Diagnostic Biomarkers For Cervical Cancer Research Articles

Up-regulated DSG2 promotes tumor growth and reduces immune infiltration in cervical cancer

BackgroundDesmoglein-2 (DSG2) has been reported to play pivotal roles in various diseases. However, its roles in cervical cancer (CC) remain insufficiently elucidated. Here, we aimed to comprehensively explore the functional mechanisms of DSG2 in CC using bioinformatics and experimental methods. MethodsSeveral online databases, including Gene Expression Profiling Interactive Analysis (GEPIA), ONCOMINE, LinkedOmics, MetaScape, Human protein atlas (HPA), OMICS and single-cell RNA sequencing (scRNA-seq) data were used to explore the expression, prognosis, gene mutations, and potential signaling pathway of DSG2 in CC. Quantitative real-time PCR (qRT-PCR) and western blotting were used to measure DSG2 expression in collected samples. Experimental assays were conducted to verify the effects of dysregulated DSG2 on cervical cell lines in vitro. ResultsBioinformatic analyses revealed that DSG2 was significantly up-regulated in CC compared to normal cervical tissues at both mRNA and protein levels. Elevated DSG2 levels were also associated with poor prognosis and clinical parameters (e.g., cancer stages, tumor grade, nodal metastasis status, etc.). DSG2 expression was predominantly observed in epithelial cells, increasing with disease progression on a single-cell resolution. Additionally, up-regulation of DSG2 significantly enhanced tumor purity by reducing the infiltration of immune cells (e.g., B cells, T cells, NK cells, etc.). Over-expression of DSG2 was further validated in collected CC samples at both mRNA and protein levels. Knockdown of DSG2 markedly reduced the proliferation and invasion of CC cell lines in vitro. ConclusionsIn summary, elevated levels of DSG2 were significantly associated with poor prognosis and diminished immune infiltration in CC. Thus, DSG2 may serve as a potential therapeutic and diagnostic biomarker for CC.

Plasma-Derived Exosomal tRF-Phe-GAA-001 and tRF-Gly-GCC-037 as Novel Diagnostic Biomarkers for Cervical Cancer

Plasma-Derived Exosomal tRF-Phe-GAA-001 and tRF-Gly-GCC-037 as Novel Diagnostic Biomarkers for Cervical Cancer

Septin9 DNA methylation as a promising biomarker for cervical cancer

Aberrant Septin9 methylation in cervical cancer has been rarely studied. We aimed to identify its diagnostic value in cervical cancer using cervical scrapings, and its predictive potential in plasma for pelvic nodal metastasis of cervical cancer. The statuses of methylated Septin9 in fresh cervical lesions and cervical scrapings were first evaluated by using quantitative methylation-specific PCR. Subsequently, the relationship between Septin9 methylation in 113 plasma samples and pelvic nodal metastasis of cervical cancer was evaluated. Methylated Septin9 was detected in all cancerous tissues, but not in cervicitis. The degrees of Septin9 methylation increased with growing severity of cervical lesions in cervical scrapings. The sensitivity of methylated Septin9 was lower than that of cytology, while it yielded a high specificity and area under the curve in detecting high-grade squamous intraepithelial lesion or cervical cancer; and when Septin9 methylation combined with HPV16/18 genotyping, the sensitivity would increase from 70.42% to 82.39%. Plasma-based Septin9 methylation had a high discriminatory power in predicting pelvic nodal metastasis of cervical cancer, with an optimal specificity of 81.48%. In conclusion, we demonstrated methylated Septin9 to be an innovative diagnostic biomarker for cervical cancer and its non-invasive predictive potential in plasma for pelvic nodal metastasis of cervical cancer. Impact statement What is already known on this subject? The occurrence of cervical cancer is related to Septin9 methylation. In fresh specimens and cervical scrapings, we found the degrees of methylated Septin9 increased with growing severity of cervical lesions. Compared with HPV16/18 genotyping and cytological detection, Septin9 methylation had a better specificity and AUC in detecting ≥ HSIL. Furthermore, plasma-based Septin9 methylation also had a high specificity for pelvic lymphatic metastasis prediction. What the results of this study add? Methylation analysis of Septin9 indicated a similar sensitivity, specificity and AUC in detecting ≥ HSIL, relative to HPV16/18 genotyping. Compared with cytological method, Septin9 methylation also yielded a higher specificity and AUC in detecting ≥ HSIL. And we also found plasma-based Septin9 methylation had a high discriminatory power in predicting pelvic nodal metastasis of cervical cancer, with an optimal specificity of 81.48%; additionally an increasing sensitivity from 50% to nearly 80% was found when combined with SCCAg. What the implications are of these findings for clinical practice and/or further research? This study aimed to evaluate the relationship between Septin9 methylation and cervical cancer, and to explore the value of methylated Septin9 in the detection of cervical (pre)cancerous lesions. Moreover, we would explore plasma-based ctDNA biomarkers for pelvic lymphatic metastasis prediction of cervical cancer, to improve non-invasive predictive accuracy of pelvic nodal metastasis and reduce the complications caused by pelvic lymphadenectomy.

