Pathogenesis Of Cervical Cancer Research Articles

The contribution and mechanism of hypoxia/USP19/Beclin-1 feed-forward loop in cervical cancer

Cervical cancer ranks fourth in female mortality. Since the mechanisms for pathogenesis of cervical cancer are still poorly understood, the effective treatment options are lacking. Beclin-1 exhibits an inhibitory role in cervical cancer via suppressing the proliferation, invasion, and migration of cervical cancer cells. It is reported that USP19 removes the K11-linked ubiquitination of Beclin-1 to protect Beclin-1 from proteasomal degradation. Interestingly, we found that hypoxia induced a significant decrease of both Beclin-1 and USP19, suggesting that hypoxia could dually inhibit the protein level of Beclin-1 through a type 2 coherent feed-forward loop (C2-FFL, hypoxia ⊸ Beclin-1 integrating with hypoxia ⊸ USP19 → Beclin-1) to promote the occurrence and development of cervical cancer. Furthermore, mathematical modeling revealed that under the hypoxic environment of solid tumor, the hypoxia/USP19/Beclin-1 coherent feed-forward loop could significantly reduce the protein level of Beclin-1, greatly enhance the sensitivity of Beclin-1 to hypoxia, strikingly restrict the heterogeneity of Beclin-1, and contribute to the low positive rate of Beclin-1 in cervical cancer. It is expected to have significance for elucidating the underlying mechanisms of the occurrence and development of cervical cancer and to provide novel targets and strategies for prevention and treatment of cervical cancer.

HPV16-miRNAs exert oncogenic effects through enhancers in human cervical cancer

BackgroundCervical cancer is a human papillomavirus (HPV)-related disease. HPV type 16 (HPV16), which is the predominant cause of cervical cancer, can encode miRNAs (HPV16-miRNAs). However, the role of HPV16-miRNAs in the pathogenesis of cervical cancer remains unclear.MethodsHuman cervical cancer cell lines SiHa (HPV16-positive) and C33A (HPV-negative), and cervical cancer tissues were collected to investigate the expression levels of two HPV16-miRNAs (HPV16-miR-H1 and HPV16-miR-H6). The overexpression and knockdown of HPV16-miR-H1 and HPV16-miR-H6 were performed using the lentiviral vector system and miRNA inhibitors, respectively. RNA-sequencing (RNA-seq) analysis and H3K27ac chromatin immunoprecipitation and sequencing (CHIP-seq) experiments were utilized to explore the roles of HPV16-miR-H1 and HPV16-miR-H6 facilitated by enhancers. CCK8, EdU, transwell, and wound healing assays were performed to verify the effects of HPV16-miR-H1 and HPV16-miR-H6 on cell proliferation and migration.ResultsHPV16-miR-H1 and HPV16-miR-H6 were highly expressed in both SiHa cells and tissue samples from HPV16-positive cervical cancer patients. RNA-seq analysis showed that HPV16-miR-H1 and HPV16-miR-H6 induced the upregulation of numerous tumor progression-associated genes. H3K27ac CHIP-seq experiments further revealed that HPV16-miR-H1 and HPV16-miR-H6 modulated the expression of critical genes by regulating their enhancer activity. The functional study demonstrated that HPV16-miR-H1 and HPV16-miR-H6 increased the migratory capacity of SiHa cells.ConclusionsOur data shed light on the role of HPV16-encoded miRNAs in cervical cancer, particularly emphasizing their involvement in the miRNA-enhancer-target gene system. This novel regulatory mechanism of HPV16-miRNAs provides new insights and approaches for the development of therapeutic strategies by targeting HPV16-positive cervical cancer.

