Cervical Adenocarcinoma Tissues Research Articles

CircMAN1A2_009 facilitates YBX1 nuclear localization to induce GLO1 activation for cervical adenocarcinoma cell growth.

The molecular mechanisms driving the development of cervical adenocarcinoma (CADC) and optimal patient management strategies remain elusive. In this study, we have identified circMAN1A2_009 as an oncogenic circular RNA (circRNA) in CADC. Clinically, circMAN1A2_009 showed significant upregulation in CADC tissues, with an impressive area under the curve value of 0.8075 for detecting CADC. Functional studies, involving both gain-of-function and loss-of-function experiments, revealed that circMAN1A2_009 suppressed reactive oxygen species accumulation and apoptosis, and boosted cell viability in CADC cells. Conversely, silencing circMAN1A2_009 reversed these effects. Further mechanistic investigations indicated that circMAN1A2_009 interacted with YBX1, facilitating the phosphorylation levels of YBX1 at serine 102 (p-YBX1S102) and facilitating YBX1 nuclear localization through sequence 245-251. This interaction subsequently increased the activity of the glyoxalase 1 (GLO1) promoter, leading to the activation of GLO1 expression. Consistently, inhibition of either YBX1 or GLO1 mirrored the biological effects of circMAN1A2_009 in CADC cells. Additionally, knockdown of YBX1 or GLO1 partially reversed the oncogenic behaviors induced by circMAN1A2_009. In conclusion, our findings propose circMAN1A2_009 as a potential oncogene and a promising indicator for diagnosing and guiding therapy in CADC patients.

CeRNA Network and WGCNA Analyses of Differentially Expressed Genes in Cervical Cancer Tissues for Association with Survival of Patients.

The study aims to search and identify differentially expressed genes (DEGs) in cervical cancer tissues as novel biomarkers to predict cervical cancer prognosis. The Cancer Genome Atlas (TCGA) data on gene expression profiles in cervical cancer were downloaded and analyzed using R software to identify DEGs in cervical cancer tissues. miRNAs targeted by differentially expressed long non-coding RNAs (DElncRNAs) and mRNAs targeted by microRNAs (miRNAs) were identified using the online miRcode, miRTarBase, TargetScan, and miRDB tools. The ceRNA network and lncRNA expression modules in cervical cancer tissues were constructed using weighted gene co-expression network analysis (WGCNA) and analyzed bioinformatically. The Kaplan-Meier analysis was performed to confirm these DEGs as prognostic markers. Immunohistochemical (IHC) analysis was used to verify expression of the hub genes in 10 paired cervical cancer and normal tissues. A total of 1914 DEmRNAs, 210 DElncRNAs, and 67 DEmiRNAs were identified in cervical cancer samples. There were 39 lncRNAs, 19 miRNAs, and 87 mRNAs involved in the ceRNA network and 25 DElncRNAs, three DEmiRNAs, and four mRNAs involved in the ceRNA sub-network. CACNA1C-AS1 was associated with the yellow and blue modules in the ceRNA sub-network, and LIFR-AS1 was associated with the blue module. The DEmRNAs were involved in cancer-related pathways, and three hub genes (i.e., E2F1, CCNB1, and CCNE1) were highly expressed in cervical squamous cell carcinoma and adenocarcinoma tissues and associated with the prognosis of patients. The ceRNA network and WGCNA analyses are useful to identify novel DEGs that can serve as prognostic markers in cervical cancer. The DEGs will be validated in future studies.

Expression of ProEXC and PRMT5 in cervical adenocarcinoma and their clinical significance

