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Abstract N6-methyladenosine (m6A) is the most prevalent modification found in eukaryotic RNA and played a significant role in various cancers. However, the mechanism by which m6A modification influences cervical cancer (CC) tumorigenesis remains unclear. Therefore, we aim to elucidate the role and mechanism of METTL3 in CC progression. In the present study, we observed a significant upregulation of METTL3 in CC tissues and cell lines. Knockdown of METTL3 resulted in reduced growth, migration, and invasion of CC cells, as well as affected apoptosis, while overexpression of METTL3 reversed these effects. Through a combined analysis of meRIP-seq and Ribo-seq data following METTL3 knockdown, NEK2 was identified as a key target of METTL3 in CC cells. Correlation analysis, MeRIP-qPCR, and luciferase reporter assay suggested that METTL3 regulates NEK2 expression through m6A modification. NEK2 synergized with METTL3 to mediate the malignant phenotype of CC cells. The METTL3-NEK2 axis promoted CC progression by activating the Wnt/β-catenin pathway and inhibiting the apoptosis pathway. In conclusion, METTL3 facilitated the malignant progression of CC and contributed to the formation of the METTL3-NEK2 regulatory axis in an m6A-dependent manner, which represented a potential target for CC therapy.

Abstract Purpose To develop and validate a deep learning‐based pathological risk score (RS) with an aim of predicting patients' prognosis to investigate the potential association between the information within the whole slide image (WSI) and cervical cancer prognosis. Methods A total of 251 patients with the International Federation of Gynecology and Obstetrics (FIGO) Stage IA1–IIA2 cervical cancer who underwent surgery without any preoperative treatment were enrolled in this study. Both the clinical characteristics and WSI of each patient were collected. To construct a prognosis‐associate RS, high‐dimensional pathological features were extracted using a convolutional neural network with an autoencoder. With the score threshold selected by X‐tile, Kaplan–Meier survival analysis was applied to verify the prediction performance of RS in overall survival (OS) and disease‐free survival (DFS) in both the training and testing datasets, as well as different clinical subgroups. Results For the OS and DFS prediction in the testing cohort, RS showed a Harrell's concordance index of higher than 0.700, while the areas under the curve (AUC) achieved up to 0.800 in the same cohort. Furthermore, Kaplan–Meier survival analysis demonstrated that RS was a potential prognostic factor, even in different datasets or subgroups. It could further distinguish the survival differences after clinicopathological risk stratification. Conclusion In the present study, we developed an effective signature in cervical cancer for prognosis prediction and patients' stratification in OS and DFS.

Abstract Background Cervical cancer is the fourth most common cancer in women. N6-dimethyladenosine (m6A) mRNA methylation is closely associated with cervical cancer. Methods Using TCGA database, we studied the expression and mutation of m6A-related genes in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and obtained genetic characteristics based on an m6A risk model and prognostic value of m6A. We studied the effects of the m6A risk score on immune features and genomic changes of patients with CESC, evaluated the sensitivity of patients with CESC to different small-molecule drugs based on the m6A risk score, and established a clinical prediction model. Results Ten m6A-related genes were differentially expressed between CESC and normal tissues. High-risk patients had a low overall survival (OS) and significantly low immune scores but showed no significantly altered stromal scores. The tumor mutation burden (TMB) and tumor neoantigen levels significantly differed between the high- and low-risk groups. In the high-risk group, copy number variation (CNV) changes mainly led to gene amplification, while in the low-risk group, CNV changes primarily manifested as gene copy number deletions. ZC3H13 expression was low in CESC tissues. ZC3H13 knockdown promoted CESC cell proliferation, migration, and invasion, reducing the RNA methylation levels. Rapamycin suppressed the CESC cell proliferation, migration, and invasion abilities, increasing the m6A levels. Conclusion m6A mRNA methylation is closely related to the occurrence, development, immune invasion, drug sensitivity, and prognosis of cervical cancer. The prognostic m6A feature model of m6A signature genes can accurately predict the OS of patients with CESC. Drugs targeting factors regulating m6A mRNA methylation might offer a good prospect for treating cervical cancer.