Unravelling The Complexities of Cervical Cancer: A Comprehensive Exploration

Cervical cancer (CC) ranks as the second most common cause of cancer-related deaths among women aged 20-39, resulting in ten premature deaths weekly. CC affects women worldwide as the most common form of genital cancer, with approximately 500,000 new cases diagnosed annually. Besides the risk of death, CC can lead to increased morbidity, causing symptoms like pain, haemorrhage, and kidney failure. These complications pose significant challenges to treatment, particularly in areas with limited healthcare access. Immune dysregulation and chronic inflammation further contribute to CC pathogenesis, creating a pro-carcinogenic microenvironment through immune cell recruitment, cytokine release, and inflammatory responses triggered by persistent HPV infection. Moreover, understanding the socio-economic determinants influencing the prevalence of CC and promoting awareness can contribute to effective public health interventions. Research endeavours in these domains are vital to reduce the burden of CC, enhance early detection, and ultimately save lives. This review covers recent research on CC global epidemiology, intricate pathogenesis insights, protein-based HPV vaccines, and diverse treatment modalities, including recurrent cases. Molecular markers indicating prognosis and the role of artificial intelligence. The review will briefly highlight preventive strategies, offering a comprehensive overview of crucial research areas in CC.

CARCINOGENIC EFFECT OF VARIOUS TYPES OF SMOKE

All types of smoke are carcinogenic. Increasing air smoke is a serious global problem. Knowledge on carcinogenic effects of various types of smoke is necessary to work out effective preventive measures.
 The purpose of the review is to characterize the general characteristics and peculiarities of the carcinogenic effects of various types of smoke. The most significant carcinogens of all types of smoke are polycyclic aromatic hydrocarbons, heavy metals and carbon microparticles. Any smoke is an etiological factor for respiratory tract cancer, and systemic neoplasms (tumors of hematopoietic and lymphoid tissues, central and peripheral nervous systems, soft tissues and skeleton). Tobacco smoke may be involved in the pathogenesis of cervical cancer due to the induction of local immunosuppression and specific tropic nitrosamines. Exhaust fumes due to high benzene content may cause hematological malignancies, especially leukemia in children. Wildfire smoke, due to significant amounts of ultra-fine carbon particles PM0.1, contributes to the development of central nervous system tumors. Severe contamination with natural and artificial radionuclides makes wildfire smoke a factor of high carcinogenic danger for the human population globally. Prevention of malignant neoplasms caused by smoke requires government measures to promote smoking cessation, hybrid and electric engines in automobiles, as well as wildfire prevention, early detection and extinction. Effective respirators and indoor air filters should be used for personal protection. To relieve environmentally caused oxidative stress, herbal medicines and food products that stimulate autophagy, as well as transfer factors for immunodeficiency correction, are recommended.

Molecular aspects of cervical cancer: a pathogenesis update.

Cervical cancer (CC) is a significant health problem, especially in low-income countries. Functional studies on the human papillomavirus have generated essential advances in the knowledge of CC. However, many unanswered questions remain. This mini-review discusses the latest results on CC pathogenesis, HPV oncogenesis, and molecular changes identified through next-generation technologies. Interestingly, the percentage of samples with HPV genome integrations correlates with the degree of the cervical lesions, suggesting a role in the development of CC. Also, new functions have been described for the viral oncoproteins E5, E6, and E7, resulting in the acquisition and maintenance of cancer hallmarks, including proliferation, immune response evasion, apoptosis, and genomic instability. Remarkably, E5 oncoprotein affects signaling pathways involved in the expression of interferon-induced genes and EGFR-induced proliferation, while E6 and E7 oncoproteins regulate the DNA damage repair and cell cycle continuity pathways. Furthermore, next-generation technologies provide vast amounts of information, increasing our knowledge of changes in the genome, transcriptome, proteome, metabolome, and epigenome in CC. These studies have identified novel molecular traits associated with disease susceptibility, degree of progression, treatment response, and survival as potential biomarkers and therapeutic targets.

Circ_0051428 targeting miR-885-3p/MMP2 axis enhances the malignancy of cervical cancer.