This study observed the expression of ProEXC protein and PRMT5 protein in cervical adenocarcinoma and adjacent tissues, exploring the relationship between the expression of ProEXC and PRMT5 and the auxiliary diagnosis of cervical adenocarcinoma, as well as the clinical pathological parameters. A total of 88 specimens diagnosed with cervical adenocarcinoma from the Second Affiliated Hospital of Soochow University between 2015 and 2020 were collected. Immunohistochemistry was employed to detect the expression of ProEXC and PRMT5 in cervical adenocarcinoma and adjacent tissues, and statistical analysis was conducted. The Cancer Genome Atlas (TCGA) database was utilized to analyze the correlation between the prognosis of cervical adenocarcinoma patients and the expression of ProEXC and PRMT5, as well as their related gene pathways. The GSE39293 dataset from the Gene Expression Omnibus (GEO) was selected to compare the expression levels of ProEXC and PRMT5 in cervical adenocarcinoma cell lines (HELA) before and after antiviral drug treatment.In cervical adenocarcinoma tissues, the expression of ProEXC protein (95.5% vs 4.6%, P<0.001) and PRMT5 protein (81.8% vs 26.1%, P<0.001) was significantly higher than in surrounding adjacent tissues. Their expression was correlated with the tumor's T stage, lymph node metastasis, and human papillomavirus (HPV) infection (P<0.05). TCGA database analysis showed that patients with high expression of MCM2 in PRMT5 and ProEXC had a lower overall survival rate (P<0.05), while the expression of TOP2A was not significantly correlated with survival. In the GSE39293 dataset, the expression of MCM2 (9.34 vs 9.68, P<0.001) and PRMT5 (8.16 vs 8.26, P=0.087) in cells decreased after treatment with cidofovir, while TOP2A (8.54 vs 8.42, P=0.056) expression did not change significantly. In the drug-resistant group, the expression of PRMT5 (8.42 vs 8.16, P=0.002) and MCM2 (9.51 vs 9.34, P=0.029) increased, while TOP2A (8.06 vs 8.54, P<0.001) expression decreased. Gene set enrichment analysis (GSEA) suggested that high expression of ProEXC mainly affected the cell cycle pathway, while high expression of PRMT5 mainly affected the RNA splicing pathway.This study found that ProEXC protein and PRMT5 protein were highly expressed in cervical adenocarcinoma tissues, and the high-expression group had a poorer prognosis, showing a certain correlation with the clinical and pathological characteristics of cervical adenocarcinoma. This may be related to their influence on the cell cycle and RNA synthesis pathways, suggesting their potential significant roles in the progression of cervical adenocarcinoma.

Comprehensive profile and contrastive analysis of circular RNA expression in cervical squamous carcinoma and adenocarcinoma.

Numerous studies have shown circular RNA (circRNA) dysregulation is associated with the pathogenesis of cervical cancer,particularly in individual carcinoma variants. The aim of this study is to investigate and contrastively analyze the expression pattern of circRNAs in cervical squamous carcinoma and adenocarcinoma mediated by human papillomavirus type 16 (HPV-16). The expression of circRNAs in cervical squamous carcinoma (SCC), adenocarcinoma (ADC) and adenosquamous carcinoma (ASC) tissues, together with the adjacent normal tissues (ANT), was profiled by high-throughput RNA sequencing (RNA-seq). Bioinformatics analysis and quantitative real time polymerase chain reaction (qRT-PCR) validation of the sequencing data were performed. A network of circRNA-miRNA (microRNA)-mRNA was then constructed according to predicted targets and function of candidate circRNAs. A total of 11,685 annotated circRNAs were identified in six cervical samples. There were 42 up-regulated and 98 down-regulated circRNAs. 215 circRNAs were up-regulated in SCC but down-regulated circRNAs in ADC, while 50 circRNAs displayed the opposite trend. Function enrichment analysis based on different expressions of circRNAs found that the most enriched pathway in all the three pathologic variants of cervical cancer was the "ubiquitin mediated proteolysis" pathway. Eight key candidate circRNAs derived from this pathway were further validated, and we noticed that several target miRNAs of candidate circRNAs could target the source genes. Based on this we constructed a related competing endogenous RNA (ceRNA) network. Through a comprehensive interpretation of differentially expressed circRNAs in different pathologic variants of cervical cancer, this study provides new insights into the process of tumor differentiation mediated by HPV. Our results may help to complement the molecular typing and stem cell theory of cervical cancer.

Screening of prognostic immune genes and establishment of prognostic model of cervical adenocarcinoma based on bioinformatics analysis.

