Biomarker For Cervical Cancer Research Articles

Identification of Hub Genes as Potential Prognostic Biomarkers in Cervical Cancer Using Comprehensive Bioinformatics Analysis and Validation Studies.

BackgroundCervical cancer belongs to one of the most common female cancers; yet, the exact underlying mechanisms are still elusive. Recently, microarray and sequencing technologies have been widely used for screening biomarkers and molecular mechanism discovery in cancer studies. In this study, we aimed to analyse the microarray datasets using comprehensive bioinformatics tools and identified novel biomarkers associated with the prognosis of patients with cervical cancer.MethodsThe differentially expressed genes (DEGs) from Gene Expression Omnibus (GEO) datasets including GSE138080, GSE113942 and GSE63514 were analysed using GEO2R tool. The functional enrichment analysis was performed using g:Profiler tool. The protein–protein interaction (PPI) network construction and hub genes identification were performed using the STRING database and Cytoscape software, respectively. The hub genes were subjected to expression and survival analysis in the cervical cancer. The EdU incorporation and Cell Counting Kit-8 assays were performed to evaluate the effects of hub gene knockdown on the proliferation of cervical cancer cells.ResultsA total of 89 overlapping DEGs (63 up-regulated and 26 down-regulated genes) were identified in the microarray datasets. The functional enrichment analysis indicated that the overlapping DEGs were mainly associated with “DNA replication” and “cell cycle”. Furthermore, the PPI network analysis revealed that the network contains 87 nodes and 309 edges. Sub-module analysis using the Molecular Complex Detection tool identified 21 hub genes from the PPI network. The expression levels of the 21 hub genes were all up-regulated in the cervical cancer tissues when compared to normal cervical tissues as analysed by GEPIA tool. The survival analysis showed that the low expression of cell division cycle 45 (CDC45), GINS complex subunit 2 (GINS2), minichromosome maintenance complex component 2 (MCM2) and proliferating cell nuclear antigen (PCNA) was significantly correlated with the shorter overall survival of patients with cervical cancer. Moreover, the protein expression levels of GINS2, MCM2 and PCNA, but not CDC45, were significantly up-regulated in the cervical cancer tissues when compared to normal cervical tissues. Finally, knockdown of MCM2 significantly suppressed the proliferation of HeLa and SiHa cells.ConclusionIn conclusion, we screened a total of 89 overlapping DEGs from the GEO datasets, and further analysis identified four hub genes (CDC45, GINS2, MCM2 and PCNA) that were likely associated with the prognosis of patients with cervical cancer. MCM2 knockdown repressed the cervical cancer cell proliferation. The current findings may provide novel insights into understanding the pathophysiology of cervical cancer and develop therapeutic targets for patients with cervical cancer.

Quantitative Real-Time PCR as a Novel Detection Method for Micro-RNAs Expressed by Cervical Cancer Tissue: A Review

The potential of microRNAs (miRNA) as biomarkers of Cervical Cancer (CC) is analyzed extensively by many researchers today. However, some studies have shown that miRNAs are expressed in cancers and may act as a better diagnostic strategy than the Pap smear or even assist it as a screening strategy. MicroRNA expression has been shown to differ in precancerous lesions as well as in cervical cancer tumours from that of normal tissue. With the use of quantitative real-time PCR (qRT-PCR), microRNAs can be detected in many sample types ranging from biopsy samples to blood (serum and plasma). Early detection of the disease is possible due to the aberrant expression of miRNAs in precancerous stages as well as advanced stages of the disease; this proves that they have the potential to be an ideal novel biomarker for CC. This review discusses studies using qRT-PCR to detect the expression of miRNAs within the years 2008-2019 and focuses on giving an insight into the types of samples and kits that have been used. Publications which have used qRT-PCR as a primary or secondary detection method were selected via Google Scholar Search and PubMed. Studies were shown to have used a variety of kits and reagents, but all have applied the main principle of qRT-PCR. Quantitative Real-Time PCR is shown to be a versatile and accurate detection technique for miRNAs of CC.

A Novel Four-Gene Prognostic Signature as a Risk Biomarker in Cervical Cancer.

