Carcinogenesis Of Cervical Cancer Research Articles

The role of NF-κB in carcinogenesis of cervical cancer: opportunities and challenges.

The nuclear factor-κB (NF-κB) family, consisting of several transcription factors, has been implicated in the regulation of cell proliferation and invasion, as well as inflammatory reactions and tumor development. Cervical cancer (CC) results from long-term interactions of multiple factors, among which persistent high-risk human papillomavirus (hrHPV) infection is necessary. During different stages from early to late after HPV infection, the activity of NF-κB varies and plays various roles in carcinogenesis and progress of CC. As the center of the cell signaling transduction network, NF-κB can be activated through classical and non-classical pathways, and regulate the expression of downstream target genes involved in regulating the tumor microenvironment and acquiring hallmark traits of CC cells. Targeting NF-κB may help treat CC and overcome the resistance to radiation and chemotherapy. Even though NF-κB inhibitors have not been applied in clinical treatment as yet, due to limitations such as dose-restrictive toxicity and poor tumor-specificity, it is still considered to have significant therapeutic potential and application prospects. In this review, we focus on the role of NF-κB in the process of CC occurrence and hallmark capabilities acquisition. Finally, we summarize relevant NF-κB-targeted treatments, providing ideas for the prevention and treatment of CC.

A research investigation into the micronuclei assay within urothelial cells as an innovative biomarker for the carcinogenesis of cervical cancer conducted at a tertiary care facility

Abstract Background: Cervical carcinoma ranks as the fourth most prevalent cancer in women worldwide, following breast, colorectal, and lung cancers. Screening is a crucial secondary prevention strategy, particularly in developing nations such as India, ensuring effective prevention and treatment. This study investigates the micronuclei assay in urothelial cells as a potential biomarker for cervical carcinoma screening, focusing on its correlation with colposcopic and histopathological observations. Materials and Methods: The prospective study was conducted from September 2016 to September 2017 at the Department of Pathology, Institute of Obstetrics and Gynecology, Madras Medical College, Chennai, Tamil Nadu, India. It involved 108 women who visited the colposcopic clinic. Urine samples were collected from 50 women with normal colposcopic findings and 58 with abnormal colposcopy results. Micronuclei scoring was performed on 1000 epithelial cells from the smears. Additionally, cervical biopsies were conducted for the 58 cases with abnormal colposcopic findings, and the resulting histopathological data were juxtaposed with the findings of the micronuclei assay. Results: The study’s findings demonstrated a sensitivity of 82.76% and a specificity of 90%, with positive predictive values of 90.75% and negative predictive values of 81.82%. Additionally, a statistically significant linear correlation was observed between the micronuclei assay and histopathological diagnosis, with a P value of less than 0.001. Conclusion: Therefore, the micronuclei assay offers a means to detect genotoxicity, monitor cervical carcinogenesis, and identify high-risk groups using simple, reliable, and cost-effective techniques suitable for large-scale screening programs.

The Role of ZNF275/AKT Pathway in Carcinogenesis and Cisplatin Chemosensitivity of Cervical Cancer Using Patient-Derived Xenograft Models

Zinc finger protein 275 (ZNF275) is a C2H2-type transcription factor that is localized on chromosome Xq28. Whether ZNF275 participates in modulating the biological behaviors of cervical cancer has not been determined to our knowledge. The present study employed CCK-8, BrdU, flow cytometry, and a transwell assay to investigate the cell viability, proliferation, apoptosis, migration, and invasion of cervical cancer cells. The application of Western blotting and immunohistochemistry (IHC) aims to assess ZNF275 protein expression and identify the signaling pathway relevant to ZNF275-mediated effects on cervical cancer. The therapeutic impact of the combined therapy of the AKT inhibitor triciribine and cisplatin was evaluated on cervical cancer patient-derived xenograft (PDX) models expressing high ZNF275. The current research illustrated that cervical cancer tissue exhibited a higher expression of ZNF275 in contrast to the surrounding normal cervical tissue. The downregulation of ZNF275 suppressed cell viability, migration, and invasion, and facilitated the apoptosis of SiHa and HeLa cells via weakening AKT/Bcl-2 signaling pathway. Moreover, triciribine synergized with cisplatin to reduce cell proliferation, migration, and invasion, and enhanced the apoptosis of SiHa cells expressing high ZNF275. In addition, the combination treatment of triciribine and cisplatin was more effective in inducing tumor regression than single agents in cervical cancer PDX models expressing high ZNF275. Collectively, the current findings demonstrated that ZNF275 serves as a sufficiently predictive indicator of the therapeutic effectiveness of the combined treatment of triciribine and cisplatin on cervical cancer. Combining triciribine with cisplatin greatly broadens the therapeutic options for cervical cancer expressing high ZNF275, but further research is needed to confirm these results.