BackgroundThere is currently a lack of clinical models to accurately predict the prognosis of cervical adenocarcinoma. This study aimed to explore the correlation between immune genes and the prognosis of cervical adenocarcinoma patients, and establish a prognostic model.MethodsTranscriptome sequencing data sets and clinical data sets of cervical adenocarcinoma samples were downloaded from the Gene Expression Omnibus (GEO) database. Information about the immune gene was obtained from the ImmPort database. Differentially expressed genes and differentially expressed immune genes were screened in cervical adenocarcinoma tissue and normal cervical group by edgeR package. Differentially expressed immune genes were screened for prognosis-related immune genes by Cox analysis. Taking the immune genes related to prognosis as variables, a prognosis prediction model was established by multivariate Cox regression analysis. Kaplan-Meier analysis and a receiver operating characteristic (ROC) curve were used to test the effectiveness of the model. According to the clinical information and risk score, univariate multivariate Cox analyses were used to screen the independent prognostic risk factors of cervical adenocarcinoma.ResultsCXCL9 was an independent prognostic factor of cervical adenocarcinoma [hazard ratio (HR) =0.63; P=0.025]. CGB5 (HR =1.22; P=0.034), CXCL12 (HR =1.33; P=0.023), PTX3 (HR =1.53; P=0.024), and CXCL10 (HR =2.31; P=0.031) were prognostic risk factors for cervical adenocarcinoma. The risk score was calculated as follows: risk score = (0.005 × CXCL10) + (0.076 × CGB5) + (0.061 × CXCL12) + (0.034 × PTX3) + (−0.004 × CXCL9). The prognosis of the low-risk score group was better than that of the high-risk score group (P=0.035). The area under the ROC curve (AUC) of the risk score was 0.713, and the predictive power was good. Multivariate Cox analysis showed that N stage (HR =1.34; P=0.035) and risk score (HR =1.37; P<0.001) were independent risk factors for the prognosis of cervical adenocarcinoma (HR >1; P<0.001).ConclusionsIn this study, an immune gene prognosis prediction model for cervical adenocarcinoma was established based on the GEO and ImmPort databases. The prediction performance of the model is good, and the prognosis of patients can be evaluated according to the gene expression, which has clinical practicability.

Correlation analysis of Ki67 and CK7 expression with clinical characteristics and prognosis of postoperative cervical adenocarcinoma patients.

The purpose of this study is to investigate the correlation between cytokeratin 7 (CK7) and marker of proliferation Ki67 protein expression and clinical characteristics and prognosis of patients with cervical adenocarcinoma after surgery. A total of 126 patients with cervical adenocarcinoma treated by surgery in our hospital from June 2011 to September 2015 were enrolled in this study. Immunohistochemistry (IHC) was used to detect the expression of CK7 and Ki67 in 126 cases of cervical adenocarcinoma tissues. The chi-square (χ2) test was used to compare the relationship between the positive expression rate of CK7 or Ki67 and clinicopathological features. Kaplan-Meier method was used to analyze the survival of different protein expression groups and Cox proportional hazards regression model was used to analyze the risk factors affecting the prognosis. The positive rate of CK7 was correlated with muscle invasion, vascular invasion, differentiation, and lymph node metastasis (all P<0.05). The positive expression rate of Ki67 was related to the degree of myometrial invasion and International Federation of Gynecology and Obstetrics (FIGO) stage (both P<0.05). Both CK7 and Ki67 may be independent risk factors for the prognosis of patients with cervical adenocarcinoma after surgery (both P<0.05), and their high expression heralds worse prognosis. The CK7 and Ki67 proteins may be key regulatory factors in the development of cervical adenocarcinoma after surgery, and their overexpression may lead to worse prognosis. Both CK7 and Ki67 may provide new markers for prognosis evaluation of cervical adenocarcinoma.

CircSPIDR acts as a tumour suppressor in cervical adenocarcinoma by sponging miR-431-5p and regulating SORCS1 and CUBN expression.