Low Level FLT3LG is a Novel Poor Prognostic Biomarker for Cervical Cancer with Immune Infiltration.

IntroductionThe FMS-related tyrosine kinase 3 (FLT3) ligand (FLT3LG), a growth factor, binds to FLT3 on dendritic cell (DCs) to enhance their differentiation and expansion. It has shown great potential as an immunotherapy target for cancers. However, the expression and function of FLT3LG in cervical cancer remain largely unknown.Materials and MethodsIn this study, we obtained the expression of FLT3LG, the clinical prognosis in cervical cancer, via multiple databases, including The Cancer Genome Atlas (TCGA), the TISIDB database, and Tumor Immune Estimate Resource (TIMER). The results were further investigated using real-time quantitative PCR (qPCR) cytology specimens in 489 patients. Furthermore, Kaplan-Meier Cox regression and prognostic nomogram analyses were used to assess FLT3LG’s clinical significance in cervical cancer patients. All calculations used the R package.ResultsAs a result, FLT3LG expression decreased in cervical cancer compared with standard samples. And the low expression of FLT3LG was associated with a poor prognosis. Furthermore, Receiver Operating Characteristics (ROC) analysis indicated that FLT3LG might serve as a valuable diagnostic biomarker for cervical cancer. Additionally, it indicated that the FLT3LG had the highest odds ratio (OR=10.519; (7.371–27.071)) for detecting CIN 2+. In addition, our result also demonstrated that expression of FLT3LG was closely related to immune cells, immune inhibitors, immunostimulators, receptors, and chemokines in CESC.ConclusionResearch on FLT3LG provided insight into its critical function. Hence, the low expression of FLT3LG may be a valuable biomarker in CESC patients linked with immune infiltration.

Meta-analysis of downregulated E-cadherin as a diagnostic biomarker for cervical cancer.

Downregulation of E-cadherin function or expression has been implicated in the progression of cervical cancer. This meta-analysis of updated publications was performed to assess the association of expression alteration of E-cadherin with disease severity and then to determine the diagnostic accuracy of E-cadherin in discriminating cervical lesions including cervical intraepithelial neoplasia (CIN) grade 1 (CIN1), CIN grade 2 (CIN2), CIN grade 3 (CIN3), and cervical cancer. The articles published from inception to January 2021 were searched in PubMed, EBSCO, CNKI, and WanFang Database and then evaluated according to the criteria of meta-analysis. The eligible studies were retrieved and further analyzed. A bivariate mixed effects binary regression model was applied to determine pooled effect estimates. 16 studies with 2436 subjects from 7 countries were eligible for this meta-analysis. When compared with CIN1 control, the pooled odds ratios (ORs) with 95% confidence interval (CI) for the association of E-cadherin positivity with CIN2, CIN3, and cervical cancer were 0.34 (95% CI 0.23-0.51), 0.23 (95% CI 0.10-0.54), and 0.10 (95% CI 0.07-0.14), respectively. The pooled sensitivity and specificity for CIN3 or worse were 0.60 (95% CI 0.48-0.70) and 0.82 (95% CI 0.73-0.88) respectively, with the AUC of 0.78 (95% CI 0.74-0.82). Similar performance was found in CIN2 or worse. These findings demonstrated that the loss of E-cadherin protein was associated with worsened cervical lesions. E-cadherin might serve as a promising diagnostic biomarker to facilitate the discrimination of precancerous and cancerous lesions.