Single-Cell and Spatial Transcriptomics Revealing the Role of IDO1 in HPV+ Cervical Cancer Tumor Immune Microenvironment and Its Implications in Radiotherapy and Immunotherapy

Persistent infection of human papillomavirus (HPV) is one major etiology of cervical cancer (CC). By now, anti-PD-1 immunotherapy is approved for advanced CC patients, but the response rate was just about 10-20%, tumor immune microenvironment (TIME) might be one factor that affect the efficacy. The indoleamine 2,3-dioxygenase (IDO), a metabolic immune checkpoint, is recently shown to have a correlation-ship with HPV carcinogenesis in CC, with unknown mechanism. This study, using the single cell transcriptomic single-cell sequencing and spatial transcription sequencing analysis/immunologic technology, aimed to exam the role of IDO1 expression in HPV+ CC TIME and explore the changes after radiotherapy. Newly diagnosed advanced HPV- CC and HPV+ CC patients were tested for the tumor and tumor immune microenvironment (TIME) heterogeneity and their changes after fractionated radiation therapy. Tumor tissues were collected, single cell suspension was made for Single-cell RNA sequencing (SCRNAseq) using the 10 × Genomics, while frozen tissue was embedded for spatial transcriptome sequencing (STRNAseq). Seurat 4.0 was used to cluster and annotate cell clusters and map SCRNAseq data to the STRNAseq data. The specific characters of cell clusters were computed by Gene Set Enrichment Analysis (GSEA). SPOTLight and CellChat were used to analyze cell location and interaction respectively. A total of 28631 cells were clustered into 31 cell subsets in HPV- CC and HPV+ CC tissues, including baseline (Pre HPV- CC and Pre HPV+ CC) and 3-week after radiotherapy (Post 3w HPV- CC and Post 3w HPV+CC). There were 10431 epithelial cells (Epi) in all these 4 tumor tissues, with heterogenous IDO1 expression, including IDO1-high Epi, IDO1-low Epi, and IDO1-neg Epi. Interestingly, more than 99% of Epi in Pre HPV- CC tissues were IDO1-neg cells, while more than 99% in Pre HPV+ CC tissue were IDO1-high. Furthermore, the proportion of IDO1-high Epi in Pre HPV+ CC patient dropped to 16.7% after radiotherapy, while the proportion of IDO1-low Epi rase to 63.3%. Using GSEA, the characters of IDO1-high Epi group was shown to have positive regulation of leukocyte chemotaxis and negative regulation of cell adhesion and differentiation. IDO1-high Epi cells also had the hallmark of interferon gamma response. These cells could mainly receive regulative information of interferon gamma pathway from exhausted CD8 T cells, which could affect the apoptosis of tumor cells. This study comprehensively analyzed the immune suppressive role of IDO1-high Epi cells in HPV+ CC TIME at the single-cell transcriptional scale and explored their functional characters in CC radiotherapy. This would be able to provide more evidence to combine with radiotherapy and immunotherapy to improve patients' prognosis.

Carcinogenesis and management of human papillomavirus-associated cervical cancer.

Approximately 95% of cervical cancer are caused by human papillomavirus (HPV) infection. Although it is estimated that HPV-associated cervical cancer will decrease with the widespread use of HPV vaccine, it may take time for HPV-associated cervical cancer to be eliminated. For the appropriate management of HPV-associated cervical cancer, it is important to understand the detailed mechanisms of cervical cancer development. First, the cellular origin of most cervical cancers is thought to be cells in the squamocolumnar junction (SCJ) of the uterine cervix. Therefore, it is important to understand the characteristics of SCJ for cervical cancer screening and treatment. Second, cervical cancer is caused by high risk HPV (HR-HPV) infection, however, the manner of progression to cervical cancer differs depending on the type of HR-HPV: HPV16 is characterized by a stepwise carcinogenesis, HPV18 is difficult to detect in precancerous lesions, and HPV52, 58 tends to remain in the state of cervical intraepithelial neoplasia (CIN). Third, in addition to the type of HPV, the involvement of the human immune response is also important in the progression and regression of cervical cancer. In this review, we demonstrate the carcinogenesis mechanism of HPV-associated cervical cancer, management of CIN, and the current treatment of CIN and cervical cancer.