To identify circular RNAs (circRNAs) with tumor suppressor activity against cervical adenocarcinoma, we compared the circRNA levels of cervical adenocarcinoma and normal cervical tissues. We found that circSPIDR was dramatically downregulated in cervical adenocarcinoma tissues. In cervical adenocarcinoma cells, overexpression of circSPIDR reduced cell viability, inhibited colony formation and promoted apoptosis, whereas knockdown of circSPIDR exerted the opposite effects. CircSPIDR overexpression also suppressed the tumorigenicity of cervical adenocarcinoma cells in a xenograft mouse model. CircSPIDR was found to sponge miR-431-5p, thereby de-repressing sortin-related VPS10 domain-containing receptor 1 (SORCS1) and cubilin (CUBN) and inhibiting the development of cervical adenocarcinoma. In clinical cervical samples, circSPIDR expression correlated negatively with miR-431-5p expression and positively with SORCS1 and CUBN expression. These results demonstrated that circSPIDR suppresses cervical adenocarcinoma by competitively binding to miR-431-5p, thus upregulating SORCS1 and CUBN. These findings suggest circSPIDR could serve as a novel therapeutic target for treatment of cervical adenocarcinoma patients.

Distribution of Human Papilloma Virus (HPV) in Cervical Adenocarcinoma and Adenosquamous Carcinoma

Approximately 20-30% of all cervical cancer cases are adenocarcinoma and adenosquamous carcinoma. Around 70% of all of these types of cancer are related to infection of Human Papillomavirus (HPV). This study evaluated the distribution of HPV genotype in cervical adenocarcinoma and adenosquamous carcinoma. A cross-sectional study was conducted at the Department of Anatomic Pathology, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia, from January to December 2015. The sample were 22 formalin-fixed paraffin-embedded (FFPE) of cervical adenocarcinoma tissues and adenosquamous carcinoma tissues. FFPE was used for DNA extraction and followed with HPV genotyping to detect 40 genotypes of HPV, including low risk (LR) and high risk (HR) HPV. The histopathological types of adenocarcinomas were adenocarcinoma NOS and mucinous adenocarcinoma, while the adenosquamous carcinoma types were adenosquamous carcinoma and adenosquamous carcinoma glassy. All of the specimens were infected by HPV. In cervical adenocarcinoma, the infection was by HPV 6, 11, 16, 18, 31, 45, 68B, and 72, and in adenosquamous carcinoma by HPV 6, 16, 18, 45, and 59. HPV 18 was predominant, which was found in 13/22 (59.1%) in adenocarcinoma and 19/22 (86.4%) in adenosquamous carcinoma. Single infection and multiple infections in adenocarcinoma were 13/22 (59.1%) and 9/22 (40.9%), while in adenosquamous carcinoma were 21/22 (95.5%) and 1/22 (4.5%) respectively. The most common HR HPVs found in this study were HPV 18, HPV 45, HPV 16 and LR HPV are HPV 11, HPV 6.

SOX1 and PAX1 Are Hypermethylated in Cervical Adenocarcinoma and Associated with Better Prognosis

Background The increased risk and poor survival outcome of cervical adenocarcinoma (CAC) demand for effective early diagnostic biomarkers that can predict the disease progression and outcome. The purpose of this study was to investigate the value of methylation status of SOX1 and PAX1 in the detection and prognosis of CAC. Methods We performed a quantitative methylation-specific polymerase chain reaction in 205 cervical paraffin-embedded specimens (175 CACs, 30 noncancer cervical tissues). Overall and progression-free survival (OS and PFS, respectively) rates were calculated and compared using the Kaplan-Meier method. The prognostic value of SOX1m and PAX1m on CAC patients was assessed by the Cox regression model. A mathematical formula combining SOX1m, PAX1m, and age was constructed for survival prediction. Results The methylation status of SOX1 and PAX1 was higher in CAC tissues than in noncancer cervical tissues. In addition, SOX1m-positive CAC patients showed a higher 5-year OS rate than SOX1m-negative patients. In CAC patients with smaller tumor size (<4 cm), the PAX1m-positive group showed a higher 5-year PFS rate than the PAX1m-negative group. In the algorithm combining SOX1m, PAX1m, and age, the low-risk group showed a better 5-year OS and PFS rate than the high-risk group. Conclusion SOX1 and PAX1 methylation levels are higher in CAC than in normal cervical tissues and are potential biomarkers for monitoring CAC prognosis.