Estrogen receptor 1 and Aurora kinase A as potential diagnostic biomarkers for cervical cancer

Cervical cancer (CC) is the fourth most common cause of death among women globally. Nearly 90% of CC mortality occurs in low- and middle-income countries. Hence there is an urgent need for identification of new biomarkers for the early diagnosis and treatment of CC. Current research aims to investigate the effect and mechanism of estrogen receptor 1 and aurora kinase A as potential diagnostic biomarkers for cervical cancer. Gene microarray datasets GSE8703 and GSE9750 were acquired from the Gene Set Omnibus and evaluated using GEO2R to identify the differentially expressed genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the differentially expressed genes were performed using the clusterProfiler R package. A protein-protein interaction (PPI) network was constructed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and visualized using Cytoscape; hub genes were screened using the cytoHubba plug-in. Receiver operating characteristic curve and survival analysis was performed for candidate genes in the Gene Expression Profiling Interactive Analysis Database. The University of California, Santa Cruz, (UCSC)-XENA platform was used to analyze the pan-cancer biomarker expression. The relative expression of biomarkers in normal and cervical cancer tissues was determined using the Human Protein Atlas Database. Estrogen receptor 1 (ESR1) and Aurora kinase A (AURKA) were identified as potential biomarkers for cervical cancer. ESR1 was actively expressed in normal cervical tissues but limited in cervical cancer tissues. AURKA was least expressed in normal tissues and highly expressed in cervical cancer tissues. The results were confirmed by immunohistochemistry. The biomarkers identified herein can enable early diagnosis and serve as the therapeutic targets for cervical cancer.

Circulating and tissue miR-100 acts as a potential diagnostic biomarker for cervical cancer.

MicroRNAs (miRNA) are promising biomarkers for cancer diagnosis and prognosis; miR-100 expression is decreased in cervical cancer tissues. To determine whether miR-100 is a useful biomarker for early cervical cancer diagnosis. Total RNA was extracted from the sera of 34 healthy controls (HC), 64 cervical intraepithelial neoplasia patients (CIN), and 46 cervical cancer patients (CC). miR-100 expression levels were measured with quantitative real-time PCR. Correlations between clinicopathological factors and miR-100 expression levels were also assessed. The cut-off value for miR-100 was calculated from the Receiver Operating Characteristic (ROC) curve. Relative expression levels of miR-100 in serum were 1.84 ± 1.72, 3.93 ± 2.52, and 5.32 ± 3.39 in CC, CIN, and HC, respectively; it was significantly lower in CC (p< 0.001). The area under the ROC curve was 0.879 and the cut-off value was 2.451. miR-100 expression levels were significantly higher in metastasis cases that were lymph node negative than positive (p< 0.05). CC patients with miR-100 expression levels below the cut-off value tended to have a poor prognosis. Serum miR-100 may be a useful diagnostic biomarker for CC, and for predicting lymph node metastasis and disease free survival in CC patients.

Diagnostic Value of Circulating PIGF in Combination with Flt-1 in Early Cervical Cancer.