Human papillomavirus independent status on pathologic response and outcomes in locally advanced cervical cancer managed with chemoradiotherapy followed by surgery

ObjectiveWhile human papillomavirus (HPV) has been shown to play a significant role in cervical cancer carcinogenesis (HPV associated cases), a considerable percentage of cervical cancers occur independently of HPV status...

Carvacrol instigates intrinsic and extrinsic apoptosis with abrogation of cell cycle progression in cervical cancer cells: Inhibition of Hedgehog/GLI signaling cascade.

Recent times have seen a strong surge in therapeutically targeting the hedgehog (HH)/GLI signaling pathway in cervical cancer. HH signaling pathway is reported to be a crucial modulator of carcinogenesis in cervical cancer and is also associated with recurrence and development of chemoresistance. Moreover, our previous reports have established that carvacrol (CAR) inhibited the proliferation of prostate cancer cells via inhibiting the Notch signaling pathway and thus, it was rational to explore its antiproliferative effects in cervical cancer cell lines. Herein, the present study aimed to investigate the anticancer and apoptotic potential of CAR on C33A cervical cancer cells and further explore the underlying mechanisms. We found that CAR significantly suppressed the growth of C33Acells, induced cell cycle arrest, and enhanced programmed cell death along with augmentation in the level of ROS, dissipated mitochondrial membrane potential, activation of caspase cascade, and eventually inhibited the HH signaling cascade. In addition, CAR treatment increased the expression of pro-apoptotic proteins (Bax, Bad, Fas-L, TRAIL, FADDR, cytochrome c) and concomitantly reduced the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL) in C33Acells. CAR mediates the activation of caspase-9 and -3 (intrinsic pathway) and caspase-8 (extrinsic pathway) accompanied by the cleavage of PARP in cervical cancer cells. Thus, CAR induced apoptosis by both the intrinsic and extrinsic apoptotic pathways. CAR efficiently inhibited the growth of cervical cancer cells via arresting the cell cycle at G0/G1 phase and modulated the gene expression of related proteins (p21, p27, cyclin D1 and CDK4). Moreover, CAR inhibited the HH/GLI signaling pathway by down regulating the expression of SMO, PTCH and GLI1 proteins in cervical carcinoma cells. With evidence of the above results, our data revealed that CAR treatment suppressed the growth of HPV-C33A cervical cancer cells and further elucidated the mechanistic insights into the functioning of CAR.

Cells with stem-like properties are associated with the development of HPV18-positive cervical cancer.

The cellular origins of cervical cancer and the histological differentiation of human papillomavirus (HPV)-infected cells remain unexplained. To gain new insights into the carcinogenesis and histological differentiation of HPV-associated cervical cancer, we focused on cervical cancer with mixed histological types. We conducted genomic and transcriptomic analyses of cervical cancers with mixed histological types. The commonality of the cellular origins of these cancers was inferred using phylogenetic analysis and by assessing the HPV integration sites. Carcinogenesis was estimated by analyzing human gene expression profiles in different histological types. Among 42 cervical cancers with known HPV types, mixed histological types were detected in four cases, and three of them were HPV18-positive. Phylogenetic analysis of these three cases revealed that the different histological types had a common cell of origin. Moreover, the HPV-derived transcriptome and HPV integration sites were common among different histological types, suggesting that HPV integration could occur before differentiation into each histological type. Human gene expression profiles indicated that HPV18-positive cancer retained immunologically cold components with stem cell properties. Mixed cervical cancer has a common cellular origin among different histological types, and progenitor cells with stem-like properties may be associated with the development of HPV18-positive cervical cancer.