AimsThis study aimed to construct a lymph node metastasis-related gene signature to predict prognosis and immune infiltration in patients with cervical cancer.MethodsClinical and RNA sequencing data of 193 patients with cervical cancer, which were divided into lymph node metastasis (N1) and non-lymph node metastasis (N0) groups, were acquired from TCGA. Differentially expressed genes (DEGs) between the N1 and N0 groups were detected, and protein-protein interaction combined with LASSO analysis was conducted to further screen lymph node metastasis-related genes. Univariate and multivariate Cox regression analyses were performed to establish a predictive signature. The genetic features, potential biological behavior, and immune infiltration characteristics of the predictive signature were explored. Furthermore, the sensitivity of patients to chemotherapy drugs was estimated based on the predictive signature and the expression of TEKT2 and RPGR was investigated in the cervical cancer tissue samples.ResultsA total of 271 lymph node metastasis-related DEGs, including 100 upregulated and 171 downregulated genes, were identified. Two genes, TEKT2 and RPGR, were associated with lymph node metastasis and prognosis in cervical cancer, and were used to construct a lymph node metastasis-related predictive signature. Based on the predictive signature, patients with cervical cancer were divided into high- and low-risk groups. The high-risk group, characterized by a higher tumor mutation burden and somatic mutation rate, indicated a poor overall survival. The activation of immune infiltration and increased expression of checkpoint genes were observed in the high-risk group, indicating that they might benefit from immunotherapy. Cytarabine, FH535, and procaspase-activating compound-1 were estimated as reasonable chemotherapy options for patients in the high-risk group, whereas two taxanes and five tyrosine kinase inhibitors, including etoposide and vinorelbine, had therapeutic significance for patients in the low-risk group. The expression of TEKT2 and RPGR was significantly downregulated in cervical cancer tissues, especially in metastatic lymph node tissues.DiscussionThe lymph node metastasis-related predictive signature based on TEKT2 and RPGR showed good performance in predicting the survival outcomes of patients with cervical cancer. The risk score of the predictive signature was related to genetic variation and immune infiltration, which could guide immunotherapy and chemotherapy strategies.

ObjectiveTo compare the 3-year oncological outcomes of robot-assisted radical hysterectomy (RRH) and abdominal radical hysterectomy (ARH) for cervical cancer.MethodsBased on the clinical diagnosis and treatment for cervical cancer in the China database, patients with FIGO 2018 stage IA with lymphovascular space invasion (LVSI)-IB2 cervical cancer disease who underwent RRH and ARH from 2004 to 2018 were included. Kaplan–Meier survival analysis was used to compare the 3-year overall survival (OS) and disease-free survival (DFS) rate between patients receiving RRH and those receiving ARH. The Cox proportional hazards model and propensity score matching were used to estimate the surgical approach-specific survival.ResultsA total of 1,137 patients with cervical cancer were enrolled in this study, including the RRH group (n = 468) and the ARH group (n = 669). The median follow-up time was 45 months (RRH group vs. ARH group: 24 vs. 60 months). Among the overall study population, there was no significant difference in 3-year OS and DFS between the RRH group and the ARH group (OS: 95.8% vs. 97.6% p = 0.244). The Cox proportional hazards analysis showed that RRH was not an independent risk factor for 3-year OS (HR: 1.394, 95% CI: 0.552–3.523, p = 0.482). However, RRH was an independent risk factor for 3-year DFS (HR: 1.985, 95% CI: 1.078–3.655 p = 0.028). After 1:1 propensity score matching, there was no significant difference in 3-year OS between the RRH group and the ARH group (96.6% vs. 98.0%, p = 0.470); however, the 3-year DFS of the RRH group was lower than that of the ARH group (91.0% vs. 96.1%, p = 0.025). The Cox proportional hazards analysis revealed that RRH was not an independent risk factor for 3-year OS (HR: 1.622, 95% CI: 0.449–5.860 p = 0.461), but RRH was an independent risk factor for 3-year DFS (HR: 2.498, 95% CI: 1.123–5.557 p = 0.025).ConclusionAmong patients with stage I A1 (LVSI +)-I B2 cervical cancer based on the FIGO 2018 staging system, RRH has a lower 3-year DFS than ARH, suggesting that RRH may not be suitable for early cervical cancer patients.