Background Cervical cancer (CC) is a major malignancy affecting women worldwide, with limited treatment options for patients with advanced disease. The aim of this study was to identify novel prognostic biomarkers for CC. Methods RNA-Seq data from four Gene Expression Omnibus datasets (GSE5787, GSE6791, GSE26511, and GSE63514) were used to identify differentially expressed genes (DEGs) between CC and normal cervical tissues. Functional and enrichment analyses of the DEGs were performed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Oncomine database, Cytoscape software, and Kaplan-Meier survival analyses were used for in-depth screening of hub DEGs. The Cox regression was then used to develop a prognostic signature, which was in turn used to create a nomogram. Results A total of 207 DEGs were identified in the tissue samples, eight of which were prognostically significant in terms of overall survival (OS). Thereafter, a novel four-gene signature consisting of DSG2, MMP1, SPP1, and MCM2 was developed and validated using stepwise Cox analysis. The area under the receiver operating characteristic (ROC) curve (AUC) values were 0.785, 0.609, and 0.686 in the training, verification, and combination groups, respectively. The protein expression levels of the four genes were well validated by the western blotting. Moreover, the nomogram analysis showed that a combination of this four-gene signature plus lymph node metastasis (LNM) status effectively predicted the 1- and 3-year OS probabilities of CC patients with accuracies of 69.01% and 83.93%, respectively. Conclusions We developed a four-gene signature that can accurately predict the prognosis in terms of OS, of CC patients, and could be a valuable tool for designing treatment strategies.

Rapid and ultrasensitive detection of circulating human papillomavirus E7 cell-free DNA as a cervical cancer biomarker.

Circulating cell-free DNA (cfDNA) has attracted attention as a non-invasive biomarker for diagnosing and monitoring various cancers. Given that human papillomavirus (HPV) DNA integration and overexpression of E6/E7 oncogenes are pivotal events for carcinogenesis, we sought to determine if HPV E7 cfDNA could serve as a specific biomarker for cervical cancer detection. We applied droplet digital PCR (ddPCR) to quantify HPV16/18 E7 cfDNA from the serum of patients with cervical cancer, cervical intraepithelial neoplasia, and controls. HPV16/18 E7 cfDNA was highly specific for cervical cancer, displaying 30.77% sensitivity, 100% specificity, and an area under the curve of 0.65. Furthermore, we developed a sensitive isothermal detection of HPV16/18 E7 and the PIK3CA WT reference gene based on recombinase polymerase amplification combined with a lateral flow strip (RPA-LF). The assay took less than 30 min and the detection limit was 5-10 copies. RPA-LF exhibited 100% sensitivity and 88.24% specificity towards HPV16/18 E7 cfDNA in clinical samples. The agreement between RPA-LF and ddPCR was 83.33% (κ = 0.67) for HPV16 E7 and 100% (κ = 1.0) for HPV18 E7, indicating a good correlation between both tests. Therefore, we conclude that HPV E7 cfDNA represents a potential tumor marker with excellent specificity and moderate sensitivity for minimally invasive cervical cancer monitoring. Moreover, the RPA-LF assay provides an affordable, rapid, and ultrasensitive tool for detecting HPV cfDNA in resource-limited settings.

TAF1A and ZBTB41 serve as novel key genes in cervical cancer identified by integrated approaches

Cervical cancer (CC) is the second most common cancer and the leading cause of cancer mortality in women. Numerous studies have found that the development of CC was associated with multiple genes. However, the mechanisms on gene level are enigmatic, hindering the understanding of its functional roles. This study sought to identify prognostic biomarkers of CC, and explore their biological functions. Here we conducted an integrated analysis to screen potential vital genes. Candidate genes were further tested by experiments in clinical specimens and cancer cell line. Then, molecular modeling was used to predict the three-dimensional structure of candidate genes’ proteins, and the interaction pattern was analyzed by docking simulation technique. Among the potential genes identified, we found that TAF1A and ZBTB41 were highly correlated. Furthermore, there was a definite interaction between the proteins of TAF1A and ZBTB41, which was affected by the activity of the p53 signaling pathway. In conclusion, our findings identified TAF1A and ZBTB41 could serve as biomarkers of CC. We confirmed their biological function and deciphered their interaction for the first time, which may be helpful for developing further researches.