CircEYA1 Functions as a Sponge of miR-582-3p to Suppress Cervical Adenocarcinoma Tumorigenesis via Upregulating CXCL14

Circular RNAs (circRNAs) function as efficient microRNA (miRNA) sponges that regulate gene expression in the pathogenesis of many human malignancies. However, their roles in cervical adenocarcinoma remain largely unknown. In this study, we aimed to seek novel circRNAs that regulate cervical adenocarcinoma carcinogenesis and to explore their regulatory mechanisms as well as clinical significance. We identified that 24 circRNAs were differentially expressed in cervical adenocarcinoma tissues by RNA sequencing. Among them, circEYA1 was the most significantly downregulated circRNA in cervical adenocarcinoma. In cervical adenocarcinoma cells, circEYA1 overexpression led to suppression of cell viability and colony formation, promotion of apoptosis, and a decrease of the xenograft tumor growth. The mechanism underlying these observations is that circEYA1 functioned as a sponge of miR-582-3p and abrogated its suppression of CXCL14 expression. Consistently, miR-582-3p inhibition phenocopied the biological effects of circEYA1 overexpression in cervical adenocarcinoma cells. Moreover, miR-582-3p overexpression reversed the suppressive behaviors of circEYA1 in vitro and in vivo. In addition, the expression, correlation, and clinical diagnostic value of circEYA1/miR-582-3p/CXCL14 were confirmed in 198 clinical cervical tissue samples. In summary, our findings highlight a novel tumor suppressive role of circEYA1 in cervical adenocarcinoma tumorigenesis and may provide a potential diagnostic marker and therapeutic target for patients with cervical adenocarcinoma.

Transcriptome analysis uncovers the diagnostic value of miR-192-5p/HNF1A-AS1/VIL1 panel in cervical adenocarcinoma

Despite the fact that the incidence of cervical squamous cell carcinoma has decreased, there is an increase in the incidence of cervical adenocarcinoma. However, our knowledge on cervical adenocarcinoma is largely unclear. Transcriptome sequencing was conducted to compare 4 cervical adenocarcinoma tissue samples with 4 normal cervical tissue samples. mRNA, lncRNA, and miRNA signatures were identified to discriminate cervical adenocarcinoma from normal cervix. The expression of VIL1, HNF1A-AS1, MIR194-2HG, SSTR5-AS1, miR-192-5p, and miR-194-5p in adenocarcinoma were statistically significantly higher than that in normal control samples. The Receiver Operating Characteristic (ROC) curve analysis indicated that combination of miR-192-5p, HNF1A-AS1, and VIL1 yielded a better performance (AUC = 0.911) than any single molecule -and could serve as potential biomarkers for cervical adenocarcinoma. Of note, the combination model also gave better performance than TCT test for cervical adenocarcinoma diagnosis. However, there was no correlation between miR-192-5p or HNF1A-AS1 and HPV16/18 E6 or E7. VIL1 was weakly correlated with HPV18 E7 expression. In summary, our study has identified miR-192-5p/HNF1A-AS1/VIL1 panel that accurately discriminates adenocarcinoma from normal cervix. Detection of this panel may provide considerable clinical value in the diagnosis of cervical adenocarcinoma.

The Contrast Research of Human Papillomavirus Infection Genotypes in Tissues of Cervical Squamous Cell Carcinoma and Cervical Adenocarcinoma

The large sample data of HPV genotypes on cervical squamous cell carcinoma (CSCC) and cervical adenocarcinoma (CAC) tissues are rarely reported in China. This study is aimed to investigate the clinical value of distribution of different kinds of genotypes of human papillomavirus (HPV) within regional (mainly in Jiangsu Province in China) patients of both CSCC and CAC. We collected tissue samples of from 1044 women with CSC (826 cases) and CAC (218 cases) in 29 hospitals of 6 Provinces in China from November 1978 to December 2017. HPV DNA was extracted and 23 genotypes of HPV were detected through the combination of gene-chip and polymerase chain reaction (PCR) technology to analyze distribution of HPV infection types among subjects of CSCC and CAC. Among 1044 cases of CSCC and CAC, 901 were found HPV positive making total HPV detection rate of 86.30% (901/1044). Total detection rate of CSCC was 91.53% (756/826) in which 16, 18, 58, 33, 52, 31 were the most common types where detection frequencies of 16 and 18 types were 56.84% (544/957) and 9.93% (95/957), respectively. Total detection rate of CAC was 66.51% (145/218) in which 16, 18, 31, 33, 52, 58 were the most common types where detection frequencies of 16 and 18 types were 35.29% (84/238) and 32.35% (77/238), respectively. The HPV detection rates were different in female CSCC and CAC tissues of region studied. The 16, 18, 31, 33, 52 and 58 types are the most common genotypes found in two sorts of cervical carcinoma tissues. The detection rate of 16 types was higher than 18 types in CSCC and were very close in CAC tissues. Conducting HPV genotypes detection of CSCC and CAC will help doctors evaluating onset risk of cervical carcinoma and tracking HPV infected patients with high cancerogenic risk. The early detection will play important role in prevention and treatment of female CSCC and CAC in our nation.

