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Background. Cervical cancer ranks as the 4th most common female cancer worldwide. Early stage cervical cancer patients can be treated with operation, but clinical staging system is not a good predictor of patients’ survival. We aimed to develop a novel prognostic model to predict the prognosis for operable cervical cancer patients with better accuracy than clinical staging system. Methods. A total of 13,952 operable cervical cancer patients were retrospectively enrolled in this study. The whole dataset was randomly split into a training set ( n = 9,068 , 65%), validation set ( n = 2,442 , 17.5%), and testing set ( n = 2,442 , 17.5%). Cox proportional hazard (CPH) model and random survival forest (RSF) model were used as baseline models for the prediction of overall survival (OS). Then, a deep survival learning model (DSLM) was developed for OS prediction. Finally, a novel prognostic model was explored based on this DSLM. Results. The C-indexes for the CPH and RSF model were 0.731 and 0.753, respectively. DSLM, which had four layers that had 50 neurons in each layer, achieved a C-index of 0.782 in the validation set and a C-index of 0.758 in the testing set. The novel prognostic model based on DSLM showed better performances than the conventional clinical staging system (area under receiver operating curves were 0.826 and 0.689, respectively). Personalized survival curves for individual patient using this novel model also showed notably different survival slopes. Conclusions. Our study developed a novel, practical, personalized prognostic model for operable cervical cancer patients. This novel prognostic model may have the potential to provide a more prognostic information to oncologists.

Cervical cancer is one of the most common tumors of women’s diseases. N6-methyladenosine (m6A) is an abundant RNA modification of mammalian mRNAs and plays a vital role in many diseases, especially tumors. In this study, we aimed to investigate the roles of m6A on macrophage function and tumor progression in cervical cancer. We measured the levels of m6A expression in cervical cancer tissues, and revealed biological functions of METTL14 (Methyltransferase14, N6-Adenosine-Methyltransferase Subunit) on tumor-associated macrophages (TAMs) and PD-1 expression. We found the METTL14-related methylation of m6A in cervical cancer was correlated with infiltration of TAMs, polarization status of infiltrated TAMs, and survival outcomes of cervical cancer patients. Mechanistically, lactate produced by tumor glycolysis in the acidic immunosuppressive tumor microenvironment (TME) has an important role as a proinflammatory and immunosuppressive mediator in this program. METTL14-related methylation of m6A may play a predictive role in the polarization and PD-1 expression of macrophages in TME. The study intends to reveal the effect of m6A on the immune microenvironment and macrophage differentiation of cervical cancer, which could be a viable therapeutic target for the treatment of advanced human cancers.

Background. The present research focuses on preeclampsia (PE), a clinically relevant pregnancy disease. To date, the majority of research on PE was centered on placental insufficiency. However, the genes that regulate these processes, and the exact molecular mechanisms modulating these processes, are still unclear. Methods. We obtained placentae from a clinically well-specified group of patients with preeclampsia and gestationally matched control pregnancies in order to evaluate the expression of homeobox gene DLX3 by immunohistochemical staining, real-time PCR, and Western immunoblotting and determine the function of DLX3 utilizing lentivirus transfection in HTR-8/SVneo cells. Results. In the present study, we detected DLX3 expression in a clinically well defined cohort of preeclampsia-affected and gestation-matched control pregnancies. As opposed to the controls, DLX3 was overexpressed in preeclampsia-affected placentae. Moreover, we found that the in vitro cell growth and invasive ability of HTR8/SVneo cells was enhanced by the exogenous overexpression of DLX3 ( P < 0.05 ). It can be seen that DLX3 influences the cell cycle of HTR-8/SVneo cells in vitro. Conclusions. DLX3 has been shown to be strongly related to normal placental growth as well as the pathophysiology of preeclampsia. The imbalanced expression of DLX3 may perform an integral function in the occurrence and progression of preeclampsia.