Polo like kinase 1 expression in cervical cancer tissues generated from multiple detection methods.

BackgroundExisting studies of PLK1 in cervical cancer had several flaws. The methods adopted by those studies of detecting PLK1 expression in cervical cancer were single and there lacks comprehensive evaluation of the clinico-pathological significance of PLK1 in cervical cancer.MethodsA total of 303 cervical tissue samples were collected for in-house tissue microarrays. Immunohistochemistry was performed for evaluating PLK1 expression between cervical cancer (including cervical squamous cell carcinoma (CESC) and cervical adenocarcinoma) and non-cancer samples. The Expression Atlas database was searched for querying PLK1 expression in different cervical cancer cell lines and different tissues in the context of pan-cancer. Standard mean difference (SMD) was calculated and the summarized receiver’s operating characteristics (SROC) curves were plotted for integrated tissue microarrays, exterior high-throughput microarrays and RNA sequencing data as further verification. The effect of PLK1 expression on the overall survival, disease-free survival and event-free survival of cervical cancer patients was analyzed through Kaplan Meier survival curves for cervical cancer patients from RNA-seq and GSE44001 datasets. The gene mutation and alteration status of PLK1 in cervical cancer was inspected in COSMIC and cBioPortal databases. Functional enrichment analysis was performed for genes correlated with PLK1 from aggregated RNA-seq and microarrays.ResultsA total of 963 cervical cancer samples and 178 non-cancer samples were collected from in-house tissue microarrays and exterior microarrays and RNA-seq datasets. The combined expression analysis supported overexpression of PLK1 in CESC, cervical adenocarcinoma and all types of cervical cancer (SMD = 1.59, 95%CI [0.56–2.63]; SMD = 2.99, 95%CI [0.75–5.24]; SMD = 1.57, 95% CI [0.85–2.29]) and the significant power of PLK1 expression in distinguishing CESC or all types of cervical cancer samples from non-cancer samples (AUC = 0.94, AUC = 0.92). Kaplan-Meier survival curves showed that the event-free survival rate of cervical cancer patients with higher expression of PLK1 was shorter than that of patients with lower PLK1 (HR = 2.020, P = 0.0197). Genetic alteration of PLK1 including missense mutation and mRNA low occurred in 6% of cervical cancer samples profiled in mRNA expression. Genes positively or negatively correlated with PLK1 were mainly assembled in pathways such as DNA replication, cell cycle, mismatch repair, Ras signaling pathway, melanoma, EGFR tyrosine kinase inhibitor resistance and homologous recombination (P < 0.05).ConclusionsHere, we provided sufficient evidence of PLK1 overexpression in cervical cancer. The overexpression of PLK1 in cervical cancer and the contributory effect of it on clinical progression indicated the hopeful prospect of PLK1 as a biomarker for cervical cancer.

Blood-based biomarkers of human papillomavirus-associated cancers: A systematic review and meta-analysis.

Despite the significant societal burden of human papillomavirus (HPV)-associated cancers, clinical screening interventions for HPV-associated noncervical cancers are not available. Blood-based biomarkers may help close this gap in care. Five databases were searched, 5687 articles were identified, and 3631 unique candidate titles and abstracts were independently reviewed by 2 authors; 702 articles underwent a full-text review. Eligibility criteria included the assessment of a blood-based biomarker within a cohort or case-control study. One hundred thirty-seven studies were included. Among all biomarkers assessed, HPV-16 E seropositivity and circulating HPV DNA were most significantly correlated with HPV-associated cancers in comparison with cancer-free controls. In most scenarios, HPV-16 E6 seropositivity varied nonsignificantly according to tumor type, specimen collection timing, and anatomic site (crude odds ratio [cOR] for p16+ or HPV+ oropharyngeal cancer [OPC], 133.10; 95% confidence interval [CI], 59.40-298.21; cOR for HPV-unspecified OPC, 25.41; 95% CI, 8.71-74.06; cOR for prediagnostic HPV-unspecified OPC, 59.00; 95% CI, 15.39-226.25; cOR for HPV-unspecified cervical cancer, 12.05; 95% CI, 3.23-44.97; cOR for HPV-unspecified anal cancer, 73.60; 95% CI, 19.68-275.33; cOR for HPV-unspecified penile cancer, 16.25; 95% CI, 2.83-93.48). Circulating HPV-16 DNA was a valid biomarker for cervical cancer (cOR, 15.72; 95% CI, 3.41-72.57). In 3 cervical cancer case-control studies, cases exhibited unique microRNA expression profiles in comparison with controls. Other assessed biomarker candidates were not valid. HPV-16 E6 antibodies and circulating HPV-16 DNA are the most robustly analyzed and most promising blood-based biomarkers for HPV-associated cancers to date. Comparative validity analyses are warranted. Variations in tumor type-specific, high-risk HPV DNA prevalence according to anatomic site and world region highlight the need for biomarkers targeting more high-risk HPV types. Further investigation of blood-based microRNA expression profiling appears indicated.

