ABSTRACT
BACKGROUND: Patients with choriocarcinoma (CC) accompanying chemoresistance conventionally present a poor prognosis. Whether ras protein activator like-1 (RASAL1) functions as a tumor promoter or suppressor depends on tumor types. However, the role of RASAL1 in process of chemoresistance of CC and underlying molecular mechanism remain elusive. METHODS: The expression pattern of RASAL1 in CC cells and tissues was measured using Western blotting, immunohistochemistry and qRT-PCR. Cell viability and proliferative ability were assessed by MTT assay, Tunnel assay and flow cytometric analysis. Additionally, the stemness was evaluated by the colony formation and tumor sphere formation. Methotrexate (MTX) was applied to exam the chemosensitivity of CC cells. RESULTS: The expression of RASAL1 was reduced both at the protein and mRNA levels in CC tissues and cells compared to hydatidiform mole (HM) and invasive mole (IM). Loss of RASAL1 was attributed to its promoter hypermethylation and could be restored by 5-Aza. Knock-down of RASAL1 promoted the viability, proliferative potential, stemness and EMT phenotype of JEG-3 cells. However, induced overexpression of RASAL1 by 5-Aza significantly prohibited cell proliferation and stemness potential of the JAR cell. Additionally, the xenograft model indicated that knockdown of RASAL1 led to a remarkable increase of tumor volume and weight in comparison with its counterpart. Moreover, the stimulatory activity brought by decrease of RASAL1 could be deprived by ß-catenin inhibitor XAV 939, yet the suppressive activity resulted from its promoter demethylation could be rescued by ß-catenin activator BML-284, indicating that function of RASAL1 depends on ß-catenin. Besides, the co-immunoprecipitation assay confirmed the physical binding between RASAL1 and ß-catenin. Further investigations showed hypermethylated RASAL1 was regulated by TET2 but not DNMTs. CONCLUSION: Taken together, the present data elucidated that reduced RASAL1 through its promoter hypermethylation regulated by TET2 promoted the tumorigenicity and chemoresistance of CC via modulating ß-catenin both in vitro and in vivo.
Subject(s)
Choriocarcinoma , DNA Methylation , DNA-Binding Proteins , Dioxygenases , Drug Resistance, Neoplasm , Promoter Regions, Genetic , Proto-Oncogene Proteins , Humans , Drug Resistance, Neoplasm/genetics , Choriocarcinoma/metabolism , Choriocarcinoma/pathology , Choriocarcinoma/genetics , Animals , Female , Mice , Dioxygenases/metabolism , Dioxygenases/genetics , Cell Line, Tumor , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , Cell Proliferation , Gene Expression Regulation, Neoplastic , Uterine Neoplasms/genetics , Uterine Neoplasms/pathology , Uterine Neoplasms/metabolism , Carcinogenesis/genetics , PregnancyABSTRACT
BACKGROUND: Neuroendocrine carcinoma (NEC) originating from the endometrium is rare, and there is limited knowledge regarding its diagnosis and optimal management. In this study, we present our experience with 11 patients with endometrial NEC, aiming to provide guidance for clinical practice. METHODS: We retrospectively collected the clinical, pathological, and treatment data of 11 patients with endometrial NEC who were treated at the First Affiliated Hospital of Zhengzhou University from January 2011 to July 2023. The clinicopathological characteristics, treatment and prognosis of these patients were analyzed. RESULTS: The median age of the patients was 55.0 (39.0-64.0) years, and the median tumor size was 40.0 (33.0-60.0) mm. Irregular vaginal bleeding was the most common symptom observed in 10 out of 11 patients, while metabolic syndrome occurred in only 2 out of 11 patients. Six out of the 11 patients were diagnosed at an early stage. Among the patients, 6 were diagnosed with endometrial NECs, while the remaining patients had a combination of endometrial NEC and other non-NEC endometrial carcinomas. All patients underwent surgery, except for one who received only chemotherapy due to multiple metastases. After surgery, adjuvant chemotherapy was administered to 5 patients, chemotherapy combined with radiotherapy was given to 3 patients, and 2 patients did not receive any adjuvant therapy. A total of 10 patients completed the follow-up, with a median follow-up time of 51.0 (14.3-81.0) months. Unfortunately, 2 patients died from the disease. CONCLUSION: NECs originating from the endometrium might not be affected by metabolic disorders. Preoperative diagnosis of these tumors was challenging. The primary approach for managing endometrial NEC can be multimodal treatment centered around surgery.