Abstract Xanthones are an important class of natural compounds bearing huge bioactivity profiles. Garcinone-E is one among most active xanthones showing potential anticancer activity against various human cancer cell lines. Therefore, the current study was performed to explore the anticancer potency of naturally occurring garcinone-E xanthone against human HeLa cervical cancer cells. The underlying mechanism of action was also tried to be explored via testifying its induction of programmed cell death, arrest of cell cycle, suppression of cell migration, cell invasion and cell adhesion. MTT assay was implemented to estimate the viability of HeLa cells after garcinone-E exposure and clonogenic assay was used to analyze the effect on clonogenic potential. Acridine orange/ethidium bromine (AO/EB) staining assay was performed for monitoring of programmed cell death along with western blotting. Flow cytometric studies were carried out to analyze cell cycle check points. Transwell chambers assays were carried out for studying the impact of garcinone-E on migration and invasion potency of HeLa cells. Western blotting was used to study the expressions of apoptosis linked proteins in HeLa cells. Results indicated that garcinone-E remarkably decreased the viability to minimum in HeLa cells in both dose and time-reliant manner. The clonogenic capacity of HeLa cells was efficiently reduced by garcinone exposure. AO/EB staining showed that the anti-viability action of garcinone-E was apoptosis allied which was supported by western blotting as well. The cell cycle check points study indicated cell cycle arrest at G2/M-phase. HeLa cell migration and invasion were reduced efficiently after being subjected to garcinone-E treatment in a dose reliant fashion. In conclusion, garcinone-E has a remarkable potential to act as anti-cervical cancer chemopreventive provided further in vivo studies are required.

ObjectiveTo compare the 5-year overall survival (OS) and disease-free survival (DFS) of patients with cervical cancer who received neoadjuvant chemotherapy followed by surgery (NACT) with those who received abdominal radical hysterectomy alone (ARH).MethodsWe retrospectively compared the oncological outcomes of 1410 patients with stage IB3 cervical cancer who received NACT (n=583) or ARH (n=827). The patients in the NACT group were divided into an NACT-sensitive group and an NACT-insensitive group according to their response to chemotherapy.ResultsThe 5-year oncological outcomes were significantly better in the NACT group than in the ARH group (OS: 96.2% vs. 91.2%, respectively, p=0.002; DFS: 92.2% vs. 87.5%, respectively, p=0.016). Cox multivariate analysis suggested that NACT was independently associated with a better 5-year OS (HR=0.496; 95% CI, 0.281-0.875; p=0.015), but it was not an independent factor for 5-year DFS (HR=0.760; 95% CI, 0.505-1.145; p=0.189). After matching, the 5-year oncological outcomes of the NACT group were better than those of the ARH group. Cox multivariate analysis suggested that NACT was still an independent protective factor for 5-year OS (HR=0.503; 95% CI, 0.275-0.918; p=0.025). The proportion of patients in the NACT group who received postoperative radiotherapy was significantly lower than that in the ARH group (p

Long noncoding RNA (lncRNA) cardiac mesoderm enhancer-associated noncoding RNA (CARMN) is a newly discovered tumor-suppressor lncRNA in cancers. However, its role in cervical cancer (CC) remains elusive. This study was conducted to analyze the molecular mechanism of CARMN in CC cell growth and provide a novel theoretical basis for CC treatment. RT-qPCR and clinical analysis revealed that CARMN and B-cell translocation gene 2 (BTG2) were downregulated, whereas miR-92a-3p was upregulated in CC tissues and cells and their expressions were correlated with clinicopathological characteristics and prognosis. MTT assay, flow cytometry, and Transwell assays revealed that CARMN overexpression reduced proliferation, migration, and invasion and increased apoptosis rate in CC cells. Mechanically, CARMN repressed miR-92a-3p to promote BTG2 transcription. Functional rescue assays revealed that miR-92a-3p overexpression or BTG2 downregulation reversed the inhibitory role of CARMN overexpression in CC cell growth. Western blot analysis elicited that Wnt3a and b-catenin were elevated in CC cells and CARMN blocked the Wnt/β-catenin signaling pathway via the miR-92a-3p/BTG2 axis. Overall, our findings demonstrated that CARMN repressed miR-92a-3p to upregulate BTG2 transcription and then blocked the Wnt/β-catenin signaling pathway, thereby suppressing CC cell growth. [ABSTRACT FROM AUTHOR]