The utility of placental growth factor (PlGF) and its receptor VEGFR-1 (Flt-1) as biomarkers for cervical cancer has not been clarified yet. To address this issue, we investigated the levels of soluble PlGF (sPlGF) and soluble Flt-1 (sFlt-1) in the serum from patients with early cervical cancer, cervical intraepithelial neoplasia (CIN) and controls in this study. sPlGF and sFlt-1 were detected in 44 preoperative patients with cervical cancer, 18 cases with CIN, and 20 controls by ELISA. It was found that both sPlGF and sFlt-1 were significantly increased in the cervical cancer group as compared with those in CIN and control groups. sPlGF presented a high diagnostic ability of cervical cancer, with a sensitivity of 61.36% and a specificity of 89.47%; and sFlt-1 with a sensitivity of 50.00% and a specificity of 92.11%. Importantly, the combined use of sPlGF and sFlt-1 could increase the diagnostic rate of cervical cancer, with a sensitivity of 70.45% and a specificity of 92.11%. These results indicated that both sPlGF and sFlt-1 in circulation can serve as possible valuable diagnostic biomarkers for cervical cancer, and the combined use of them can be more valuable to diagnose the patients with early cervical cancer.

AGR2: A Potential Diagnostic Biomarker for Cervical Cancer

Background: The squamocolumnar (SC) junction was found to be the novel cellular origin of the cervical cancer (CC). This study comprehensively explored the diagnostic value of the SC junction marker anterior gradient 2 (AGR2) in CC. Methods: Patients (N=779) with CC (N=131), high-grade squamous intraepithelial lesions (HSILs; N=215), low-grade squamous intraepithelial lesions (LSILs; N=214) and chronic cervicitis (as normal controls, NCs; N=219) were recruited between January 2014 and December 2016. AGR2 expression was scored in the tissue by immunohistochemistry and quantified as a secretary protein in the peripheral serum by ELISA among the diagnosis groups and before and after CC operations. Receiver operating characteristic (ROC) curves were used to analyse the diagnostic performance. Findings: ROC analysis showed that AGR2 had significantly greater diagnostic accuracy than Krt7 and p16INK4a to differentiate patients with CC and HSIL from those with LSIL and NCs (AUC=0·843). The AGR2 serum concentration was much higher in CC patients than in non-cancerous patients (p< 0·0001). After complete resection, the AGR2 serum level decreased dramatically (p<0·0001). ROC curves showed that the accuracy of serum AGR2 in the diagnosis of CSCC was equivalent to that of squamous cell carcinomarelated antigen (SCCA). While, up to 36 (80·0%) of the 45 SCCA-negative patients with squamous carcinoma of the cervix (CSCC) were classified correctly by AGR2. Moreover, serum AGR2 showed a very prominent role in differentiating cervical adenocarcinoma (CADC) patients from all non-cancerous control patients (AUC=0·805). Interpretation: The SC junction marker AGR2 has important clinical significance for the histopathological diagnosis of CC and HSILs. Serum AGR2 is a promising novel tumour marker of CC and has a unique value, especially in CADC. Funding Statement: This study was supported by National Natural Science Foundation of China (grant number 81372305), Shanghai Municipal Health Commission Key Project of Scientific Research Project (grant number 201540386), Shanghai Municipal Medical and Health Discipline Construction Projects (grant number 2017ZZ02015). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: This study was approved by the Ethical Committee of Shanghai First Maternity and Infant Hospital, Tongji University, Shanghai, China, and informed consent was obtained from all subjects. All procedures were performed in accordance with the Declaration of Helsinki.

Identification of a six lncRNAs signature as novel diagnostic biomarkers for cervical cancer.

Cervical cancer is a tumor with the second highest morbidity and mortality in the world, and it is also the most common cancer and the eighth lethal factor among malignant tumors in Chinese female. This study aimed to identify long noncoding RNAs (lncRNAs) that related to diagnosis and prognosis in cervical cancer to improve early diagnosis and treatment. First, we extracted transcriptome profilings of cervical cancer samples from the cancer genome atlas (TCGA) database, and then extracted the lncRNAs and mRNAs expression profiles. Based on the lncRNAs expression profiles of test set, we screened lncRNAs that related to progression of cervical cancer tumors. We found six lncRNAs associated with tumor progression in cervical cancer patients, in which five lncRNAs have highly similar expression patterns but the other one has the opposite expression pattern. We found that these six lncRNAs might be related to keratinization and immunity by enrichment analysis, and two of them (AC126474 and C5orf66-AS1) were associated with prognosis in patients with cervical cancer. And these results were validated using the validation set. Overall, we identified six lncRNAs that played an important role in the development of cervical cancer, and two of them might be associated with the prognosis of cervical cancer, which provides new insight into the diagnosis and treatment of cervical cancer.