Circular RNAs (circRNAs) are key regulators of cervical cancer (CC) progression. This study aimed to elucidate the role and mechanism of circ_0051428, a novel circRNA, in CC tumorigenesis. Quantitative real-time polymerase chain reaction and western blotting analyses confirmed that circ_0051428 and matrix metalloprotein-2 (MMP2) were overexpressed in CC, whereas the microRNA miR-885-3p was poorly expressed. After performing a series of in vitro and in vivo experiments, circ_0051428 knockdown was shown to repress CC cell invasion and proliferation in vitro, and hamper tumor formation in vivo. Dual-luciferase reporter and RNA-binding protein immunoprecipitation experiments verified that circ_0051428 interacts with miR-885-3p to regulate the target gene MMP2 of miR-885-3p in CC. In addition, miR-885-3p knockdown offset the anticancer effects of circ_0051428 or MMP2 knockdown on CC cell malignancy. Overall, this study revealed that circ_0051428 executes a tumor-promoting function in CC pathogenesis by modulating the miR-885-3p/MMP2 axis. Our findings provide a novel approach for CC treatment.

Unfurling the functional association between long intergenic noncoding RNAs (lincRNAs) and HPV16-related cervical cancer pathogenesis through weighted gene co-expression network analysis of differentially expressed lincRNAs and coding genes.

Long intergenic noncoding RNAs (lincRNAs) do not overlap annotated coding genes and are located in intergenic regions, as opposed to antisense and sense-intronic lncRNAs, located in genic regions. LincRNAs influence gene expression profiles and are thereby key to disease pathogenesis. In this study, we assessed the association between lincRNAs and HPV16-positive cervical cancer (CaCx) pathogenesis using weighted gene co-expression network analysis (WGCNA) with coding genes, comparing differentially expressed lincRNA and coding genes (DElincGs and DEcGs, respectively) in HPV16-positive patients with CaCx (n = 44) with those in HPV-negative healthy individuals (n = 34). Our analysis revealed five DElincG modules, co-expressing and correlating with DEcGs. We validated a substantial number of such module-specific correlations in the HPV16-positive cancer TCGA-CESC dataset. Four such modules, displayed significant correlations with patient traits, such as HPV16 physical status, lymph node involvement, and overall survival (OS), highlighting a collaborative effect of all genes within specific modules on traits. Using the DAVID bioinformatics knowledgebase, we identified the underlying biological processes associated with these modules as cancer development and progression-associated pathways. Next, we identified the top 10 DElincGs with the highest connectivity within each functional module. Focusing on the prognostic module hub genes, downregulated CTD-2619J13.13 expression was associated with poor patient OS. This lincRNA gene interacted with 25 coding genes of its module and was associated with such biological processes as keratinization loss and keratinocyte differentiation, reflecting severe disease phenotypes. This study has translational relevance in fighting various cancers with high mortality rates in underdeveloped countries.

The causal correlation between gut microbiota abundance and pathogenesis of cervical cancer: a bidirectional mendelian randomization study.

Observational studies and animal experiments suggested potential relevance between gut microbiota (GM) and cervical cancer (CC), but the relevance of this association remains to be clarified. We performed a two-sample bidirectional Mendelian randomization (MR) analysis to explore whether there was a causal correlation between GM and CC, and the direction of causality. In primary outcomes, we found that a higher abundance of class Clostridia, family Family XI, genus Alloprevotella, genus Ruminiclostridium 9, and order Clostridiales predicted higher risk of CC, and a higher abundance of class Lentisphaeria, family Acidaminococcaceae, genus Christensenellaceae R7 group, genus Marvinbryantia, order Victivallales, phylum Actinobacteria, and phylum Lentisphaerae predicted lower risk of CC. During verifiable outcomes, we found that a higher abundance of class Methanobacteria, family Actinomycetaceae, family Methanobacteriaceae, genus Lachnospiraceae UCG 010, genus Methanobrevibacter, order Actinomycetales, and order Methanobacteriales predicted a higher risk of CC, and a higher abundance of family Streptococcaceae, genus Dialister, and phylum Bacteroidetes predicted a lower risk of CC, and vice versa. Our study implied a mutual causality between GM and CC, which provided a novel concept for the occurrence and development of CC, and might promote future functional or clinical analysis.

LncRNA799/TBL1XR1/ZEB1 Axis Forms a Feedback Loop to Promote the Epithelial-Mesenchymal Transition of Cervical Cancer Cells.