IMPACT OF OXIDATIVE STRESS IN THE PATHOGENESIS OF CERVICAL CANCER: THERAPEUTIC APPROCHES

Cervical cancer (CC) is acknowledged as the most ubiquitous carcinoma among females along with the utmost prevalence in developing nations. The major cause of CC is HPV exposure, especially HPV16 and 18. Inflammation is linked to the carcinogenesis of CC in addition to HPV infection. Although the precise cause of CC is yet unknown, using oral contraceptives, being immunosuppressed, and smoking may enhance the risk of the disease. Oxidative stress (OS), in addition to HPV, is linked to cervical cancer. Across several clinical and preclinical research, the dysfunctional redox system and the impact of oxidative stress throughout the aetiology of CC have been examined. Redox homeostasis must therefore be maintained, which calls for both enzymatic and nonenzymatic redox regulators. In this study, we explored the therapeutic strategies used to preserve redox balance, lower cervical cancer mortality, and illustrate the contribution of oxidative stress in the aetiology of the disease.

Detection of human papillomavirus, viral load and risk factors in patients with precancerous diseases and malignant neoplasms in St. Petersburg

Molecular genetic studies have revealed the involvement of different genotypes of human papillomavirus (HPV) in the carcinogenesis of cervical cancer and malignant lesions of other localizations. It is reported that patients with HPV-positive cancer have a better prognosis of the disease and survival than patients with unconfirmed HPV infection or with a low viral load. The objective was to identify the detectability, viral load, genotypes of human papillomavirus in HPV-associated precancerous and malignant neoplasia of various localization and to determine risk factors for their occurrence in the metropolis of St. Petersburg at the present time.
 Materials and methods. A total of 80 samples taken from morphologically confirmed tissues of oropharyngeal and anal cancer, malignant tumors of vulva, vagina, cervix and cervical intraepithelial neoplasia were studied in St. Petersburg Clinical Oncologic Center. Detection, quantification and genotyping of HPV DNA were carried out by real-time PCR at the St. Petersburg Pasteur Institute.
 Results. HPV was detected in 89.7% (61/68) of patients with malignant tumors and 83.3% (10/12) with severe cervical dysplasia. The vast majority (85.9%) of HPV-positive patients were infected with HPV genotype 16; papillomavirus mixed infection (genotypes 16, 18, 31, 33, 35, 39, 45) was detected in anal cancer, cancer and severe cervical dysplasia. The average viral load in stages IIIIV of anal cancer, cervical cancer and severe cervical dysplasia exceeded 5.7 lg HPV DNA/105 cells. Among patients with oropharyngeal cancer, men predominated (85.7%); anal cancer was detected in women (90.0%). No statistically significant risk factors (smoking and alcohol consumption) for the occurrence of HPV-associated malignancies were identified.
 Conclusions. The detection of HPV, mainly of genotype 16, varied depending on the location of the neoplasia: anal cancer 100%, cancer of the female genitalia 94% (in case of cancer of the vagina and cervix 100.0%), head and neck cancer 76.2%. The highest HPV DNA load in the tumor tissue was found in IIIIV stages of the cervical and anal cancer.

A prognostic model for cervical cancer based on ferroptosis-related genes.

BackgroundFerroptosis is widely involved in the occurrence and development of various cancers, but a specific mechanism involving ferroptosis in cervical cancer is still unclear.MethodsBased on the expressions of ferroptosis-related genes, a prognostic model was constructed using lasso regression, and the overall predictive performance of this model was verified. An in-depth analysis of the prognostic model was then conducted.ResultsThe prognostic model showed good predictive performance in both the validation and test sets. Mechanism analysis indicated that differences in the tumor microenvironment were the basis of the predictive ability of the model. Notably, CA9 mRNA was significantly overexpressed in cervical carcinoma, tissues but not in normal cervix tissues. A pair of ceRNAs (CA9/ULBP2) could be involved in the carcinogenesis and development of cervical cancer, and the potential target might be hsa-miR-34a. In addition, predicted miRNAs and drugs for these DEGs were identified.ConclusionsWe constructed a prognostic model with good predictive performance, based on the expression of ferroptosis-related genes. Further research found that the ceRNA pairs of ULBP2/CA9 could regulate cervical cancer through hsa-miR-34a. These results identified the mechanism of ferroptosis in cervical cancer, and might provide novel therapeutics for cervical cancer patients.

