Cervical Cancer Invasion Research Articles

Combined treatment of marizomib and cisplatin modulates cervical cancer growth and invasion and enhances antitumor potential in vitro and in vivo.

Proteasome inhibition is an attractive approach for anticancer therapy. Cisplatin (cis-diamminedichloroplatinum, CDDP) is widely used as a standard chemotherapy drug in the treatment of solid malignant tumors, such as cervical cancer, ovarian cancer, colorectal cancer, and lung cancer. However, the development of CDDP resistance largely limits its clinical application. Proteasome inhibitors may enhance traditional chemotherapy agent-induced cytotoxicity and apoptosis. Marizomib (NPI-0052, salinosporamide A, Mzb), a second-generation proteasome inhibitor, shows synergistic anticancer activity with some drugs. Currently, the effect of Mzb on cervical cancer cell proliferation remains unclear. In this study, we explored the role of Mzb in three cervical cancer cell lines, HeLa, CaSki, and C33A, representing major molecular subtypes of cervical cancer and xenografts. We found that Mzb alone showed noteworthy cytotoxic effects, and its combination with CDDP resulted in more obvious cytotoxicity and apoptosis in cervical cancer cell lines and xenografts. In order to investigate the mechanism of this effect, we probed whether Mzb alone or in combination with CDDP had a better antitumor response by enhancing CDDP-induced angiopoietin 1 (Ang-1) expression and inhibiting the expression of TEK receptor tyrosine kinase (Tie-2) in the Ang-1/Tie-2 pathway, FMS-like tyrosine kinase 3 ligand (Flt-3L) and stem cell factor (SCF) as identified by a cytokine antibody chip test. The results suggest that Mzb has better antitumor effects on cervical cancer cells and can sensitize cervical cancer cells to CDDP treatment both in vitro and in vivo. Accordingly, we conclude that the combination of CDDP with Mzb produces synergistic anticancer activity and that Mzb may be a potential effective drug in combination therapy for cervical cancer patients.

TRNA-derived fragment tRF-Glu49 inhibits cell proliferation, migration and invasion in cervical cancer by targeting FGL1.

A transfer RNA (tRNA)-derived fragment (tRF) was found to be a new possible biological marker and target in carcinoma therapy. However, the effect exerted by tRFs on cervical carcinoma remains unclear. In the present study, the potential tumor suppressor gene tRF-Glu49 was identified in cervical carcinoma through tRF and tiRNA microarray investigation. A reverse transcription-quantitative PCR assay then demonstrated that tRF-Glu49 was downregulated in the cervical carcinoma tissue. Further clinicopathological analysis proved that tRF-Glu49 was associated with less aggressive clinical features and improved prognosis. Cell Counting Kit-8 tests, Transwell and Matrigel tests, and xCELLigence system tests revealed that tRF-Glu49 inhibited cervical cell proliferation, migration and invasion processes. Mechanistic investigation revealed that tRF-Glu49 directly regulated the oncogene, fibrinogen-like protein-1 (FGL1). In general, according to the result achieved in the present study, tRF-Glu49 can modulate cervical cell proliferation, migration, and invasion processes through the target process for FGL1, and tRF-Glu49 is likely to be a possible prognostic biological marker in patients with cervical carcinoma.

Multi-parametric MRI-based peritumoral radiomics on prediction of lymph-vascular space invasion in early-stage cervical cancer.