Tumor-suppressor gene SOX1 is a methylation-specific expression gene in cervical adenocarcinoma.

The present study is to analyze the difference of gene methylation in early cervical adenocarcinoma and to find molecular markers for predicting the occurrence and development of cervical adenocarcinoma.A total of 15 cases of primary cervical adenocarcinoma and 10 cases of primary cervical squamous cell carcinoma at stages IB1 or IIA1 were included in the study. Infinium MethylationEPIC BeadChip (850K) was used to screen specifically expressed genes in cervical adenocarcinoma tissues. Bisulfite sequencing polymerase chain reaction (BSP) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to verify the methylation levels in cervical adenocarcinoma, cervical squamous cell carcinoma, and normal cervical tissues.Sex determining region Y-box 1 (SOX1) and cyclin D1 (CCND1) genes participated in multiple signaling pathways, being the central nodes of gene regulatory networks. SOX1 gene, but not CCND1 gene, was a specifically methylated gene in cervical adenocarcinoma according to BSP. According to qRT-PCR, methylation level of SOX1 in cervical adenocarcinoma tissues is significantly different from that in cervical squamous cell carcinoma tissues or normal cervical tissues, and the methylation level of CCND1 in cervical adenocarcinoma tissues or cervical squamous cell carcinoma tissues is significantly different from that in normal cervical tissues.The present study demonstrates that tumor-suppressor gene SOX1 is a methylation-specific expression gene of cervical adenocarcinoma and is expected to become a specific molecular marker for the diagnosis of cervical adenocarcinoma. However, CCND1 gene was not proven to be a specific methylation expression gene in cervical adenocarcinoma in the present study.

High methylation of ZNF582 in cervical adenocarcinoma affects radiosensitivity and prognosis.

Our previous study demonstrated hypermethylation of the ZNF582 gene in cervical cancer, but its prognostic value in cervical cancer, especially in cervical adenocarcinoma (CAC), remains unclear. The present study aimed to investigate the value of ZNF582 gene methylation for diagnosis and prediction of radiochemotherapy sensitivity and prognosis in CAC. We first determined ZNF582 methylation levels using quantitative methylation-specific PCR in a training set. Disease-free survival and overall survival (DFS and OS) rates were estimated using the Kaplan-Meier method. A Cox regression model was used to assess the prognostic significance of ZNF582 gene methylation in CAC patients. Immunohistochemistry was used to test ZNF582 protein expression in CAC tissues, and an MTT assay evaluated the sensitivity of Hela cells (with or without ZNF582 transfection) to radiation and chemotherapy. The ZNF582 gene showed a higher level of methylation in the CAC group than in the noncancer group, and patients negative for ZNF582 methylation had worse prognoses. We also found that ZNF582 methylation levels were reduced in concomitant chemo-radio-therapy (NCRT) patients compared with that in non-NCRT patients. Methylation-negative status was correlated with high ZNF582 protein expression, and ZNF582 protein overexpression could increase resistance to radiation and chemotherapy in Hela cells. Aberrant high methylation of ZNF582 may be a potential biomarker for CAC detection and prognosis monitoring. Overexpression of ZNF582 protein could increase CAC chemoradiotherapy resistance.

Bioinformatics analysis of methylation in cervical adenocarcinoma in Xinjiang, China.