HPV-CCDC106 integration promotes cervical cancer progression by facilitating the high expression of CCDC106 after HPV E6 splicing.

Human papillomavirus (HPV) integration and high expression of HPV oncogenes (E6 and E7) are important mechanisms for HPV carcinogenesis in cervical cancer. However, the relationship between HPV integration and HPV E6 spliced transcripts, as well as the underlying mechanisms of HPV integration in carcinogenesis after HPV E6 splicing remains unclear.We analyzed HPV-coiled-coil domain containing 106 (CCDC106) integration samples to characterize the roles of HPV integration, E6 spliceosome I (E6*I), and high CCDC106 expression in cervical carcinogenesis. We found that E6 was alternatively spliced into the E6*I transcript in HPV-CCDC016 integration samples with low p53 expression, in contrast to the role of E6*I in preventing p53 degradation in cervical cancer cells. In addition, CCDC106 was highly expressed after HPV-CCDC106 integration, and interacted with p53, resulting in p53 degradation and cervical cancer cell progression in vitro and in vivo. Importantly, when E6*I was highly expressed in cervical cancer cells, overexpression of CCDC106 independently degraded p53 and promoted cervical cancer cell progression.In this study, we explored the underlying mechanisms of HPV-CCDC106 integration in HPV carcinogenesis after HPV E6 splicing, which should provide insight into host genome dysregulation in cervical carcinogenesis.

HPV16 E6-Activated OCT4 Promotes Cervical Cancer Progression by Suppressing p53 Expression via Co-Repressor NCOR1.

Human papillomaviruses (HPV), mainly HPV16 and HPV18, of high-risk classification are involved in cervical cancer carcinogenesis and progression. Octamer-binding transcription factor 4 (OCT4) is a key transcription factor that is increased in various cancer types. Cervical cancer patients with higher levels of OCT4 had worse survival rates. However, the definite mechanisms underlying its function in the development of cervical cancer still remain to be explicated. Here, our study demonstrated that OCT4 expression was slightly increased in cervical cancer tissues than in precancerous ones. However, OCT4 was significantly upregulated in HPV16-positive tissues, in contrast to the expression profiling for p53. Moreover, knockdown of HPV16 E6 in SiHa cells suppressed the expression of OCT4 with impaired activities of cell proliferation, migration, and invasion, while it recovered the expression of p53. Overexpression of OCT4 and p53 exerted opposite roles on cell proliferation, migration, invasion, and colony formation of cervical cancer cells. More importantly, the enforced expression of OCT4 augmented p53-inhibited cell migration, invasion, and colony formation in human cervical cancer by promoting EMT. Finally, we identified that OCT4 could bind to the p53 promoter region to repress p53 expression by recruiting co-repressor NCOR1 using luciferase, ChIP, and co-IP experiments. We further illustrated that OCT4 not only increased the lung metastasis of cervical cancer but also effectively reversed p53-inhibited lung metastasis. In conclusion, our results suggested that HPV16 E6 activated the expression of OCT4 and subsequently crippled the transcription of p53 via co-repressor NCOR1, which contributed to cervical cancer progression.

ERBB3 methylation and immune infiltration in tumor microenvironment of cervical cancer

ERBB3, a member of the ERBB family of receptor tyrosine kinases, plays an important role in cancer, despite its lack of intrinsic carcinogenic mechanism of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Research on bioinformatics methods through multi-omics, this work proves that ERBB3 gene mutation, methylation modification have extensive regulatory mechanisms on the CESC microenvironment. We found that ERBB3 is involved in carcinogenesis of cervical cancer and is not associated with its prognosis. The carcinogenic mechanism is mainly related to the suppression of the immune system between tumor infiltrating lymphocytes (TILs) and the methylation of the RNA level. Our study indicated ERBB3 is more likely to be a carcinogenic factor than a key prognostic factor for cervical cancer. Methylation of ERBB3 may work as a checkpoint immunotherapy target in CESC, DNA methylation modification of the 4480 base pair downstream of ERBB3 transcription initiation site was the highest.