PURPOSE This retrospective study aims to evaluate the use of multi-parametric magnetic resonance imaging (MRI) in predicting lymph-vascular space invasion (LVSI) in early-stage cervical cancer using radiomics methods. METHODS A total of 163 patients who underwent contrast-enhanced T1-weighted (CE T1W) and T2-weighted (T2W) MRI scans at 3.0T were enrolled between January 2014 and September 2019. Radiomics features were extracted and selected from the tumoral and peritumoral regions at different dilation distances outside the tumor. Mann-Whitney U test, the least absolute shrinkage and selection operator logistic regression, and logistic regression was applied to select the predictive features and develop the radiomics signature. Univariate analysis was performed on the clinical characteristics. The radiomics nomogram was constructed incorporating the radiomics signature and the selected important clinical predictor. Prediction performance of the radiomics signature, clinical model, and nomogram was evaluated with the area under the curve (AUC), specificity, sensitivity, calibration, and decision curve analysis (DCA). RESULTS A total of 5 features that were selected from the peritumoral regions with 3- and 7-mm dilation distances outside tumors in CE T1W and T2W MRI, respectively, showed optimal discriminative performance. The radiomics signature comprising the selected features was significantly associated with the LVSI status. The radiomics nomogram integrating the radiomics signature and degree of cellular differentiation exhibited the best predictability with AUCs of 0.771 (specificity (SPE)=0.831 and sensitivity (SEN)=0.581) in the training cohort and 0.788 (SPE=0.727, SEN=0.773) in the validation cohort. DCA confirmed the clinical usefulness of our model. CONCLUSION Our results illustrate that the radiomics nomogram based on MRI features from peritumoral regions and the degree of cellular differentiation can be used as a noninvasive tool for predicting LVSI in cervical cancer.

The splicing factor SF3B4 drives proliferation and invasion in cervical cancer by regulating SPAG5

Regulation of alternative splicing (AS) by the splicing factor 3b (SF3B) family plays an essential role in cancer. However, the biological function of SF3B family members in cervical cancer (CC) needs to be further elucidated. In this study, we found that splicing factor 3b subunit 4 (SF3B4) was highly expressed in CC by bioinformatics analysis using cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) data from The Cancer Genome Atlas (TCGA). Then, we demonstrated that high expression of SF3B4 promoted proliferation and invasion abilities of CC cells in vitro and in vivo and that reduced expression of SF3B4 performed the opposite effect. Further RNA-seq and AS analysis showed that sperm-associated antigen 5 (SPAG5) was a downstream target gene of SF3B4. Interestingly, SPAG5 expression was decreased after SF3B4 knockdown because of retained introns (RIs) and reduced maturation of SPAG5 pre-mRNA. Importantly, SPAG5 deficiency impaired the oncogenic effects of SF3B4 overexpression on CC cells. In conclusion, SF3B4 promotes CC progression by regulating the effective splicing of SPAG5. SF3B4 could be a promising target for CC.

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

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

Circ_0060551 promotes the migration and invasion of cervical cancer by upregulating TPD52.

Cervicalcancerhas been recognized as the second most commoncancerin women worldwide. Previous studies have reported that some circular RNAs (circRNAs) can influence the progression of cervical cancer. However, more researches are still required to unveil the underlying mechanism of how circRNAs regulate the progression of such cancer. We aimed at unveiling the mechanism of how circ_0060551 effected the progression of cervical cancer. RT-qPCR and western blot assays were used to detect the expression and protein levels. Mechanism experiments were conducted to investigate the relationship among circ_0060551, TPD52, miR-520a-5p and ELAVL1. Rescue assays were mainly carried out to verify how circ_0060551 influenced the migration and invasion of cervical cancer cells. According to the results, circ_0060551 was upregulated in cervical cancer cells and could promote the migration and invasion of cells via TPD52. In addition, circ_0060551 could up-regulate TPD52 expression through a ceRNA model to target miR-520a-5p. Moreover, circ_0060551 could stabilize the mRNA expression of TPD52 via recruiting ELAVL1. Our study proved that circ_0060551 could promote the migration and invasion of cervical cancer cells.