This study is to investigate the genomic methylation in cervical adenocarcinoma in Xinjiang, China, using the DNA methylation analysis chips.Methylation of 5 cases of cervical adenocarcinoma tissues and 5 cases of normal cervical tissues were analyzed by the Illumina 850K methylation chip. The genes with abnormal methylation modification were screened out and analyzed by the gene ontology (GO) functional annotation analysis. Enrichment analysis of kyoto encyclopedia of genes and genomes (KEGG) signal transduction pathways was also performed.Totally 4056 sites showed differential expression patterns in cervical adenocarcinoma tissues compared to normal cervical tissues, of which 3738 were hypermethylated, and 318 were hypomethylated. The distribution of these sites covered from the 1st to 22nd chromosomes. GO functional annotation analysis showed that the differentially expressed genes in cervical adenocarcinoma tissues were mainly involved in the processes of tumor growth, development, metabolism, ion transport, transcriptional regulation, cell division, cell cycle regulation, and signal transduction. KEGG signaling pathway analysis showed that the most significantly different signaling pathway was the neuroactive ligand–receptor interaction. Gene-net-work analysis suggested that CCND1, CTNNB1, MAPK10, and PRKCA were involved.Methylated genes are specifically expressed in cervical adenocarcinoma tissues in Xinjiang, China. Four of these genes (CCND1, CTNNB1, MAPK10, and PRKCA) with differential expression patterns may play important regulatory roles in cervical adenocarcinoma development through affecting the neuroactive ligand–receptor interaction.

MiR-362-3p functions as a tumor suppressor through targeting MCM5 in cervical adenocarcinoma.

Our previous study suggested that minichromosome maintenance protein 5 (MCM5) overexpression was observed in cervical adenocarcinoma and closely associated with advanced clinical stage, more metastatic lymph nodes, present distant metastasis, low histological grade, and poor prognosis. Down-regulation of MCM5 inhibited cervical adenocarcinoma cell proliferation. The purpose of the present study is to search and confirm valuable microRNAs (miRNAs), which target MCM5 to modulate cervical adenocarcinoma cell proliferation. In our results, we found that levels of miR-362-3p expression were reduced in cervical adenocarcinoma tissues and cell lines. Moreover, 3′-UTR of MCM5 had binding site of miR-362-3p through analyzing Targetscan database and miRanda database, and there were an inverse association between miR-362-3p and MCM5 in cervical adenocarcinoma tissues. Furthermore, we verified miR-362-3p directly targeted to 3′-UTR of DCLK1 by luciferase reporter assay, and negatively regulated mRNA and protein expressions of MCM5 by qPCR and Western blot. Then, we conducted gain-of-function study and rescued-function study, and found that miR-362-3p served as a tumor suppressive miRNA to modulate cervical adenocarcinoma cell proliferation through regulating the functional target MCM5. Finally, we analyzed correlations between miR-362-3p expression and clinicopathological characteristics and observed that miR-362-3p low expression was associated with advanced clinical stage and poor prognosis. In conclusion, miR-362-3p is a tumor suppressive miRNA in cervical adenocarcinoma.

Molecular Localization of Latent Epstein – Barr Virus Early Repeats (EBERS) in Cervical Tissues with Adenocarcinoma by RNA-In Situ Hybridization