Serum bradykinin levels as a diagnostic marker in cervical cancer with a potential mechanism to promote VEGF expression via BDKRB2.

Bradykinin (BK) is one of the kinin peptides and preferentially binds to bradykinin B2 receptor (BDKRB2). A recent study indicated that BK played an important role in the occurrence and progression of cancer. In this study, we evaluated the serum BK levels in 130 cervical cancer (CC) cases (including 65 cases with pre- and post-surgery paired samples, another 65 cases with only pre-surgery samples), 35 cervical intraepithelial neoplasia (CIN) cases (pre- and post-surgery paired) and 35 control cases. We found that BK was overexpressed in patients with CC compared to patients with CIN and the control group. When combined with squamous cell carcinoma-related antigen (SCCA), the diagnostic efficacy of BK was prominently enhanced. Moreover, we detected the expression level of the BK receptor BDKRB2 in CC, CIN and normal cervical tissues and observed a higher expression in the CC and CIN tissues than in the normal cervix. We then explored the possible mechanisms of action of BK in promoting the progression of CC. When BK was added to the cell culture medium, human umbilical vein endothelial cell (HUVEC) angiogenesis increased and vascular endothelial growth factor (VEGF) expression in CC cell lines was also elevated. The BK antagonist, HOE140, exerted an opposite effect. The knockdown or the overexpression of BDKRB2 in CC cell lines further confirmed its oncogenic role in angiogenesis. Taken together, the findings of this study suggest that BK may be a diagnostic biomarker for CC and may notably improve the diagnostic efficacy when combined with SCCA. BK promotes the progression of CC by upregulating the expression of VEGF via BDKRB2 and subsequently facilitating angiogenesis.

Long noncoding RNA GIHCG functions as an oncogene and serves as a serum diagnostic biomarker for cervical cancer.

Cervical cancer is the most common and lethal gynaecological tumor. Long noncoding RNAs (lncRNAs) have critical roles in various cancers, including cervical cancer. However, few studies investigated the diagnostic value of lncRNAs for cervical cancer. In this study, we investigated the expression pattern of a recently identified lncRNA GIHCG in cervical cancer tissues, cell lines, and serums by qRT-PCR. Furthermore, we explored the roles of GIHCG in cervical cancer using gain-of-function and loss-of-function assays. Our results revealed that GIHCG is up-regulated in cervical cancer tissues and cell lines compared with adjacent normal tissues and normal cervical epithelial cell line, respectively. Furthermore, serum GIHCG is significantly up-regulated in cervical cancer patients compared with healthy controls. ROC curve analysis revealed that serum GIHCG could accurately discriminate cervical cancer patients from healthy controls. Functionally, we found that overexpression of GIHCG promotes cell proliferation, inhibits cell apoptosis, and promotes cell migration of cervical cancer cells. Conversely, depletion of GIHCG inhibits cell proliferation, induces cell apoptosis, and inhibits cell migration of cervical cancer cells. Mechanistically, we found that GIHCG represses the expression of miR-200b. The expression of miR-200b is inversely correlated with the expression of GIHCG in cervical cancer tissues. Moreover, overexpression of miR-200b attenuates the roles of GIHCG in promoting cervical cancer tumor growth in vivo. In summary, this study demonstrated that GIHCG functions as an oncogene in cervical cancer via repressing miR-200b. This study also suggested that GIHCG may be a non-invasive diagnostic biomarker and a potential therapeutic target for cervical cancer.