Calponin 3 Acts as a Potential Diagnostic and Prognostic Marker and Promotes Glioma Cell Proliferation, Migration, and Invasion

Calponin 3 (CNN3) is involved in the proliferation and invasion of cervical cancer and osteosarcoma cells. However, the role of CNN3 in glioma tumorigenesis remains to be elucidated. CNN3 mRNA expression in normal brain tissue and gliomas, including glioblastoma multiforme and lower-grade glioma, was analyzed using GEPIA 2 and Oncomine. CNN3 levels in glioma tissues were identified using immunohistochemical data provided by the Human Protein Atlas website. The relationship between CNN3 mRNA expression and clinical characteristics of patients with glioma was analyzed using the Oncomine database and The Cancer Genome Atlas. The diagnostic value of CNN3 expression in glioma was analyzed using receiver operating characteristic analysis according to The Cancer Genome Atlas and Genotype-Tissue Expression data. The relationship between CNN3 and prognosis was analyzed using GEPIA 2. The function of CNN3 knockdown in glioma cell lines was analyzed using cell proliferation, Transwell, and Western blot assays. Both mRNA and protein levels of CNN3 were distinctly higher in lower-grade glioma and glioblastoma multiforme tissues than those in normal brain tissues, particularly glioblastoma. A higher CNN3 mRNA level had significant relationship with higher World Health Organization grade, isocitrate dehydrogenase wild-type status, and 1p/19q noncodeletion. CNN3 mRNA expression is a highly accurate marker for the diagnosis of glioma. Patients with glioma in the high-CNN3 group had significantly lower disease-free survival and survival rates. In addition, CNN3 silencing significantly inhibited cell proliferation, migration, invasion, and the phosphorylation of P65 NF-κB. CNN3 expression is increased in glioma, particularly glioblastoma. Silencing CNN3 expression inhibited the proliferation, migration, and invasion of glioma cell lines.

RacGAP1 promotes the malignant progression of cervical cancer by regulating AP-1 via miR-192 and p-JNK

Cervical cancer (CC) is the most frequently diagnosed genital tract cancer in females worldwide. Rac GTPase-activating protein 1 (RacGAP1) is one of the specific GTPase-activating proteins. As a novel tumor protooncogene, overexpression of RacGAP1 was related to the occurrence of various tumors, but its function in CC is still unclear. In this study, bioinformatics analyses showed that RacGAP1 might be a key candidate gene in the progression of CC. RacGAP1 was significantly overexpressed in CC tissues. High RacGAP1 expression was positively associated with poor prognosis. Downregulating RacGAP1 significantly inhibited the proliferation, migration, and invasion of CC cells, while overexpressing RacGAP1 had the opposite effects. Further research showed that miR-192, which plays as a tumor suppressor in CC, was identified as a downstream target of RacGAP1 in CC cells. miR-192 inhibition could partially rescue the decrease in cell proliferation, migration, and invasion caused by RacGAP1 downregulation. In opposite, miR-192 overexpression could decrease the promotion of malignant progression caused by RacGAP1 upregulation. Mechanism studies revealed that RacGAP1 could regulate the expression and phosphorylation of c-Jun, which was the component of AP-1, via miR-192 and p-JNK separately. These findings suggested that RacGAP1 promoted tumorigenicity, migration, and invasion of CC. Therefore, it represented a potential novel prognostic marker in CC and may probably be a therapeutic target.

Expression of CD44v6 and RCAS1 in Uterine Cervical Carcinoma Infected with Human Papillomavirus and Its Effect on Cell Proliferation and Differentiation.