MiR-326 inhibits the cell proliferation and cancer stem cell-like property of cervical cancer in vitro and oncogenesis in vivo via targeting TCF4.

BackgroundCervical cancer ranks as one of the most prevalent female malignancies globally, and its treatment with new targets has been the focus of current research. The present study set out to investigate the function of microRNA-326 (miR-326) in vitro and in vivo and to verify the direct targeting of transcription factor 4 (TCF4) by miR-326.MethodsThe detection of messenger RNA (mRNA) expressing miR-326 and TCF4 in cervical cancer cell lines and tumor samples was conducted using quantitative real-time polymerase chain (qRT-PCR). A dual-luciferase reporter assay was carried out to detect the target relationship of miR-326 with TCF4. A Cell Counting Kit-8 (CCK-8) assay was employed to detect the effect of miR-326 on CasKi cell viability. Flow cytometry and western blotting were employed to examine the effects of miR-326 on cancer stem cell (CSC)-like property. Tumor weight was measured in orthotopic xenograft mouse models. Immunohistochemistry was employed to analyze the protein expression levels of Ki-67, proliferating cell nuclear antigen (PCNA), CD44, and SRY-box 4 (SOX4).ResultDownregulation of the mRNA expression levels of miR-326 was observed in cervical cancer cell lines and tumor tissue, while the levels of TCF4 were upregulated. The dual-luciferase reporter assay revealed binding of miR-326 to the three prime untranslated region (3'-UTR) of TCF4. In vitro assays demonstrated that miR-326 inhibited CasKi cell proliferation through regulating TCF4. miR-326 also suppressed the CSC-like property of CasKi cells by targeting TCF4. Furthermore, the protein expression levels of cyclin D1, β-catenin, and c-Myc were decreased when miR-326 was added to TCF4-transfected cells. In vivo assays demonstrated that miR-326 inhibited tumor weight, growth, and the protein expression levels of Ki-67, PCNA, CD44, SOX4, and β-catenin.ConclusionsmiR-326 acted in a tumor-suppressive manner through its regulation of TCF4, and has potential as a biomarker or therapeutic target for cervical cancer.

Apolipoprotein C1 (APOC1): A Novel Diagnostic and Prognostic Biomarker for Cervical Cancer.

BackgroundPrevious reports showed that APOC1 was associated with several cancers but the function of APOC1 in cervical cancer was unknown. This study aimed to investigate the clinical effect and function of APOC1 in cervical cancer.Materials and MethodsIn this study, the relative expression of APOC1 in cervical cancer was detected by RT-qPCR. In order to determine the cell proliferation and migration and invading ability and apoptosis more accurately, we used CCK8 assay, Edu assay, wound healing assay, migration and invasion assay, flow cytometry assay, co-immunoprecipitation, proteomics and Western blot by silencing and overexpressing APOC1, respectively. The role of APOC1 on tumor progression was explored in vitro and vivo.ResultsThe relative expression of APOC1 in cervical cancer tissues was up-regulated (P<0.05). In cervical cancer cell lines, silencing of APOC1 restrained cell progression and EMT, while over-expression of APOC1 accelerated cell progression and EMT in vivo and vitro (P<0.05).ConclusionAPOC1 acts as an oncogene in cervical cancers and knockdown of APOC1 inhibited cervical cancer cells growth in vitro and in vivo. There is a close relationship between the relative expression of APOC1 and clinical outcome in cervical cancer patients.

