cells. Murine xenograft studies demonstrated that TGR5 suppressed the tumor formation of CC cells and downregulated HCP5 and DDIT4 while increasing miR-139-5p in the xenografts. Taken together, these findings, for the first time, indicate that TGR5 inhibits CC progression by regulating the HCP5/miR-139-5p/DDIT4 axis, suggesting that it may represent a novel and potent target for CC treatment.