Epstein-Barr virus (EBV) has an etiological relevancy to the pathogenesis of an increasing number of cancers. Cervical carcinogenesis is a multifactorial stepwise process that has a possible link with many infective factors, including EBV infections where the standard procedures in their histopathological diagnosis rely on in situ hybridization. This retrospective research was designed to(1) investigate the frequency of EBV infections in correlation with the age of patients with cervical adenocarcinoma, (2)validate the impact this virus on the histopathological grade expression of those cancers; and(3)rating the EBV-infections by evaluating the signal scores and intensities of RNA -in situ hybridization (RISH) reactions. A total number of 49 patients, who had undergone hysterectomies or punch biopsies from their cervices were enrolled in this study. Twentyone tissues were collected from cervical adenocarcinoma where as the control groups comprised 28 blocks from cervical tissues either without any significant pathological changes or from chronic cervicitis. Molecular detection of Latent EpsteinBarr Virus Early Repeats (EBERS) was performed by using ultra-sensitive versions of RNA-in situ hybridization (RISH) technique. The mean age of this group of Iraqi patients with cervical adenocarcinoma was 46.7 ± 11.6 years and histopathologically, well and poor grades of cervical adenocarcinoma each constituted 14.3% whereas 71.4% was moderately differentiated. The EBV was detected in 38.1% (8 out of 21) of cervical adenocarcinoma tissues while EBERs were neither detected in chronic cervicitis tissues nor in those healthy cervical tissues. Seven out of eight cases (87.5%) with positive EBERs–ISH reactions have well and moderate differentiation grades while only one case (12.5%) has poor differentiation. It may conclude that EBV infections in cervical adenocarcinoma could point for an initiating and/or cofactor roles, along with other important oncogenic viruses, in cervical oncogenesis. The observed impact of EBV on the differentiation of cervical adenocarcinoma could possibly shade light on an early- eventual occurrence of such molecular attack in cervical carcinogenesis.

The role of MCM5 expression in cervical cancer: Correlation with progression and prognosis

Minichromosome maintenance protein 5 (MCM5) has been suggested overexpressed in cervical cancer, but the clinical value and biological function of MCM5 in cervical cancer is still unknown. In our study, MCM5 mRNA and protein were significantly overexpressed in cervical cancer tissues and cell lines compared with normal cervical tissues and cell lines, and were obviously increased in cervical adenocarcinoma tissues and cell lines in comparison to cervical squamous cell carcinoma tissues and cell lines. In cervical adenocarcinoma patients, we firstly found that MCM5 expression was closely correlated with clinical stage, lymph node metastasis, distant metastasis and histological grade. Univariate and multivariate analysis showed MCM5 high-expression was an independent unfavorable prognostic factor. In conclusion, MCM5 is associated with the malignant status and poor prognosis in cervical adenocarcinoma patients, and modulates cervical adenocarcinoma cells proliferation.

Study on Type Distribution of Human Papillomavirus Infection in Cervical Adenocarcinoma Tissue

Study on Type Distribution of Human Papillomavirus Infection in Cervical Adenocarcinoma Tissue

Let‑7a suppresses cell proliferation via the TGF‑β/SMAD signaling pathway in cervical cancer.

Cervical cancer is the second most commonly diagnosed type of cancer among women after breast cancer. Recent research has addressed the role of microRNAs in cervical cancer. In the present study, we aimed to determine the effect of let‑7a on the regulation of the cell proliferation of cervical cancer and the related signaling pathway. Real‑time RT‑PCR was used to detect the expression of let‑7a in the blood of cervical cancer patients and normal controls. The expression of let‑7a was also assessed in cervical cancer cell lines: HeLa, SiHa and normal human immortalized keratinocyes HaCaT. Cell proliferation was tested by MTT assay, and cell apoptosis and cell cycle were examined by flow cytometric analysis in HeLa cells. Moreover, bioinformatic analysis, dual‑luciferase reporter assay and western blotting were used to confirm the target gene for let‑7a. In addition, the expression of TGF‑β1, SMAD4 and p53 were assessed by western blotting and real‑time PCR. Our studies showed that the expression of let‑7a in cervical cancer was significantly reduced in cervical cancer patients compared with the expression in the normal control group. Cell proliferation of HeLa cells was inhibited by overexpression of let‑7a. The cell cycle analysis showed that an increased population was arrested in the G2phase in the let‑7a mimic group when compared with that in the mimic control and untreated groups. In addition, the cell cycle‑related factor p53 was increased in the let‑7a overexpression group compared with that in the control and untreated groups. Furthermore, TGFBR1 was confirmed to be a target of let‑7a. Moreover, the expression of TGF‑β1 and SMAD4 proteins was elevated in cervical squamous carcinoma and cervical adenocarcinoma tissues. However, the expression of TGF‑β1 and SMAD4 was decreased in the let‑7a‑overexpressing cervical cancer cell lines (HeLa, SiHa and CaSki). Our data suggest that let‑7a may play a role in the cell proliferation of cervical cancer by regulating the TGF‑β/SMAD pathway, and may participate in the regulation of the occurrence and development of cervical cancer.