Circulating exosomal miR-125a-5p as a novel biomarker for cervical cancer.

Exosomal microRNAs (miRs/miRNAs) have been reported to be associated with cervical cancer. The aim of the present study was to investigate circulating exosomal miRNA as a biomarker for cervical cancer diagnosis. In the present study, samples from 6 patients with cervical cancer and 6 healthy control subjects were retrieved for exosomal RNA-sequencing. The results revealed that a total of 39 miRNAs were differentially expressed between patients with cervical cancer and healthy controls (P<0.001; fold-change >2.0). Exosomal miR-125a-5p was further quantified in plasma from 60 subjects, which included 22 healthy individuals and 38 patients with cervical cancer. miR-16a-5p served as the reference miRNA for quantitative PCR analysis of exosomal miR-125a-5p in patients with cervical cancer and healthy individuals. The results revealed that exosomal miR-125a-5p expression levels in the patients with cervical cancer were significantly lower than those in the healthy controls (P<0.001). Receiver operating characteristic (ROC) curve analyses were performed and the results revealed that the level of plasma exosomal miR-125a-5p was a potential marker for differentiating between non-cervical cancer and cervical cancer, with an ROC area under the curve of 0.7129. At the cut-off value of 2.537 for miR-125a-5p, cervical cancer diagnostic sensitivities and specificities were 59.1 and 84.2%, respectively. The present study provides confirmation that exosomal miR-125a-5p could potentially serve as a biomarker for cervical cancer diagnosis. The present study involved only a small number of clinical samples; more samples are required to support the conclusions of the present study.

Role of Cervical Cancer Biomarkers p16 and Ki67 in Abnormal Cervical Cytological Smear.

Cervical cancer is the most common cancer in India. Screening for cervical cancer helps in marked reduction of invasive cervical cancers. The low sensitivity of Papanicolaou cytology (Pap smear) and high-risk human papillomavirus (HR-HPV) in excluding high-grade intraepithelial lesion (ASC-H) leads to unnecessary referrals to colposcopy-guided biopsy. The combined cervical cytology screening and HR-HPV have its own limitations and still need further standardization. Using additional biomarkers like staining with p16 and Ki-67 might help in triaging abnormal pap smear. A prospective, cross-sectional study was performed over a period of 16 months in the Department of Obstetrics and Gynaecology, in collaboration with Department of Pathology. Study was conducted to know the efficacy of immunostaining with p16/Ki-67 in predicting the presence of significant lesion in cases of mild cytological atypia. PAP smears (conventional and LBC) along with P16, Ki-67 and available biopsies were correlated. Liquid-based cytology (LBC) was done in 2134 cases, out of which 46 cases showed abnormal cytological findings such as [22 atypical squamous cells of undetermined significance (ASCUS), 3 low-grade squamous intraepithelial lesion (LSIL), 8 atypical squamous cells cannot exclude high-grade lesion (ASC-H), 6 high-grade squamous intraepithelial lesion (HSIL), 5 squamous cell carcinoma (SCC), 2 adenocarcinoma, 1 atypical glandular cells of undetermined significance (AGUS)]. Immunostaining with p16 and Ki-67 was performed on 38 cases of abnormal cytological smears. Out of 38 abnormal cytology cases, 28 cases had shown co-staining for both p16 and Ki-67, suggestive of true HPV infection of the cells. Of the 38 cases, 07/14 ASCUS, 06/06 HSIL, 07/08 ASC-H, 05/05 squamous cell carcinoma and 02/02 adenocarcinoma also showed dual positivity for p16 and Ki-67. One case of AGUS was diagnosed, but the smear was unsatisfactory for immunocytochemical evaluation and excluded from the study. Three cases of LSIL were also diagnosed on cytological evaluation, and 1 of them however showed positivity for p16 and Ki-67 on immunocytochemistry (ICC). In the ASC-US group, the sensitivity and specificity of the immunostaining in diagnosing CIN2 + lesions were 87.51%, and in LSIL group, the sensitivity and specificity of the immunostaining in diagnosing CIN2 + lesions were 100%. p16/Ki-67 positivity also increased with cytological severity which in turn corresponded with histological findings: it reached from 50% in ASC-US to 100% in both HSIL and SCC categories. This immunostaining with p16 and Ki67 can be a useful method in the triaging of the ASC-US and the LSIL group as considering the high sensitivity and specificity values.