Abstract 3267: Cervical microbiota and the urinary metabolome in patients with high-risk and low-risk HPV infections

Abstract Genital human papillomavirus (HPV) is the world's most commonly diagnosed sexually transmitted infection, and high-risk HPV types are strongly linked to cervical dysplasia and carcinoma. The microbiota of the human cervico-vaginal tract is the interface between the host and environment, and its constituents may act as determinants of susceptibility for HPV infection. There exists the potential for reliable diagnostic biomarkers for cervical cancer in the cervical microbiome as well as in urine, which would be an important biospecimen due to its abundance and non-invasive collection strategy. In this study, we performed comprehensive metabolomic analysis on urine samples from 65 women (54 HPV+, 38 of whom have cervical intraepithelial neoplasia (CIN), and 11 HPV-) and discuss the potential diagnostic implication and metabolic description of high-risk and low-risk HPV infected patients. The experimental procedure employed gas chromatography mass spectrometry (GC-MS) on the urine-derived products and HPV genotyping was determined by reverse hybridization with the HPV SPF10-LiPA25 kit. We further characterized resident cervical bacteria in these patients using Illumina sequencing of the V4 region of the 16S ribosomal RNA with a high-resolution bioinformatics methodology (Resphera Insight v2.2) for species-level taxonomic assignment. The hybridization assay detected 11 low-risk and 10 high-risk HPV types many of them co-occurring in the cervical samples. Lactobacillus iners OTUs were shared by all samples but were significantly more dominant in women with low-risk HPV strains (p-value=0.05), while G. vaginalis, S. sanguinegens and L. jensenii were associated with high-risk strains. CIN1 and CIN3 dysplasic biopsies, detected significant enrichments of Gardnerella vaginalis, L.crispatus and Prevotella amnii (p-values &amp;lt;0.05). Preliminary GC-MS analysis identified elevated levels of palmitic (C16:0) and stearic fatty acids (C18:0) as well as lactic acid, abundant in the HPV+ samples while 5-oxo-proline and Neu5Ac (N-Acetylneuraminic acid) were abundant in the HPV- samples. Our preliminary data identifies possible microbial and metabolic biomarkers associated with oncogenic HPV and cervical intraepithelial neoplasia in women living in Puerto Rico. Citation Format: Gilmary Ortiz, Natalyia Chorna, Josefina Romaguera-Agrait, Magaly Martinez-Ferrer, Maria Sanchez, Ana P. Ortiz, Rafael Guerrero-Preston, James R. White, Filipa Godoy-Vitorino. Cervical microbiota and the urinary metabolome in patients with high-risk and low-risk HPV infections [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3267.

Promoter Methylation of Ezrin and its Impact on the Incidence and Prognosis of Cervical Cancer

Background/Aims: Aberrant localization and over-expression of Ezrin have been reported to be implicated in cervical cancer (CC). Aberrant promoter methylation of some gene families may serve as potential diagnostic biomarkers for CC. In this study, we explored the correlation of promoter methylation of the Ezrin gene with the incidence and prognosis of CC. Methods: Cervical tissues from a total of 483 patients with CC were collected from the China-Japan Union Hospital of Jilin University. Samples were assigned into four groups accordingly to pathological diagnosis, namely the control group, the cervical intraepithelial neoplasia (CIN) I group, the CIN II-III group and the CC group. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to detect the mRNA expression of Ezrin. Methylation-specific polymerase chain reaction (MSP) was used to detect the promoter methylation of the Ezrin gene. The Kaplan-Meier product-limit method and the log-rank analysis were used for survival analysis, the Cox regression analysis for the prognostic factors for CC, and the logistic regression analysis for the risk factors for the occurrence of CC. Results: The methylation rate of the Ezrin gene was correspondingly increased from the control, the CIN I, the CIN II-III to the CC groups. Over-expressed mRNA of Ezrin was determined in CC tissues. The mRNA expression of Ezrin was correlated with tumor size, lymphatic metastasis, pathological grade and clinical stage (FIGO). The risk factors for the occurrence of CC were the number of abortions and the promoter methylation of the Ezrin gene. Poor prognosis of CC correlated to lymphatic metastasis, higher pathological grade, higher FIGO stage and positive Ezrin promoter methylation. Conclusion: These findings indicate that promoter methylation of the Ezrin gene may play a crucial role in carcinogenesis, progression and prognosis of CC.

Aberrant single-minded homolog 1 methylation as a potential biomarker for cervical cancer.