To investigate the expression of CD44v6 and RCAS1 and the presence of HPV in cervical cancer tissues, to determine serum RCAS1 levels, and to evaluate these components in correlation with clinicopathologic features and survival. A total of 52 patients consisting of 28 squamous cell carcinoma (SCC) and 24 adenocarcinoma cases, were studied. RCAS1 and CD44v6 expression was evaluated using immunohistochemical staining. HPV 16 and 18 E6 genes were detected using PCR, and serum RCAS1 concentrations were measured using ELISA. Associations between these factors and clinicopathologic features and survival were analyzed. CD44v6 expression was significantly higher in SCC compared with that in adenocarcinoma (P<0.001). It also showed a significant relation to histologic grade (P<0.001) and tumor size (P=0.03). RCAS1 expression was higher in adenocarcinoma than in SCC (P=0.001), and it showed a borderline relation with histological grade (P=0.057). Overall survival was not significantly different in both CD44v6 and RCAS1 expression; however, FIGO stage (P=0.025) and tumor size (P=0.042) resulted statistically different. The pre-surgical treatment serum RCAS1 levels were not associated with any clinicopathological variables. The presence of HPV 16 E6 was higher in SCC, while the presence of HPV 18 E6 was higher in adenocarcinoma (P<0.001). Detection of HPV 16 E6 was significantly associated with expression of CD44v6. The presence of HPV both HPV 16 E6 and HPV 18 E6 was found in cancer tissues with RCAS1 expression, but without any statistical significance. CD44v6 and RCAS1 expression seems to be involved in tumor proliferation and differentiation, but it is not implicated in the progression and invasion of cervical cancer infected by HPV. Pre-treatment levels of serum RCAS1 in cervical cancer are not a diagnostic and predictive biomarker.

Collagen type X alpha 1 promotes proliferation, invasion and epithelial-mesenchymal transition of cervical cancer through activation of TGF-β/Smad signaling.

Collagen type X alpha 1 (COL10A1) belongs to the collagen family and constitutes the main component of the interstitial matrix. COL10A1 was found to be dysregulated in various cancers, and to participate in tumorigenesis. However, the role of COL10A1 in cervical cancer (CC) remains unclear. Expression of COL10A1 in CC cells and tissues was detected by western blot and qRT-PCR. CC cells were transfected with pcDNA-COL10A1 or si-COL10A1, and the effect of COL10A1 on cell proliferation of CC was assessed by MTT and colony formation assays. Cell metastasis was detected by wound healing and transwell assays. Western blot was applied to evaluate epithelial-mesenchymal transition. COL10A1 was significantly elevated in CC tissues and cells (P < 0.001). Over-expression of COL10A1 increased cell viability of CC (P < 0.001), and enhanced the number of colonies (P < 0.001). However, knockdown of COL10A1 reduced the cell proliferation of CC (P < 0.001). Over-expression of COL10A1 also promoted cell migration (P < 0.001) and invasion (P < 0.001) of CC, whereas silencing of COL10A1 suppressed cell metastasis (P < 0.001). Protein level of E-cadherin in CC was reduced (P < 0.05), whereas N-cadherin and vimentin were enhanced by COL10A1 over-expression (P < 0.001). Silencing of COL10A1 reduced the protein level of TGF-β1 (P < 0.01), and down-regulated the phosphorylation of Smad2 andSmad3 in CC (P < 0.001). Down-regulation of COL10A1 suppressed cell proliferation, metastasis, and epithelial-mesenchymal transition of CC through inactivation of TGF-β/Smad signaling.

Changes of immune microenvironment before and after chemoradiotherapy in cervical cancer.

e17503 Background: Cervical cancer is the fourth most common cancer in women worldwide. Metastasis and invasion of cervical cancer are closely related to the tumor microenvironment. As an effective treatment, chemoradiotherapy plays a vital role in immune-related cells and factors. However, little is known about the effect of chemoradiotherapy on the immune microenvironment in cervical cancers. Therefore, we studied the immune microenvironment alterations before and after chemoradiotherapy and analyzed their prognostic significance in cervical cancer patients. Methods: We recruited 15 patients with stage IB1-IVA cervical squamous cell carcinoma. Pelvic intensity-modulated radiotherapy (IMRT) was performed with conventional segmentation of 2Gy per irradiation (IB3 stage was treated with synchronous cisplatin for weeks), FFPE samples pre-treatment, and one-week after-chemoradiotherapy were conducted an exploratory biomarker analysis based on gene expression profiling (GEP). The panel of 289 genes was customized based on critical genes and pathways during tumor immunoregulation (e.g., tumor antigen release, T cell activation, and immune metabolism). The differential expressed genes between these two groups were then assessed. Results: Forty-two genes were found to be differentially expressed, with 21 genes having &gt; 1.5-fold mean expression difference after chemoradiotherapy. Analysis of important GO terms and KEGG pathways indicated that the pathways enriched by different genes are located in immune-related pathways, specifically, T cell activation (GO-BP), cytokine activity (GO-MF), and cytokine-cytokine receptor interaction (KEGG). After-chemoradiotherapy, the enrichment of tumor-infiltrating lymphocytes (TILs) varied greatly, especially the macrophages. Conclusions: This study preliminarily demonstrated that chemoradiotherapy caused the release of pro-inflammatory like CCR7 and CD69 and immune cell (macrophages) infiltration alterations after chemoradiotherapy in cervical cancer patients.