GDF15 knockdown suppresses cervical cancer cell migration invitro through the TGF-β/Smad2/3/Snail1 pathway.

Growth differentiation factor 15 (GDF15), a member of the transforming growth factor β (TGF-β) superfamily, is a prognostic biomarker of cervical cancer. In addition, GDF15 has been reported to enhance the migration of colorectal cancer cells and liver cancer stem-like cells. However, the mechanism by which GDF15 promotes cervical cancer cell migration is not completely understood. Here, we report that GDF15 expression is enhanced in cervical cancer tissues, as well as in cultured cervical cancer cells. ShGDF15 transfection markedly inhibited expression of Vimentin, N-cadherin and Snail1, and resulted in up-regulation of E-cadherin expression in HT-3 and HeLa cells. Moreover, knockdown of GDF15 suppressed wound healing rate and reduced the number of invasive cells. Furthermore, knockdown of GDF15 significantly suppressed the expression of phosphorylated Smad2 and Smad3. The addition of TGF-β1 partially abolished the inhibitory effects of GDF15 knockdown on the migration and invasion of cervical cancer cells. In summary, we report here that GDF15 knockdown inhibits migration and invasion of cervical cancer cells invitro through the TGF-β/Smad2/3/Snail1 pathway.

Genetic markers and phosphoprotein forms of beta-catenin pβ-Cat552 and pβ-Cat675 are prognostic biomarkers of cervical cancer.

BACKGROUNDCervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality world wide and constitutes the third most common malignancy in women. The RAIDs consortium (http://www.raids-fp7.eu/) conducted a prospective European study [BioRAIDs (NCT02428842)] with the objective to stratify CC patients for innovative treatments. A “metagene” of genomic markers in the PI3K pathway and epigenetic regulators had been previously associated with poor outcome [2].METHODSTo detect new, more specific, targets for treatment of patients who resist standard chemo-radiation, a high-dimensional Cox model was applied to define dominant molecular variants, copy number variations, and reverse phase protein arrays (RPPA).FINDINGSSurvival analysis on 89 patients with all omics data available, suggested loss-of-function (LOF) or activating molecular alterations in nine genes to be candidate biomarkers for worse prognosis in patients treated by chemo-radiation while LOF of ATRX, MED13 as well as CASP8 were associated with better prognosis. When protein expression data by RPPA were factored in, the supposedly low molecular weight and nuclear form, of beta-catenin, phosphorylated in Ser552 (pβ-Cat552), ranked highest for good prognosis, while pβ-Cat675 was associated with worse prognosis.INTERPRETATIONThese findings call for molecularly targeted treatments involving p53, Wnt pathway, PI3K pathway, and epigenetic regulator genes. Pβ-Cat552 and pβ-Cat675 may be useful biomarkers to predict outcome to chemo-radiation, which targets the DNA repair axis.FUNDINGEuropean Union's Seventh Program for research, technological development and demonstration (agreement N°304,810), the Fondation ARC pour la recherche contre le cancer.

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.

HOXD-AS1 facilitates cell migration and invasion as an oncogenic lncRNA by competitively binding to miR-877-3p and upregulating FGF2 in human cervical cancer

BackgroundLong non-coding RNAs (LncRNAs) are dysregulated in multiple human cancers and they are highly involved in tumor progression. Previous studies have identified the oncogenic lncRNA HOXD cluster antisense RNA 1 (HOXD-AS1) in human cancers, while its roles in cervical cancer (CC) remain unclear. Herein we intended to characterize the implication of HOXD-AS1 in CC.MethodsqRT-PCR was applied to examine the relative expression of HOXD-AS1 in CC tissues, cell lines and transfected cells. Wound healing and transwell assays were applied to detect cell migration and invasion alteration. The targeting relationship between miRNA and mRNA/lncRNA was determined by dual luciferase reporter, qRT-PCR and western blot assays.ResultsHOXD-AS1 was overexpressed in CC tissues and cell lines. Its higher level predicted worse prognosis of CC patients. SiRNA mediated knockdown of HOXD-AS1 repressed CC cell migration and invasion, and its overexpression did the opposite. Mechanistically, HOXD-AS1 acted as a competing endogenous RNA (ceRNA) to sponge miR-877-3p and led to upregulation of FGF2, a target of miR-877-3p. Importantly, either miR-877-3p overexpression or FGF2 inhibition could abolish the migration and invasion promotion induced by HOXD-AS1.ConclusionHOXD-AS1 functions as a tumor-promoting lncRNA via the miR-877-3p/FGF2 axis in CC. HOXD-AS1 might be a promising therapeutic target as well as a novel prognostic biomarker for CC.