Cervical cancer is a common malignancy among women worldwide. Long non-coding RNAs (lncRNAs) are frequently involved in the pathogenesis of cervical cancer. Therefore, the present study aimed to investigate the potentials of lncRNA799 in cervical cancer. mRNA and protein expression were detected by reverse transcription-quantitative polymerase chain reaction and Western blot analysis, respectively. Cellular functions were assessed using CCK-8, wound healing and transwell analysis. The binding potential of zinc finger E-box-binding homeobox 1 (ZEB1) on the promoter of lncRNA799 was predicted utilizing the JASPAR database, and was then verified by luciferase and chromatin immunoprecipitation (ChIP) assays. Furthermore, the gene interactions were assessed using RNA immunoprecipitation and co-immunoprecipitation assays. The results demonstrated that lncRNA799 was upregulated in cervical cancer cells. However, lncRNA799 deficiency suppressed the proliferation and epithelial-mesenchymal transition of cervical cancer cells. Furthermore, lncRNA799 could interact with eukaryotic translation initiation factor 4A3 to maintain the mRNA stability of transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) and promote the interaction between ZEB1 and TBL1XR1. Additionally, the results showed that ZEB1 could transcriptionally activate lncRNA799. Taken together, the present study suggested that the lncRNA799/TBL1XR1/ZEB1 axis could form a positive feedback loop in cervical cancer and could be, therefore, considered as a potential therapeutic strategy for cervical cancer.

Characteristics of Cervical Cancer Caused by the Human Papillomavirus 18 and Its Genetic Variations in Vietnamese Women

BackgroundThe involvement of HPV18 in cervical cancer pathogenesis, as well as its high oncogenic potential and influence on the variation of cervical cancer distribution in different geographical regions, makes assessing the characteristics of cervical cancer and its variants the basis for considering potential carcinogenic HPV18 sequence variations and vaccine strategies. MethodsA prospective study was conducted at Vietnam Central Obstetrics Hospital from January 1, 2019 to December 31, 2020. HPV18 infection was confirmed in cervical cancer patients using molecular diagnostics. Nucleotide sequences of the HPV18 E6, E7, and L1 genes were used to analyze genetic variations. The demographic, clinical, and laboratory data of the patients were collected and statistically analyzed. ResultsAmong 48 patients with HPV18-infected cervical cancer, 79.2% were between the ages of 35–54; while only 20.8% were < 35 and > 54 years old. 100% of patients have been pregnant at some point in their lives, with ≥3 pregnancies accounting for 83.3%. Patients with cervical cancer caused by HPV18 infection were predominantly in stages 0 and I, with no patients in stages II, III, or IV. A single HPV18 infection generates much more cervical cancer cases than multiple HPV18 infections. Symptoms such as lower abdomen pain, unusual anginal discharge, and vaginal bleeding were observed in both stages 0 and I; however, vaginal bleeding after sex was only detected in women with stage I cervical cancer. Cervicitis, cervical ectropion, and ulcers are reported in cervical status stages 0 and I; however, warts and ulcers were only present in stage I. Magnetic resonance imaging produces far superior outcomes than ultrasound. All cytology and pathology tests confirmed L/HSIL, SCC, AC, and CIS. On the other hand, a single HPV18 infection was associated with a significantly higher risk of L/HSIL, SCC, AC, and CIS than multiple HPV18 infections. Nulceotide sequences of the E6, E7, and L1 genes revealed 20 mutations, including three (E6), five (E7), and twelve (L1) mutations. High-frequency mutations (95.8%–100% of HPV18 samples had mutations) occur at the following positions: C287G - P61P (E6 gene), G5503A - R25Q, C5701G - P91R, C6460G - P344R, C6625G - P399R, and C6842G - P471R (L1 gene). A phylogenetic tree based on the E6/E7/L1 gene sequence revealed that 100% belonged to A lineage, with 97.9% belonging AA (Asian Amerindian - A1) and 2.1% belonging to the E (European - A5). ConclusionPatients with a single HPV18 infection have a higher risk of cervical cancer than those infected with HPV18 and other high-risk strains simultaneously. HPV18 single-infection, on the other hand, had considerably higher incidences of L/HSIL, SCC, AC, and CIS than HPV18 co-infection. The HPV18 strain that was found in Vietnam belonged to lineage A (A1 and A5), which contains several oncogene mutations.