Subject(s)
Carcinoma, Neuroendocrine , Endometrial Neoplasms , Humans , Female , Endometrial Neoplasms/pathology , Endometrial Neoplasms/therapy , Endometrial Neoplasms/mortality , Carcinoma, Neuroendocrine/pathology , Carcinoma, Neuroendocrine/therapy , Carcinoma, Neuroendocrine/mortality , Middle Aged , Retrospective Studies , Adult , Prognosis , Chemotherapy, Adjuvant , Endometrium/pathology , Neoplasm StagingABSTRACT
PURPOSE: Vascular endothelial growth factor receptor 3 (VEGFR-3) plays a critical role in tumor lymphangiogenesis and metastasis, holding promise as a promising therapeutic target for solid tumors. TMVP1 (LARGR) is a 5-amino acid peptide previously identified in our laboratory from bacterial peptide display system that specifically targets VEGFR-3. Radiolabeled TMVP1 can be used for non-invasive imaging of VEGFR-3 expressing tumors. Homodimeric peptides have better targeting ability than monomeric peptides, and it is worth exploring whether homodimers of TMVP1 ((TMVP1)2) can achieve better imaging effects. This study aimed to explore the peptide properties and tumor assessment value of [68Ga]Ga-labeled (TMVP1)2. METHODS: In this study, we developed a TMVP1 homodimer that was conjugated with 1,4,7-triazacyclononane-N, N', Nâ³-triacetic acid (NOTA) via tetraethyleneglycol (PEG4) and triglyicine (Gly3) spacer, and labeled with 68Ga, to construct [68Ga]Ga-NOTA-(TMVP1)2. Binding of VEGFR-3 by TMVP1 and (TMVP1)2, respectively, was modeled by molecular docking. The affinity of [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 and its ability to bind to cells were evaluated. MicroPET imaging and biodistribution studies of [68Ga]Ga-NOTA-(TMVP1)2 were performed in subcutaneous C33A cervical cancer xenografts. Five healthy volunteers and eight patients with cervical cancer underwent whole-body PET/CT acquisition 30-45 min after intravenous injection of [68Ga]Ga-NOTA-(TMVP1)2. RESULTS: Both molecular docking and cellular experiments showed that homodimeric TMVP1 had a higher affinity for VEGFR-3 than monomeric TMVP1. [68Ga]Ga-NOTA-(TMVP1)2 was excreted mainly through the renal route and partly through the liver route. In mice bearing C33A xenografts, [68Ga]Ga-NOTA-(TMVP1)2 specifically localized in the tumor (2.32 ± 0.10% ID/g). Pretreatment of C33A xenograft mice with the unlabeled peptide NOTA-(TMVP1)2 reduced the enrichment of [68Ga]Ga-NOTA-(TMVP1)2 in tumors (0.58 ± 0.01% ID/g). [68Ga]Ga-NOTA-(TMVP1)2 proved to be safe in all healthy volunteers and recruited patients, with no side effects or allergies noted. In cervical cancer patients, a majority of the [18F]-FDG identified lesions (18/22, 81.8%) showed moderate to high signal intensity on [68Ga]Ga-NOTA-(TMVP1)2. SUVmax and SUVmean were 2.32 ± 0.77 and 1.61 ± 0.48, respectively. With normal muscle (gluteus maximus) as background, tumor-to-background ratios were 3.49 ± 1.32 and 3.95 ± 1.64 based on SUVmax and SUVmean, respectively. CONCLUSION: The favorable characterizations of [68Ga]Ga-NOTA-(TMVP1)2 such as convenient synthesis, high specific activity, and high tumor uptake enable the evaluation of VEGFR-3 in cervical cancer patients and warrant further clinical studies. TRIAL REGISTRATION: ChiCTR-DOD-17012458. Registered August 23, 2017 (retrospectively registered).