Aberrant expression of oncogenes and/or tumor suppressors play a fundamental effect on the pathogenesis and tumorigenicity of cervical cancer (CC). B-cell CLL/lymphoma 3 (BCL3) was previously found to be a putative proto-oncogene in human cancers and regulated signal transducer and activator of transcription 3 (STAT3), a critical oncogene, in CC cell line. However, its expression status, clinical significance and biological functions in CC remain largely unclear. The expressions of BCL3 and STAT3 in CC specimens were determined by immunohistochemistry. MTT, colony formation assays and flow cytometry analysis were carried out to test proliferation and cell cycle of CC cells. Here, the levels of BCL3 were overexpressed in CC compared to adjacent cervical tissues. Furthermore, high levels of BCL3 protein were confirmed by immunoblotting in CC cells as compared with normal cervical epithelial cells. The positive expression of BCL3 was correlated with adverse prognostic features and reduced survival rate. In addition, BCL3 regulated STAT3 abundance in CC cells. STAT3 was found to be upregulated and positively correlated with BCL3 expression in CC specimens. BCL3 overexpression resulted in prominent increased proliferation and cell cycle progression in Hela cells. By contrast, inhibition of BCL3 in CaSki cells remarkably suppressed proliferative ability and cell cycle progression. In vivo studies showed that knockdown of BCL3 inhibited tumor growth of CC in mice xenograft model. Notably, we confirmed that STAT3 mediated the oncogenic roles of BCL3 in CC. In conclusion, we suggest that BCL3 serves as an oncogene in CC by modulating proliferation and cell cycle progression, and its oncogenic effect is mediated by its downstream target gene, STAT3. [ABSTRACT FROM AUTHOR]

Cervical cancer is the third most commonly diagnosed cancer in women. The human wings apart-like (hWAPL) gene, which is 30,793 bp long and located on 10q23.2., is a human homologue of the WAPL gene in Drosophila melanogaster. hWAPL has the characteristics of an oncogene in uterine cervical cancer. The present study investigated the expression of the hWAPL gene in tissues, including 9 common cancers, consisting of cervical, gastric and lung cancers, liver, bladder, esophageal, endometrial, renal and rectal carcinomas, cervical intraepithelial neoplasia (CIN) and benign squamous epithelia. The immunohistochemical analysis was conducted using paraffin-embedded tissues obtained from 413 patients, consisting of 27 benign squamous epithelial tissue samples, and 47 cervical cancer, 30 cervical intraepithelial neoplasia (CIN)I, 33 CINII, 38 CINIII, 29 gastric cancer, 28 liver carcinoma, 26 bladder carcinoma, 35 esophageal carcinoma, 25 endometrial, 26 renal carcinoma, 36 rectal carcinoma and 33 lung cancer tissues. The expression of hWAPL mRNA was evaluated by reverse transcription-quantitative polymerase chain reaction in 8 benign squamous epithelia and 11 cervical cancer tissues. Compared to benign squamous epithelia and the 8 other cancers, hWAPL protein was significantly increased in cervical cancer (P<0.001). The expression of the hWAPL protein in cervical cancer and CINIII tissues was markedly increased compared to the expression in CINI and CINII tissues (P<0.001). Despite the significant difference in the staining scores (P<0.001), no significant difference was observed in the percentage of tissues expressing hWAPL (P=0.102) between cervical cancer and CINIII. The hWAPL gene may therefore be specifically overexpressed in cervical cancer. The overexpression of hWAPL may play an important role in occurrence and development of cervical cancer. [ABSTRACT FROM AUTHOR]