EIF4A3-regulated circ_0087429 can reverse EMT and inhibit the progression of cervical cancer via miR-5003-3p-dependent upregulation of OGN expression.

BackgroundCircular RNAs (circRNAs) are noncoding RNAs with stable structures with high expression and tissue-specific expression. Studies have shown that circRNA dysregulation is closely related to the progression of tumours. However, the function and regulatory mechanism of most circRNAs in cervical cancer are still unclear. MethodsCircRNAs related to cervical cancer were screened through the Gene Expression Omnibus (GEO) database. qRT-PCR was used to verify the expression of circ_0087429 in cervical cancer tissues and cells. Then, in vivo and in vitro experiments were conducted to evaluate the role of circ_0087429 in the progression of cervical cancer. The role of the circ_0087429/miR-5003-3p/osteoglycin (OGN) axis in the epithelial to mesenchymal transition (EMT) was confirmed by rescue experiments, fluorescence in situ hybridization, luciferase reporter assays, immunofluorescence staining and western blotting. The inhibitory effect of Eukaryotic initiation factor 4A-III (EIF4A3) on the biogenesis of circ_0087429 was verified by RNA immunoprecipitation (RIP) assays and qRT-PCR.Resultscirc_0087429 is significantly downregulated in cervical cancer tissues and cells and negatively correlated with International Federation of Gynecology and Obstetrics (FIGO) staging and lymphatic metastasis in cervical cancer patients. circ_0087429 can significantly inhibit the proliferation, migration, invasion and angiogenesis of cervical cancer in vitro and tumour growth and metastasis in vivo. OGN is significantly downregulated in cervical cancer tissues and cells. circ_0087429 can upregulate the expression of OGN by competitively binding with miR-5003-3p, thereby reversing EMT and inhibiting the progression of cervical cancer. EIF4A3 can inhibit circ_0087429 expression by binding to its flanking regions.ConclusionsAs a tumour suppressor, circ_0087429 regulated by EIF4A3 can reverse EMT and inhibit the progression of cervical cancer through the miR-5003-3p/OGN axis. It is expected to become a potential target for the treatment of cervical cancer.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13046-022-02368-4.

DNA methylation of miR-138 regulates cell proliferation and EMT in cervical cancer by targeting EZH2