Transcriptomes of cervical cancer provide novel insights into dysregulated pathways, potential therapeutic targets, and repurposed drugs

Cervical cancer ranks as the fourth most prevalent gynaecological malignancy and is a significant contributor to mortality among women globally. With the exception of HPV-mediated oncogenesis, the molecular etiology of the disease is poorly understood, and there is a critical dearth of knowledge concerning cancer that is not caused by HPV. Moreover, none of the options presently accessible for the treatment of cancers specifically target cervical cancer. In context with this, this research aims to identify the critical genes, regulators, and pathways that contribute to the pathogenesis of cervical cancer, in addition to prospective pharmacological targets and repurposed therapeutic agents that can be directed against the targets. A total of eleven different global gene expression (transcriptome) datasets were subjected to analysis utilizing a variety of in silico tools. The present study reveals a previously unknown correlation between cervical cancer and five genes: SHC1, CBL, GNAQ, GNA14, and PPP2CA. Significant dysregulation was observed in four crucial transcription factors (KLF4, E2F1, FOXM1, and AR) that modulate the expression of numerous genes in cervical cancer. Furthermore, it was observed that AKT1, MAPK1, and MAPK3 ranked the highest among the regulatory genes that hold promise as therapeutic targets in the context of cervical cancer. Additional research, both in vitro and in vivo, is required to validate and establish the therapeutic potential of these crucial genes in the context of cervical cancer.

Role of rs2366152 single-nucleotide variant located in the long noncoding RNA HOTAIR gene in the cervical cancer susceptibility in a Polish population.

Previous studies have demonstrated an association of the NC_000012.12:g.53962605A > G, (rs2366152) single-nucleotide variant (SNV) situated in the long noncoding homeobox transcript antisense intergenic RNA (HOTAIR) gene with HPV16-related cervical cancer pathogenesis. However, little is known about the role of rs2366152 in cervical cancer progression and how oral birth control pills use, parity, menopausal status, and cigarette smoking influence the role of rs2366152 in cervical carcinogenesis. HRM analysis was used to determine the rs2366152 SNV prevalence in patients with cervical squamous cell carcinoma (SCC) (n = 470) and control group (n = 499) in a Polish Caucasian population. Logistic regression analyses were adjusted for age, using birth control pills, parity, menopausal status, and cigarette smoking. Our genetic studies revealed that the G/A vs. A/A (p = 0.031, p = 0.002) and G/A + G/G vs. A/A (p = 0.035, p = 0.003) genotypes of rs2366152 SNV were significantly related to the grade of differentiation G3 and tumor stage III, respectively. Moreover, cervical cancer risk increased among patients with rs2366152 SNV who smoked cigarettes and used birth control pills. We conclude that rs2366152 may promote the invasion and rapid growth of cervical SCC. Moreover, rs2366152 with cigarette smoking and using birth control pills can also be a risk factor for cervical cancerogenesis.

Analysis of cancer-associated fibroblasts in cervical cancer by single-cell RNA sequencing.

Since scRNA-seq is an effective tool to study tumor heterogeneity, this paper intends to reveal the differences of cervical cancer in patients at the individual cell level by scRNA-seq, and focus on the biological functions of cancer-associated fibroblasts (CAFs) in cervical cancer, facilitating the provision of a new interpretation of the heterogeneity of the microenvironment of cervical cancer, and an in-depth exploration of the pathogenesis of cervical cancer as well as pursuit of effective means of treatment intake. 3 cervical cancer specimens were collected by clinical surgery for single-cell RNA sequencing. Cell suspensions of fresh cervical cancer tissues were prepared, and cDNA libraries were created and sequenced on the machine. Furthermore, the sequencing data were analyzed using bioinformatics, including descending clustering of cells, identification of cell populations, mimetic time series analysis, inferCNV, cell communication analysis, and identification of transcription factors. A total of 9 cell types were identified, encompassing T cells, epithelial cells, smooth muscle cells, CAFs, endothelial cells, macrophages, B cells, lymphocytes, and plasma cells. CAFs were further divided into three cell subtypes, named type1 cells, type2 cells, and type3 cells. With key transcription factors for the three cells, TCF21, ZC3H11A, and MYEF2 obtained, this research revealed the communication relationship between CAFs and several other cells, and found an important role of CAFs in the MK signaling pathway. scRNA-seq technology contributed to exploring the tumor heterogeneity of cervical cancer more deeply, and also further gaining insight into the biological functions of CAFs in cervical cancer.