Herpes Virus Simple tipo 2 ¿factor y/o cofactor en el cáncer del cuello uterino? Revisión narrativa de la literatura

Objective: To review and analyze the possible role of herpes simplex virus type 2 as a factor and/or cofactor in the origin and development of cervical cancer. Methods: The Latin American and international literature was reviewed between 1970 and Junio 2020. The terms were used:herpes simplex virus type 2 and/or epidemiology, human papillomavirus and cervical cancer. Results: Herpes simplex virus type 2 is considered one of the most frequent sexually transmitted infections in the world. It has been related to the origin and evolution of cervical neoplasms and their precursors. The possible mechanisms by which it could participate in the carcinogenesis of cervical cancer are analyzed, as a cofactor with papillomavirus or as an independent factor. Conclusions: More clinical, epidemiological, serological and molecular studies are required to elucidate the pathogenesis of herpes simplex virus type 2 in the carcinogenesis of cervical cancer

Causal Association between Chronic Kidney Disease and Risk of 19 Site-Specific Cancers: A Mendelian Randomization Study.

Results of previous observational studies examining the risk of cancer among patients with chronic kidney disease (CKD) are conflicting. We here explore the causal relationship between estimated glomerular filtration rate (eGFR) and albuminuria, two principal measurements of CKD, and 19 site-specific cancers using Mendelian randomization (MR) analysis. Single-nucleotide polymorphisms reported to be strongly correlated with eGFR and albuminuria in recent large genome-wide association studies were used as instrumental variables to investigate the causal relationship with cancer using summary-level statistics from several cancer-specific consortia, as well as data of 347,408 participants in the UK Biobank and 260,405 participants in the FinnGen. Our data showed that impaired kidney function was associated with higher odds of leukemia [OR = 1.23; 95% confidence interval (CI), 1.06-1.43; P = 0.007], cervical cancer (OR = 1.22; 95% CI, 1.04-1.43; P = 0.017), and female renal cell carcinoma (OR = 1.4; 95% CI, 1.12-1.77; P = 0.004), per 10% decrease in eGFR. The ORs were 1.21 (95% CI, 1.07-1.36; P = 0.002) for colorectal cancer and 0.76 (95% CI, 0.62-0.92; P = 0.006) for non-Hodgkin lymphoma, per doubling odds of albuminuria. In multivariable MR, effect sizes of eGFR-cervical cancer remained strong after adjusting for confounders. The current study indicates that progression of CKD contributes to carcinogenesis of renal cell carcinoma, leukemia, cervical, and colorectal cancer. The potential association of kidney function and albuminuria with certain cancers warrants further investigation in order to provide appropriate recommendations regarding cancer screening among patients with CKD.

Immunotherapy for Cervical Cancer: Are We Ready for Prime Time?

The prognosis of invasive cervical cancer (CC) remains poor, with a treatment approach that has remained the same for several decades. Lately, a better understanding of the interactions between the disease and the host immune system has allowed researchers to focus on the employment of immune therapy in various clinical settings. The most advanced strategy is immune checkpoint inhibitors (ICIs) with numerous phase II and III trials recently concluded with very encouraging results, assessing single agent therapy, combinations with chemotherapy and radiotherapy. Apart from ICIs, several other compounds have gained the spotlight. Tumor Infiltrating Lymphocytes (TILs) due to their highly selective tumoricidal effect and manageable adverse effect profile have received the FDA’s Breakthrough Therapy designation in 2019. The antibody drug conjugate (ADC) Tisotumab-Vedotin has shown activity in metastatic CC relapsed after at least one line of chemotherapy, with a phase III trial currently actively enrolling patients. Moreover, the deeper understanding of the ever-changing immune landscape of CC carcinogenesis has resulted in the development of active therapeutic vaccines. This review highlights the different immunotherapeutic strategies being explored reflects on what role immunotherapy might have in therapeutic algorithms of CC and addresses the role of predictive biomarkers.

FNDC3B and BPGM Are Involved in Human Papillomavirus-Mediated Carcinogenesis of Cervical Cancer.