Circular RNAs: Novel biomarkers for cervical, ovarian and endometrial cancer (Review).

Cervical, ovarian and endometrial cancer are the three most common types of malignant tumor and the leading causes of cancer-associated death in women. Tumor debulking surgery followed by platinum and paclitaxel chemotherapy is the current treatment regime of choice. However, as a result of late diagnosis and chemoresistance, the survival rates of patients with advanced gynecological cancers remains unsatisfactory. Circular RNAs (circRNAs) are stable noncoding RNAs that are present in a wide variety of tissue and cell types. With the enhancement of RNA sequencing methods, increasing numbers of circRNAs have been identified, and their functions are gradually being revealed. In recent years, circRNAs have received increasing attention for their regulatory roles in cervical, ovarian and endometrial cancer. The aim of the present review was to summarize the possible mechanisms of recently identified circRNAs; we hypothesize that a novel diagnostic and therapeutic biomarker may be identified to prolong the survival time of patients with gynecological malignancies.

A serum lipidomic strategy revealed potential lipid biomarkers for early-stage cervical cancer

AimsCervical cancer (CC) is a common tumor of women worldwide. Here, we conducted a non-targeted lipidomic study to discover novel lipid biomarkers for early-stage CC. Main methodsThe lipidomic analysis of 71 samples in discovery set and 72 samples in validation set were performed by coupling ultra-high-pressure liquid chromatography (UHPLC) with quadrupole time-of-flight tandem mass spectrometry (Q-TOF-MS). Lipids with variable importance (VIP) values greater than 1, adj. p < 0.05 (the adjusted p value obtained from false discovery rate correction) and fold change (FC) higher than 1.5 were reserved as potential biomarkers. Subsequently, receiver operating characteristic (ROC) curve and binary logistic regression were implemented to assess the diagnostic potential of these biomarkers and to acquire the best biomarker combination. Key findingsA lipid biomarker panel, including phosphatidylcholine (PC, PC 14:0/18:2) and phosphatidylethanolamine (PE, PE 15:1e/22:6 and PE 16:1e/18:2), was established. This panel was effective in distinguishing between CC and non-CC (squamous intraepithelial lesions [SIL] and healthy controls) within the area under the ROC curve (AUC), sensitivity, and specificity reaching 0.966, 0.952, and 0.860 for discovery set and 0.961, 0.920, and 0.915 for external validation set. Furthermore, this panel was also capable of discriminating early-stage CC from SIL with AUC, sensitivity, and specificity reaching 0.946, 0.952, and 0.800 for discovery set and 0.956, 0.960, and 0.815 for external validation set. SignificanceThe combination of PC 14:0/18:2, PE 15:1e/22:6, and PE 16:1e/18:2 could serve as a promising serum biomarker for discriminating early-stage CC from SIL and healthy subjects.

MOLECULAR MARKERS FOR THE DIAGNOSIS OF HIGH-RISK HUMAN PAPILLOMAVIRUS INFECTION AND TRIAGE OF HUMAN PAPILLOMAVIRUS-POSITIVE WOMEN.