BackgroundThe aim was to develop a personalized survival prediction deep learning model for adenosarcoma patients using the surveillance, epidemiology and end results (SEER) database.MethodsA total of 797 uterine adenosarcoma patients were enrolled in this study. Duplicated and useless variables were excluded, and 15 variables were selected for further analyses, including age, grade, positive lymph nodes or not, marital status, race, tumor extension, stage, and surgery or not. We created our deep survival learning (DSL) model to manipulate the data, which was randomly split into a training set (n = 519, 65%), validation set (n = 143, 18%) and testing set (n = 143, 18%). The Cox proportional hazard (CPH) model was also included comparatively. Finally, personalized survival curves were plotted for randomly selected patients.ResultsThe c-index for the CPH model was 0.726, and the Brier score was 0.17. For our deep survival learning model, we achieved a c-index of 0.774 and a Brier score of 0.14 in the external testing set. In addition, the limitations of the traditional staging system were revealed, and a personalized survival prediction system based on our risk scoring grouping was developed.ConclusionsOur study developed a deep neural network model for adenosarcoma. The performance of this model was superior to that of the traditional Cox proportional hazard model. In addition, a personalized survival prediction system was developed based on our deep survival learning model, which provided more accurate prognostic information for adenosarcoma patients.

Regulatory T (Treg) cells expressing tumor necrosis factor receptor 2 (TNFR2) are highly suppressive and are associated with immune homeostasis in various diseases. However, the role of TNFR2+Treg subset and relevant cytokines in the development of cervical cancer (CC) remained unclear. In this study, 72 patients with CC, 30 patients with cervical intraepithelial neoplasia (CIN) and 30 healthy volunteers were enrolled. The level of circulating TNFR2+Tregs was investigated through flow cytometry. The plasma concentrations of soluble TNFR1 (s-TNFR1) and soluble TNFR2 (s-TNFR2) were determined by enzyme-linked immunosorbent assay. In addition, the mRNA expression levels of TNF-α, TNFR1, TNFR2, and Foxp3 were measured using real-time polymerase chain reaction. Results showed that both peripheral and tumor infiltrating TNFR2+Tregs significantly increased in patients with CIN and CC and levels of circulating s-TNFR1 and s-TNFR2 increased in patients with CC. Moreover, the percentage of peripheral TNFR2+Tregs was inversely correlated with the clinical stages of CC. Furthermore, the mRNA expression levels of TNF-α, TNFR2, and Foxp3 increased in patients with CIN and CC. Overall, these results indicate that TNFR2+Tregs and relevant cytokines contribute to CC development and are promising targets in future immunotherapeutic approaches.

Uterine leiomyosarcoma (ULMS) is the most lethal gynecologic malignancy with few therapeutic options. Chemoresistance prevails as a major hurdle in treating this malignancy, yet the mechanism of chemoresistance remains largely unclear. In this study, we certified MELK as a poor prognostic marker through bioinformatic analysis of the GEO database. Cellular experiments in vitro revealed that MELK played an essential role in ULMS cells' chemoresistance and that a high expression of MELK could lead to doxorubicin resistance. mRNA profiling uncovered the pathways that MELK was involved in which led to doxorubicin resistance. MELK was found to affect ULMS cells' chemoresistance through an anti-apoptotic mechanism via the JAK2/STAT3 pathway. miRNA profiling also revealed that upregulated MELK could induce the decrease of miRNA-34a (regulated by JAK2/STAT3 pathway). We detected that MELK overexpression could induce M2 macrophage polarization via the miR-34a/JAK2/STAT3 pathway, contributing to doxorubicin chemoresistance in the tumor microenvironment. OTSSP167, a MELK inhibitor, may increase ULMS sensitivity to doxorubicin. Our investigation could propose novel targets for early diagnosis and precision therapy in ULMS patients.