HPV18 L1 and long control region sequences variation and E6/E7 differential expression in nasopharyngeal and cervical cancers: a comparative study

BackgroundThe role of high-risk human papillomaviruses (hr-HPVs) in cervical cancer (CC) pathogenesis has long been established. Knowledge about the involvement of hr-HPVs in the etiology of nasopharyngeal cancers (NPC) was not well appreciated until the early 2000s when a clear link began to emerge. However, it is not clear whether HPV oncogenesis in the different epithelial cancers is associated with L1 gene and long-control region (LCR) sequences variation. This study aimed to investigate the HPV18 L1 gene and LCR sequences variation in cervical and nasopharyngeal biopsies, and assessed E6 and E7 genes expression level in both cancers.MethodFour-hundred and three (403) formalin-fixed paraffin-embedded tissues originating from nasopharyngeal (NPC) (279) and cervical (CC) (124) sites were collected from a pathology laboratory, Pathologist Without Borders, Accra, Ghana. Haematoxylin and eosin staining was carried out to confirm the presence of cancer on prepared biopsy sections. DNA was extracted from the confirmed cancer biopsies, followed by PCR using MY09/GP5+ /6+ primers to detect the presence of HPV and specific primers for the amplification of L1 gene and LCR. Sanger sequencing was carried out to determine HPV genotypes, and L1 and LCR sequences variant of HPV18s in CC and NPC biopsies. The HPV18 E6/E7 mRNA expression pattern in both cancers was determined using RT-qPCR.ResultsMost of the NPC (45%) and CC (55%) biopsies were HPV18 positive. Comparison of HPV18 L1 sequences obtained from cervical and nasopharyngeal cancer tissues, the L1 sequences from the NPC were highly dissimilar with a 59–100% variation among themselves, and in relation to the reference strains. However, the L1 sequences from the CC were more similar with a 91.0–100% variation among the amplified sequences. Also, the LCR sequences from CC were quite different relative to that of NPC. Results for the differential expression of E6/E7 in the two cancers showed a higher fold change in E6 expression in the CC tissues than the NPC tissues while a reverse expression pattern was found for E7 gene.ConclusionThe current study reports for the first-time variations in HPV18 L1 and LCR sequences, and differential expression of E6/E7 genes in NPC compared to CC, suggesting a possible adaptation mechanism of the virus at different cancer sites.

Treatment of Cervical Precancers is the Major Remaining Challenge in Cervical Screening Research.

Deepening understanding of cervical cancer pathogenesis has yielded one-dose prophylactic human papillomavirus (HPV) vaccines and accurate HPV-based cervical screening tests. Knowing the heterogeneous carcinogenic potential of the individual high-risk HPV types permits prioritization of vaccination and screening strategies. However, "correct" (i.e., safe and effective) treatment of women found to have precancer is still undefined, forcing reliance on one or more rounds of untargeted destructive/excisional treatment. Both over-treatment and under-treatment are common results. Until safe and effective anti-HPV therapies are invented, defining optimal destructive/excisional treatment of precancer remains a fundamental and under-researched challenge, especially in resource-constrained settings. See related article by King et al., p. 681.

Whole genome sequencing in high-grade cervical intraepithelial neoplasia patients from different ethnic groups in China.