Infection with high-risk human papillomavirus (HPV) increases the likelihood of developing cervical cancer (CC). A plethora of cellular processes is required to produce pre-malignant lesions, which in turn may become malignant if left untreated. Those changes are induced by viral oncoproteins, which represent an ideal target to identify the viral presence, or by some particularities of the host that ultimately promote the establishment of CC. This article describes the different methods used for HPV detection and quantification, as well as the current trend of secondary screening approaches to detect premalignant lesions and CC. In addition, we analyzed validated biomarkers and those under clinical investigation for the classification (triage) of women at risk of developing CC after an initial positive HPV test and that could be used as prognostic biomarkers for CC. The use of molecular biomarkers, together with the detection of HPV DNA sequences, provides a high impact diagnostic and prognostic tool in the detection of patients at increased risk of developing CC and also may guide their clinical management. In addition, some of those biomarkers could represent pharmacological targets for the future design of therapeutic approaches to CC treatment.

Integrin subunitβ1 and laminin γ1 chain expression: a potential prognostic biomarker in cervical cancer.

Aim: The aim of this study was to analyze the prognostic value of integrin subunit β1 and laminin γ1 chain in patients with cervical cancer (CC). Materials & methods: The study included 96 samples. Cytological diagnosis, human papillomavirus (HPV)genotyping, HPV integration status and integrin subunit β1 and laminin γ1 chain expressions were performed or determined using Papanicolaou smear, INNO-LiPA® Genotyping Extra Kit, in situ hybridization, and immunocytochemistry, respectively. The association between variables was calculated using chi-squared and Fisher's exact test; logistic regression analysis was performed to calculate odds ratios and CI at 95%. Results: Our results show that integrin subunitβ1and laminin γ1 chain expressions increase according to tumor progression. Integrin subunit β1 and laminin γ1 chain expressions are associated with cytological diagnosis (p <0.001 and p =0.001, respectively) and laminin γ1 chain expression with the integration status of HPV (p <0.001). Moderate/high expressions of integrin subunit β1 and laminin γ1 chain were correlated with overall survival and increased risk of CC (6.86 and 3.75, respectively), the odds ratiowas 12.91 when the moderate/high expression of integrin subunit β1 and laminin γ1 chain were combined. Conclusion: Our results suggest that integrin subunit β1 and laminin γ1 chain expressions could be a prognostic biomarker in CC.

PET/MRI in Cervical Cancer: Associations Between Imaging Biomarkers and Tumor Stage, Disease Progression, and Overall Survival.

Positron emission tomography (PET)/MRI biomarkers have been shown to have prognostic significance in patients with cervical cancer. Their associations with progression-free survival (PFS) and overall survival (OS) merit further investigation. To evaluate the association between PET/MRI biomarkers and tumor stage, PFS, and OS in patients with cervical cancer. Prospective cohort study. In all, 54 patients with newly diagnosed cervical cancer and measurable tumors (>1 cm) were included in the image analysis. 3.0T integrated PET/MRI including diffusion-weighted echo-planar imaging (b = 50 and 1000 s/mm2 ) and [18F]fluorodeoxyglucose PET. Two radiologists measured the minimum and mean apparent diffusion coefficient (ADCmin and ADCmean ), maximum standardized uptake value (SUVmax ), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumors. A Mann-Whitney U-test was used to evaluate the association between the imaging biomarkers and tumor stage. A Cox proportional hazards model was used to assess the relationships between the imaging biomarkers and survival. In advanced tumors (T ≥ 1b2, M1, stage ≥ IB3), ADCmin was significantly lower and MTV, TLG, MTV/ADCmin , and TLG/ADCmin were significantly higher (P values between <0.001 and 0.036). In N1 tumors, ADCmin was significantly lower and MTV and MTV/ADCmin were significantly higher (P values between 0.005 and 0.016). In survival analysis, SUVmax was an independent predictor of PFS (hazard ratio [HR] = 4.57, P < 0.05), and ADCmin was an independent predictor of OS (HR = 0.02, P < 0.05). In subgroup analysis of patients with different stages, MTV/ADCmin was a predictor of PFS in stage I disease (P = 0.003), ADCmin (P = 0.038), and MTV (P = 0.020) in stage II, SUVmax (P = 0.006), and TLG (P = 0.006) in stage IV; and ADCmin was a predictor of OS in stage III disease (P = 0.008). PET/MRI biomarkers of cervical cancer are associated with tumor stage and survival. SUVmax and ADCmin are independent predictors of PFS and OS, respectively. 1 TECHNICAL EFFICACY: 3.