Background Cervical cancer screening by combined cytology and HPV test has reduced the incidence of cervical cancer, but cytological screening lacks a higher sensitivity while HPV testing possesses a lower specificity. Most patients with invasive cervical cancer are treated with radiotherapy. However, insensitivity to radiotherapy leads to poor efficacy. Methods Illumina Methylation EPIC 850k Beadchip was used for genomic screening. We detected methylation of SEPT9 and mRNA expression in different cervical tissues by using methylation-specific PCR and qRT-PCR. Then using CCK8, migration assay, and flow cytometry to detect the biological function and irradiation resistance of SEPT9 in vitro and in vivo. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (CoIP) were used to find the interacting gene with SEPT9. Immunostaining of CD206 in cervical cancer and polarization of macrophages (M2) were evaluated by immunofluorescence and WB. The Cancer Genome Atlas (TCGA) database was used for screening the potential miRNAs induced by SEPT9. Results Hyper-methylation of SEPT9 detects cervical cancer and normal tissues, normal+CIN1 and CIN2+CIN3+cancer with high sensitivity and specificity (AUC = 0.854 and 0.797, respectively, P

Table S1. The detail information of SEPT9 CpG site in Illumina MethylationEPIC [850K] BeadArray. (DOCX 16 kb)

Circular RNAs (circRNAs) participate in gene regulation and malignant tumor progression, including uterine cervical cancer (CC). In this study, the expression profile of circRNAs in CC was detected using circRNA microarrays. Then, we selected hsa_circ_0000745 for further examination from the significantly dysregulated circRNAs. Proliferation assays, Transwell assays, quantitative reverse transcription polymerase chain reaction, western blot analysis and tumorigenesis tests in vivo were used to validate the role of hsa_circ_0000745 in CC. hsa_circ_0000745 was upregulated in CC, and its level positively correlated with the level of its linear messenger RNA isoform. Patients with poorly differentiated tumors or vascular/lymphatic invasion presented higher expression of hsa_circ_0000745. The role of hsa_circ_0000745 was illuminated by knocking down hsa_circ_0000745 in CC cells, and the results revealed that reducing hsa_circ_0000745 inhibited cell proliferation, migration, and invasion in CC by upregulating E‐cadherin (E‐cad) expression. In summary, as a tumor promoter in CC, hsa_circ_0000745 enhances the cell's ability to proliferate, migrate, and invade by reducing the expression of E‐cad. hsa_circ_0000745 is a candidate target for the treatment of CC in the clinic., Hsa_circ_0000745 is upregulated and functions as a tumor promoter in cervical cancer. Hsa_circ_0000745 enhances the cell's ability to proliferate, migrate, and invade by reducing the expression of E‐cadherin in cervical cancer.

Increasing evidence demonstrates that the four and a half LIM domain (FHL) gene and its protein products have different functions in the progression of various malignancies. However, the role of FHL protein 2 (FHL2) in cervical cancer (CC) has not been fully elucidated. In this study, we investigated the prognostic value of FHL2 expression in human CC tissues and the potential molecular mechanisms through which FHL2 modulates CC cell proliferation and apoptosis.We measured FHL2 expression in CC cell lines and tissues by quantitative real-time polymerase chain reaction and Western blot assays. The effects of FHL2 knockdown on cell proliferation and apoptosis in two CC cell lines were examined using RNA interference, cell counting kit-8, Western blot and flow cytometry assays. Furthermore, we assessed phosphorylated protein kinase B (p-AKT) and phosphorylated mammalian target of rapamycin (p-mTOR) expression in two CC cell lines to determine whether the AKT/mTOR pathway is involved in the effects of FHL2 silencing on cell proliferation and apoptosis. Nude mice tumorigenicity experiments were also performed to evaluate the effects of FHL2 on HeLa cell growth in vivo.We found that FHL2 was significantly upregulated in CC cell lines and tissues. According to survival curves, high FHL2 expression levels in patients were correlated with poor prognosis. Moreover, by decreasing p-AKT and p-mTOR protein levels, silencing FHL2 significantly inhibited cell proliferation and induced apoptosis. FHL2 knockdown also induced apoptosis by increasing the Bax-to-Bcl2 ratio. By contrast, FHL2 overexpression significantly promoted cell proliferation. Finally, decreased tumour growth in an in vivo animal model also demonstrated the tumour-suppressing effects of FHL2 knockdown.Our findings indicate that FHL2 is an important prognostic factor in CC and that it plays a crucial oncoprotein role by promoting cell proliferation and inhibiting apoptosis in CC, possibly by targeting the AKT/mTOR pathway.