Human papillomavirus (HPV)-mediated cervical carcinogenesis is a multistep progressing from persistent infection, precancerous lesion to cervical cancer (CCa). Although molecular alterations driven by viral oncoproteins are necessary in cervical carcinogenesis, the key regulators behind the multistep process remain not well understood. It is pivotal to identify the key genes involved in the process for early diagnosis and treatment of this disease. Here we analyzed the mRNA expression profiles in cervical samples including normal, cervical intraepithelial neoplasia (CIN), and CCa. A co-expression network was constructed using weighted gene co-expression network analysis (WGCNA) to reveal the crucial modules in the dynamic process from HPV infection to CCa development. Furthermore, the differentially expressed genes (DEGs) that could distinguish all stages of progression of CCa were screened. The key genes involved in HPV-CCa were identified. It was found that the genes involved in DNA replication/repair and cell cycle were upregulated in CIN compared with normal control, and sustained in CCa, accompanied by substantial metabolic shifts. We found that upregulated fibronectin type III domain-containing 3B (FNDC3B) and downregulated bisphosphoglycerate mutase (BPGM) could differentiate all stages of CCa progression. In patients with CCa, a higher expression of FNDC3B or lower expression of BPGM was closely correlated with a shorter overall survival (OS) and disease-free survival (DFS). A receiver operating characteristic (ROC) analysis of CIN and CCa showed that FNDC3B had the highest sensitivity and specificity for predicting CCa development. Taken together, the current data showed that FNDC3B and BPGM were key genes involved in HPV-mediated transformation from normal epithelium to precancerous lesions and CCa.

Gene expression analysis of RCC1, VAV2, RPA3, and SRPK1 for human cervical cancer biomarkers

Cervical cancer is the most common cancer in women worldwide, with developing countries accounting for 80% of the disease burden. Infection with a high-risk group of human papilloma viruses (HPVs) is caused mainly by carcinogenesis of cervical cancer. Although, active diagnosis has been improved treatment efficacy in reducing the incidence and mortality rate. Cervical cancer is generally classified into four histopathological subtypes; adenocarcinoma, squamous cell carcinoma, papilloma and carcinoma. In this study, the gene expression profiles of these four subtypes in cervical cancer cell lines were compared to normal cervical tissue using quantitative real-time PCR (qPCR). Sixty-one genes from public DNA microarray data were selected. The expression of 30 candidate genes including a housekeeping gene, GAPDH, were quantified with qPCR in HeLa, SiHa, C-4 I and SW756 cell lines showing more than 1.5-fold difference in their expression. VAV2 gene was found to overexpress in Adenocarcinoma (HeLa), Squamous cell carcinoma (SiHa) and Carcinoma (SW756) and RCC1 gene was overexpressed in papilloma (C-4 I) of cervical cell lines. Based on their upregulation level, VAV2 gene was identified as a candidate marker for adenocarcinoma, squamous cell carcinoma, and carcinoma while RCC1 gene was promising as a candidate marker for papilloma subtype of cervical cancer. In addition, of RCC1, VAV2, RPA3, and SRPK1 were potential gene candidates for cervical cancer markers. The candidate biomarkers may useful for screening and diagnosis.

Silent Information Regulator 1 Promotes Proliferation, Migration, and Invasion of Cervical Cancer Cells and Is Upregulated by Human Papillomavirus 16 E7 Oncoprotein

Objective: Silent information regulator 1 (SIRT1), an NAD+-dependent III class histone deacetylase, plays crucial roles in cell proliferation, apoptosis, senescence, metabolism, and stress responses. Nevertheless, the role of SIRT1 in tumorigenesis remains unclear. Methods: In the present study, we measured expression levels of SIRT1 and HPV16 E7 protein in cervical cancer (CC) tissue and calculated their correlations. We measured the effect of silencing SIRT1 on the proliferation, migration, invasion, and apoptosis in human CC SiHa cells. Results: Immunohistochemistry results revealed that the expression of SIRT1 was upregulated with progression from CIN II–III to CC, but was not expressed in normal cervical tissues and CIN I. There was a positive correlation between SIRT1 expression and HPV16 E7 expression in CC tissues, and silencing of HPV16 E7 downregulated the expression of SIRT1. Depletion of SIRT1 downregulated SIRT1 expression, and inhibited proliferation, migration, and invasion of SiHa cells, inducing apoptosis. Conclusions: Taken together, the data suggest that SIRT1 promotes CC carcinogenesis. SIRT1 inhibition is a potential treatment strategy for CC.