The aim of this study is to evaluate the possibility of using the methylation status of single-minded homolog 1 (SIM1) as a diagnostic biomarker for cervical cancer. All the patient and normal specimens including the normal cervix (n = 10), cervical cancer tissues (n = 45), blood (n = 45), and cervical brush specimens (n = 110) were retrospectively obtained. Quantitative methylation-specific PCR was performed to detect SIM1 methylation in primary tumors, cervical brush specimens, and plasma circulating cell-free DNA (ccfDNA). SIM1 expression was detected by western blot analysis. We found that SIM1 was highly methylated in the majority of the cervical cancer tissues that we tested, but not in any of the normal tissues. Hypermethylation of SIM1 led to a pronounced reduction in SIM1 expression in cervical cancer tissues compared with normal cervix. SIM1 methylation status on cervical brush specimens also distinguished cervical cancer from normal, cervical intraepithelial neoplasia (CIN) 1 and 2. The degree of SIM1 methylation was significantly associated with the severity of the disease (Ptrend < .0001). We also investigated the possibility of detecting methylated SIM1 in plasma ccfDNA from cervical cancer patients. Methylated SIM1 was detected in 36.6% (15/41) of ccfDNA samples, and concordance rate with the matched cancer tissues was 41.5% (17/41) with sensitivity 38.5% and specificity 100%. This study has shown that SIM1 is frequently hypermethylated in cervical cancer, compared with normal cervix tissue, CIN1 and 2 samples, suggesting that the methylation status of SIM1 could be a potential diagnostic biomarker for cervical cancer.

Down-regulation of miR-1246 in cervical cancer tissues and its clinical significance

ObjectiveMicroRNAs (miRNAs) are non-coding RNAs that regulate the expression of mRNAs by binding to their 3′-untranslated regions (UTRs). Accumulating evidences show that miRNAs are involved in tumorigenesis such as lung cancer, liver cancer, colon cancer, and cervical cancer. In this study, we focused on the expression of miR-1246 in clinical cervical cancer tissues as well as the relationship between miR-1246 and HPV16E6 infection status. MethodsReal-time quantitative polymerase chain reaction technology was used to detect the expression of miR-1246 in 68 cervical cancer tissues and 52 normal tissues. The expression of miR-1246 also was tested in HPV16E6 negative cervical cell line (SiHa) or HPV16E6 positive cell line (C33A). Western blot was performed to detect the expression of DYRK1A after knocking down HPV16E6. ResultsOur data showed that the expression of miR-1246 was dramatically decreased in cervical cancer tissue, compared with normal control group (p=0.0012), and miR-1246 was negatively correlated with clinical stage and HPV16E6 infected status (p=0.0410), but no correlation was observed with age, tumor diameter, cervical invasion depth, lymph node metastasis, or vascular invasion (p>0.05). Knock down of HPV16E6 significantly raised DYRK1A protein expression targeted by miR-1246. ConclusionsThe expression of miR-1246 is negatively correlated with cervical cancer procedure as well as HPV16E6 infection status and the miR-1246 may act as a diagnostic biomarker for cervical cancer. In addition, HPV16E6 infection may be a major reason leading to decrease the expression of miR-1246 in cervical cancer. This finding contributes to deep understanding of the miR-1246 function in cervical carcinogenesis.

Circulating soluble neuropilin-1 in patients with early cervical cancer and cervical intraepithelial neoplasia can be used as a valuable diagnostic biomarker.

Objective. To investigate soluble neuropilin-1 (sNRP-1) in circulating and NRP-1 protein in cervical tissues from patients with cervical cancer or cervical intraepithelial neoplasia (CIN). Methods. sNRP-1 was measured in 64 preoperative patients and 20 controls. NRP-1 protein in cervical tissue was detected in 56 patients and 20 controls. Results. Both sNRP-1 and NRP-1 proteins were correlated with stage. sNRP-1 presented a high diagnostic ability of cervical cancer and CIN, with a sensitivity of 70.97% and a specificity of 73.68%. Conclusions. sNRP-1 in circulating can serve as a possible valuable diagnostic biomarker for cervical cancer and CIN.