BackgroundEmerging evidence has identified miR-138 as a tumor suppressor that can suppress the proliferation of various cancers. Meanwhile, the cause of abnormal miR-138 expression in cervical cancer remains uncertain. This study clarified the mechanism by which miR-138 regulates proliferation, invasion, metastasis, and EMT in cervical cancer cells.ResultsmiR-138 expression in human cervical cancer and adjacent normal tissue was measured using qPCR. SiHa and C33A cells were used to determine the function of miR-138 via miR-138 mimic or inhibitor transfection, followed by wound healing, Cell Counting Kit-8, flow cytometry, and Transwell assays. Epithelial and mesenchymal marker expression was analyzed using Western blotting. DNA methylation in the miR-138 promoter was examined using bisulfite sequencing PCR. The downstream target genes of miR-138 were identified via bioinformatics analysis and luciferase reporter assays. A tumor xenograft model was employed to validate DNA methylation-induced miR-138 downregulation and tumor growth inhibition in cervical cancer in vivo. miR-138 levels were significantly lower in cervical cancer tissues than in adjacent control tissues. Furthermore, lower miR-138 expression and higher CpG methylation in the miR-138 promoter were identified in lymph node-positive metastatic cervical cancer tumors versus that in non-metastatic tumor tissues. Upon miR-138 overexpression, cell proliferation, metastasis, invasion, and EMT were suppressed. miR-138 agomir transfection and demethylating drug treatment significantly inhibited cervical tumor growth and EMT in tumor xenograft models. DNA methylation inhibited miR-138 transcription, and enhancer of zeste homolog 2 (EZH2) downregulation mediated the tumor suppressor function of miR-138 in cervical cancer.ConclusionWe demonstrated that miR-138 suppresses tumor progression by targeting EZH2 in cervical cancer and uncovered the role of DNA methylation in the miR-138 promoter in its downregulation. These findings demonstrated the potential of miR-138 to predict disease metastasis and/or function as a therapeutic target in cervical cancer.

Preparation and effect against cervical cancer invasion in vitro of harmine-loaded photosensitive liposomes

Despite the development of HPV vaccines and screening programs, cervical cancer is still a serious threat to women's health. Early-stage cervical cancer is mainly treated by surgery. However, considering the serious complications after surgery, hyperthermia is recommended to enhance the effect of chemotherapy, retain the integrity of cervix, improve the treatment effect, which provides a therapeutic basis for the early treatment of cervical cancer. The photosensitive liposomes containing harmine and dye IR-780 were prepared by thin-film dispersion method and separated by Sephadex G-50 dextran gel column. The preparation conditions were optimized as the mass ratio of phospholipid to cholesterol membrane material being 8∶1 and that of drug to lipid being 1∶20. The results of HPLC showed that the encapsulation efficiency of harmine was 55.6%±0.18%. The prepared photosensitive liposomes were round and evenly distributed under transmission electron microscope, with the particle size of(125.2±0.62) nm determined by Marvin particle size analyzer and the Zeta potential of(-2.55±0.76) mV. Additionally, the photosensitive liposomes had the photothermal conversion efficiency, an important property of photothermal agent, of 27.1%±0.86%. The photosensitive liposomes stored at 4 ℃ showed stable encapsulation efficiency in the first 14 days without flocculation. The sulforhodamine B(SRB) assay was employed to determine the inhibitory effect of the liposomes on the proliferation of HeLa cells under near-infrared(NIR) irradiation or not, which showcased stronger inhibitory effect under NIR irradiation. The results of Transwell assay indicated that the prepared liposomes significantly inhibited the invasion and migration of HeLa cells in vitro. The findings of this study provide a basis for the treatment of cervical cancer with harmine.

Suppressive effect of Hsa-miR-125a-5p on cervical cancer proliferation and invasion via regulation of Rab25- PI3K/AKT pathway

Purpose: To study the suppressive effect of Hsa-miR-125a-5p on the proliferation and invasion of cervical cancer (CC) cells through the modulation of the Rab25-PI3K/AKT pathway.Methods: 66 pairs of CC and neighboring cell samples were harvested from patients who underwent surgical resection in the Oncology Department from August 2017 to December 2018. The expression levels of Hsa-miR-125a-5p in CC and neighboring cell samples were assessed by quantitative polymerase chain reaction (qPCR). The overexpression vector was transfected into CC cells (siHa cell line), and the proliferation, invasion, migration, and apoptosis of siHa cells were determined. The regulatory role of Hsa-miR-125a-5p in PI3K/AKT pathway was determined using Western blotting.Results: CC tissues, relative to the neighboring tissues, exhibited remarkably lower Hsa-miR-125a-5p levels (p &lt; 0.05), and their upregulation significantly inhibited the growth, migration, and intrusion of siHa cells while repressing apoptosis (p &lt; 0.05). Dual-luciferase reporter assay (DLRA) data indicate that luciferase activity decreased when Hsa-miR-125a-5p was bound to Rab25 (p &lt; 0.05). The HsamiR-125a-5p mimics group had significantly lower PI3K/AKT levels, relative to the negative control mimics group (p &lt; 0.05).Conclusion: Hsa-miR-125a-5p represses CC cell proliferation and invasion through the modulation of Rab25-PI3K/AKT pathway, thus suggesting that this pathway is a target for drug development

The Regulatory Functions and the Mechanisms of Long Non-Coding RNAs in Cervical Cancer.