Cervical cancer (CC) is the fourth most common cancer in women worldwide. It develops through precancerous lesions (cervical intraepithelial neoplasia (CIN), graded from low-grade (CIN1) to high-grade (CIN2-3)). It is well established that precancerous and cancerous cervical lesions are caused by a persistent infection with high-risk types of the human papilloma virus (hrHPV). To have a deeper understanding of the pathogenesis of CIN and CC, we systematically analyzed the landscape of genomic alterations and HPV integration profiles in high-grade CIN2/3. We performed deep whole genome sequencing on exfoliated cervical cells and matched peripheral blood samples from a cohort of 51 Chinese patients (of whom 35 were HPV+) with high-grade CIN from 3 ethnic groups and constructed strict integrated workflow of genomic analysis. In addition, the HPV types and integration breakpoints in the exfoliated cervical cells from these patients were examined. Genomic analysis identified 6 significantly mutated genes (SMGs), including CDKN2A, PIK3CB, FAM20A, RABEP1, TMPRSS2 and SS18L1, in 51 CIN2/3 samples. As none of them had previously been identified as SMGs in the Cancer Genome Atlas cervical squamous cell carcinoma and endocervical adenocarcinoma (TCGA-CESC) cohort, future studies with larger sample size of CINs may be needed to validate our findings. Mutational signature analysis showed that mutational signatures of CINs were dramatically different from CCs, highlighting their different mutational processes and etiologies. Moreover, non-silent somatic mutations were detected in all of the CIN2/3 samples, and 88% of these mutations occurred in genes that also mutated in CCs of TCGA cohort. CIN2 samples had significantly less non-silent mutations than CIN3 samples (P = .0006). Gene ontology and pathway level analysis revealed that functions of mutated genes were significantly associated with tumorigenesis, thus these genes may be involved in the development and progression of CC. HPV integration breakpoints occurred in 28.6% of the CIN2/3 samples with HPV infection. Integrations of common high risk HPV types in CCs, including HPV16, 52, 58 and 68, also occurred in the CIN samples. Our results lay the groundwork for a deeper understanding of the molecular mechanisms underlying the pathogenesis of CC and pave the way for new tools for screening, diagnosis and treatment of cervical precancerous and cancerous lesions.

Cancer/testis-45A1 promotes cervical cancer cell tumorigenesis and drug resistance by activating oncogenic SRC and downstream signaling pathways

BackgroundCancer/testis antigen-45A1 (CT45A1) is overexpressed in various types of cancer but is not expressed in healthy women. The role of CT45A1 in cervical cancer has not yet been described in the literature.PurposeThe aim of this research was to study the role of CT45A1 in cervical cancer progression and drug resistance, elucidate the mechanisms underlying CT45A1-mediated tumorigenesis and investigate CT45A1 as a biomarker for cervical cancer diagnosis, prognostic prediction, and targeted therapy.MethodsThe CT45A1 levels in the tumors from cervical cancer patients were measured using immunohistochemical staining. The role and mechanisms underlying CT45A1-mediated cervical cancer cell tumor growth, invasion, and drug resistance were studied using xenograft mice, cervical cancer cells, immunohistochemistry, RNA-seq, real-time qPCR, Chromatin immunoprecipitation and Western blotting.ResultsCT45A1 levels were notably high in the tumor tissues of human cervical cancer patients compared to the paracancerous tissues (p < 0.001). Overexpression of CT45A1 was closely associated with poor prognosis in cervical cancer patients. CT45A1 promoted cervical cancer cell tumor growth, invasion, neovascularization, and drug resistance. Mechanistically, CT45A1 promoted the expression of 128 pro-tumorigenic genes and concurrently activated key signaling pathways, including the oncogenic SRC, ERK, CREB, and YAP/TAZ signaling pathways. Furthermore, CT45A1-mediated tumorigenesis and drug resistance were markedly inhibited by the small molecule lycorine.ConclusionCT45A1 promotes cervical cancer cell tumorigenesis, neovascularization, and drug resistance by activating oncogenic SRC and downstream tumorigenic signaling pathways. These findings provide new insight into the pathogenesis of cervical cancer and offer a new platform for the development of novel therapeutics against cervical cancer.