Cervical cancer is one of the leading causes of death in gynecology cancer worldwide. High-risk human papillomaviruses (HPVs) are the major etiological agents for cervical cancer. Still, other factors also contribute to cervical cancer development because these cancers commonly arise decades after initial exposure to HPV. So far, the molecular mechanisms underlying the pathogenesis of cervical cancer are still quite limited, and a knowledge gap needs to be filled to help develop novel strategies that will ultimately facilitate the development of therapies and improve cervical cancer patient outcomes. Long non-coding RNAs (lncRNAs) have been increasingly shown to be involved in gene regulation, and the relevant role of lncRNAs in cervical cancer has recently been investigated. In this review, we summarize the recent progress in ascertaining the biological functions of lncRNAs in cervical cancer from the perspective of cervical cancer proliferation, invasion, and metastasis. In addition, we provide the current state of knowledge by discussing the molecular mechanisms underlying the regulation and emerging role of lncRNAs in the pathogenesis of cervical cancer. Comprehensive and deeper insights into lncRNA-mediated alterations and interactions in cellular events will help develop novel strategies to treat patients with cervical cancer.

Identification and Validation of Invasion-Related Molecular Subtypes and Prognostic Features for Cervical Cancer.

Background As one of the main causes leading to female cancer deaths, cervical cancer shows malignant features of local infiltration and invasion into adjacent organs and tissues. This study was designed to categorize novel molecular subtypes according to cervical cancer invasion and screen reliable prognostic markers. Methods Invasion-related gene sets and expression profiles of invasion-related genes were collected from the CancerSEA database and The Cancer Genome Atlas (TCGA), respectively. Samples were clustered by nonnegative matrix factorization (NMF) to obtain different molecular subgroups, immune microenvironment characteristics of which were further systematically compared. Limma was employed to screen differentially expressed gene sets in different subtypes, followed by Lasso analysis for dimension reduction. Multivariate and univariate Cox regression analysis was performed to determine prognostic characteristics. The Kaplan-Meier test showed the prognostic differences of patients with different risks. Additionally, receiver operating characteristic (ROC) curves were applied to validate the prognostic model performance. A nomogram model was developed using clinical and prognostic characteristics of cervical cancer, and its prediction accuracy was reflected by calibration curve. Results This study filtered 19 invasion-related genes with prognosis significance in cervical cancer and 2 molecular subtypes (C1, C2). Specifically, the C1 subtype had an unfavorable prognosis, which was associated with the activation of the TGF-beta signaling pathway, focal adhesion, and PI3K-Akt signaling pathway. 875 differentially expressed genes were screened, and 8 key genes were finally retained by the dimension reduction analysis. An 8-gene signature was established as an independent factor predictive of the prognosis of cervical cancer. The signature performance was even stronger when combined with N stage. Conclusion Based on invasion-related genes, the present study categorized two cervical cancer subtypes with distinct TME characteristics and established an 8-gene marker that can accurately and independently predict the prognosis of cervical cancer.