The impact of oleuropein on miRNAs regulating cell death signaling pathway in human cervical cancer cells.

Cervical cancer is known as the second most pervasive malignancy in women across the globe. The role played by microRNAs (miRNAs) in the initiation, progression, and metastasis of this cancer has received specific attention. The use of natural compounds leading cancer cells toward apoptosis is a feasible strategy for cancer therapy. Oleuropein, an olive-extracted phenolic substance, displays anticancer properties. Here, it was attempted to assess the role played by oleuropein in cell viability in cervical cancer and changes in the expression of some miRNAs associated with cervical cancer as well as some of their possible target genes selected using bioinformatics analysis. For this purpose, HeLa cell line was exposed to several oleuropein concentrations for 48 and 72h. After that, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay and flow cytometry were employed to assess cell viability and apoptosis, respectively. In addition, to conduct bioinformatics analysis, Cytoscape computer program was used based on STRING database. Furthermore, to examine the role played by oleuropein in the expression of miRNAs of interest as well as their potential target genes, real-time PCR was employed. The findings indicated that oleuropein reduced cell viability through inducing apoptosis. As a result of treatment with oleuropein, miR-34a, miR-125b, and miR-29a showed increased expression levels, whereas miR-181b, miR-221, and miR-16 showed decreased expression levels. Furthermore, oleuropein reduced the expression of the anti-apoptotic genes Bcl-2 and Mcl1, whereas it elevated the expression of the pro-apoptotic Bid, Fas, and TNFRSF10B genes and the p53 tumor suppressor. Our results indicate that the apoptosis induction is a mechanism of action of oleuropein in HeLa cells. Because of its effect on the reflation of the expression of genes and miRNAs effective in the pathogenesis of cervical cancer, oleuropein shows potential as an effective research tool for developing new natural drugs for treating cervical cancer.

USF1 regulated circPRDM4 modulates tumorigenesis and immune escape in chemoresistant cervical cancer.

Cervical cancer (CC) represents a major global health concern, characterized by chemoresistance and immune evasion mechanisms. Circular RNAs (circRNAs), which play a crucial role in cancer pathogenesis, particularly in the case of CC, have gained significant attention. The primary objective of this study was to investigate the functional significance of circRNAs in chemoresistant CC. A significant upregulation of circPRDM4 expression in chemoresistant CC cells. To investigate the functional consequences, we conducted circPRDM4 knockdown experiments, which resulted in the effective blockade of immune escape mechanisms employed by chemoresistant CC cells. Furthermore, circPRDM4 knockdown demonstrated a significant suppression of tumorigenesis in CC cells, highlighting its contribution to the oncogenic potential of CC. Investigating the regulatory mechanisms involved, we found that the transcriptional factor upstream stimulatory factor 1 (USF1) acts as an inducer of circPRDM4 expression. Remarkably, USF1 was found to effectively modulate CC cell immune escape via its interaction with circPRDM4. Moreover, our results revealed that USF1 is intricately involved in CC cell tumorigenesis through the regulation of circPRDM4. Collectively, our study elucidates the significant roles of circPRDM4 and its upstream regulator USF1 in chemoresistant CC cells. These findings underscore the importance of circRNAs in CC pathogenesis and provide valuable insights into the mechanisms underlying immune escape and tumorigenesis.

Phytochemicals in Cervical Cancer: An Epigenetic Overview

Cervical cancer is the fourth most common female malignancy worldwide and a complex disease that typically starts with HPV infection. Various genetic and epigenetic alterations are implicated in its development. The current cervical cancer therapies have unsatisfactory outcomes due to their serious adverse effects, necessitating the need for safe, effective preventive and therapeutic modalities. Phytochemicals have been addressed in cervical cancer prevention and treatment, and further understanding the epigenetics of cervical cancer pathogenesis is critical to investigate new preventive and therapeutic modalities. Addressing the epigenetic mechanisms of potential phytochemicals will provide an overview of their use individually or in combination. The primary aim of this review is to highlight the epigenetic effects of the phytochemicals addressed in cervical cancer therapy.