G6PC indicated poor prognosis in cervical cancer and promoted cervical carcinogenesis in vitro and in vivo

BackgroundThe glucose-6-phosphatase catalytic subunit (G6PC) is a key enzyme that is involved in gluconeogenesis and glycogen decomposition during glycometabolism. Studies have shown that G6PC is abnormally expressed in various cancers and participates in the proliferation and metastasis of tumors. However, the role of G6PC in cervical cancer remains poorly established.MethodsTo analyze the expression of G6PC in cervical cancer tissues in patients by immunohistochemistry. Effects of G6PC deregulation on cervical cancer phenotype were determined using MTT, colony formation, transwell, and wound-healing assays. And constructed a nude mouse xenograft tumor model and CAM assay in vivo. The effect of G6PC on glycolysis in cervical cancer was also evaluated. Effect of G6PC on PI3K/AKT/mTOR pathway was detected by Western blot assay.ResultsIn this study, G6PC expression was found to be upregulated in cervical cancer tissues, and this upregulated expression was associated with LN metastasis, clinical stage, recurrence, and disease-free survival and overall survival rates, indicating that G6PC could serve as a novel marker of early diagnosis in cervical cancer. G6PC promoted proliferation, invasion, epithelial mesenchymal transition (EMT) progression, and angiogenesis of cervical cancer cells. Mechanistically, G6PC activated PI3K/AKT/mTOR pathways. The PI3K/AKT pathway inhibitor, LY294002 could partially attenuate the effect.ConclusionsG6PC plays a key role in the progression of cervical cancer, and overexpressed G6PC is closely related to patient LN metastasis, clinical stage, recurrence and shortened survival. G6PC promoted cervical cancer proliferation, invasion, migration, EMT progression, and angiogenesis, partially through activating the PI3K/AKT pathway. G6PC, as a metabolic gene, not only plays a role in metabolism, but also participates in the development of cervical cancer. Its complex metabolic and non metabolic effects may be a potential therapeutic target and worthy of further study.

The Value of Three-Dimensional Tomographic Ultrasound Imaging under Backpropagation Algorithm in the Local Staging Diagnosis of Cervical Cancer

Based on three-dimensional tomographic ultrasound imaging (TUI) of the backpropagation algorithm, this study evaluated the consistency of three-dimensional TUI technology, pelvic examination, and magnetic resonance imaging (MRI) technology in the local staging diagnosis of cervical cancer, aiming to explore the application value of TUI technology in local staging diagnosis of cervical cancer. The backpropagation algorithm was adopted to segment images, and 35 patients who were confirmed to be cervical cancer by tissue biopsy were included in this study. All selected patients underwent transvaginal TUI examination and pelvic MRI examination. Then, the 2010 Federation Internationale of Gynecologie and Obstetrigue (FIGO) was adopted to determine the clinical stage, and the K index and the percentage of consistency were calculated to evaluate the consistency between TUI and MRI. Comparison of tumor size measurements showed that obvious correlation could be found between MRI and three-dimensional TUI (r = 0.842; P &lt; 0.001), MRI, and clinical examination (r = 0.654; P &lt; 0.001) to the assessment of tumor size. In terms of parauterine invasion, there was a moderate consistency between pelvic examination and MRI (K = 0.413; 95% confidential interval (CI) = 0.085–0.762; the overall coincidence rate (OCR) = 78.0%), and there was good consistency between three-dimensional TUI and MRI (K = 0.655, 95% CI = 0.335–0.949; overall coincidence rate = 87.8%). In terms of vaginal infiltration, pelvic examination and MRI showed moderate consistency (K = 0.434; 95% CI = 0.119–0.733; the OCR = 74.2%), and three-dimensional TUI examination and MRI showed excellent consistency (K = 0.568, 95% CI = 0.274–0.881; the OCR = 81.9%). The accuracy of the backpropagation segmentation algorithm was 82%. The results revealed that the three-dimensional TUI technology and MRI showed a good consistency in assessing parauterine invasion of cervical cancer. When the tumor size was evaluated, there was a clear correlation between three-dimensional TUI scans and MRI. Therefore, three-dimensional TUI technology showed relatively high application value for the local stage of cervical cancer.

MicroRNA-302 inhibits cell migration and invasion in cervical cancer by targeting DCUN1D1.

[This retracts the article DOI: 10.3892/etm.2018.6223.].