Subject(s)
Gallium Radioisotopes , Heterocyclic Compounds, 1-Ring , Uterine Cervical Neoplasms , Vascular Endothelial Growth Factor Receptor-3 , Uterine Cervical Neoplasms/diagnostic imaging , Uterine Cervical Neoplasms/metabolism , Humans , Female , Animals , Mice , Heterocyclic Compounds, 1-Ring/chemistry , Vascular Endothelial Growth Factor Receptor-3/metabolism , Vascular Endothelial Growth Factor Receptor-3/chemistry , Gallium Radioisotopes/chemistry , Cell Line, Tumor , Heterocyclic Compounds/chemistry , Tissue Distribution , Peptides/chemistry , Peptides/pharmacokinetics , Positron Emission Tomography Computed Tomography/methods , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/chemistry , Middle Aged , Protein Multimerization , Radioactive TracersABSTRACT
The tumor heterogeneity is an important cause of clinical therapy failure and yields distinct prognosis in ovarian cancer (OV). Using the advantages of integrated single cell RNA sequencing (scRNA-seq) and bulk data to decode tumor heterogeneity remains largely unexplored. Four public datasets were enrolled in this study, including E-MTAB-8107, TCGA-OV, GSE63885, and GSE26193 cohorts. Random forest algorithm was employed to construct a multi-gene prognostic panel and further evaluated by receiver operator characteristic (ROC), calibration curve, and Cox regression. Subsequently, molecular characteristics were deciphered, and treatments strategies were explored to deliver precise therapy. The landscape of cell subpopulations and functional characteristics, as well as the dynamic of macrophage cells were detailly depicted at single cell level, and then screened prognostic candidate genes. Based on the expression of candidate genes, a stable and robust cell characterized gene associated prognosis signature (CCIS) was developed, which harbored excellent performance at prognosis assessment and patient stratification. The ROC and calibration curves, and Cox regression analysis elucidated CCIS could serve as serve as an independent factor for predicting prognosis. Moreover, a promising clinical tool nomogram was also constructed according to stage and CCIS. Through comprehensive investigations, patients in low-risk group were charactered by favorable prognosis, elevated genomic variations, higher immune cell infiltrations, and superior antigen presentation. For individualized treatment, patients in low-risk group were inclined to better immunotherapy responses. This study dissected tumor heterogeneity and afforded a promising prognostic signature, which was conducive to facilitating clinical outcomes for patients with OV.
Subject(s)
Ovarian Neoplasms , Humans , Female , Prognosis , Ovarian Neoplasms/genetics , Ovarian Neoplasms/therapy , Immunotherapy , Nomograms , Antigen PresentationABSTRACT
BACKGROUND: Vaginectomy has been shown to be effective for select patients with vaginal high-grade squamous intraepithelial lesions (HSIL) and is favored by gynecologists, while there are few reports on the robotic-assisted laparoscopic vaginectomy (RALV). The aim of this study was to evaluate the safety and treatment outcomes between RALV and the conventional laparoscopic vaginectomy (CLV) for patients with vaginal HSIL. METHODS: This retrospective cohort study was conducted in 109 patients with vaginal HSIL who underwent either RALV (RALV group) or CLV (CLV group) from December 2013 to May 2022. The operative data, homogeneous HPV infection regression rate and vaginal HSIL regression rate were compared between the two groups. Student's t-test, the Mann-Whitney U test, Pearson χ2 test or the Fisher exact test, Kaplan-Meier survival analysis and Cox proportional-hazards models were used for data analysis. RESULTS: There were 32 patients in the RALV group and 77 patients in the CLV group. Compared with the CLV group, patients in the RALV group demonstrated less estimated blood loss (41.6 ± 40.3 mL vs. 68.1 ± 56.4 mL, P = 0.017), lower intraoperative complications rate (6.3% vs. 24.7%, P = 0.026), and shorter flatus passing time (2.0 (1.0-2.0) vs. 2.0 (2.0-2.0), P < 0.001), postoperative catheterization time (2.0 (2.0-3.0) vs. 4.0 (2.0-6.0), P = 0.001) and postoperative hospitalization time (4.0 (4.0-5.0) vs. 5.0 (4.0-6.0), P = 0.020). In addition, the treatment outcomes showed that both RALV group and CLV group had high homogeneous HPV infection regression rate (90.0% vs. 92.0%, P > 0.999) and vaginal HSIL regression rate (96.7% vs. 94.7%, P = 0.805) after vaginectomy. However, the RALV group had significantly higher hospital costs than that in the CLV group (53035.1 ± 9539.0 yuan vs. 32706.8 ± 6659.2 yuan, P < 0.001). CONCLUSIONS: Both RALV and CLV can achieve satisfactory treatment outcomes, while RALV has the advantages of less intraoperative blood loss, fewer intraoperative complications rate and faster postoperative recovery. Robotic-assisted surgery has the potential to become a better choice for vaginectomy in patients with vaginal HSIL without regard to the burden of hospital costs.
Subject(s)
Laparoscopy , Papillomavirus Infections , Robotic Surgical Procedures , Squamous Intraepithelial Lesions , Female , Pregnancy , Humans , Retrospective Studies , Colpotomy , Blood Loss, SurgicalABSTRACT
STUDY OBJECTIVE: To describe the long-term anatomic and sexual functional results of vaginoplasty with acellular dermal matrix (ADM) in patients with Mayer-Rokitansky-Küster-Hauser (MRKH) and to evaluate the changes in body image pre- and postoperatively in these patients. DESIGN: A retrospective study from March 2015 to September 2021. SETTING: A tertiary teaching hospital. PATIENTS: Forty-two patients with MRKH syndrome who underwent vaginoplasty with ADM (the MRKH group) and 30 sexually active, nulliparous, aged-matched women (the control group). INTERVENTION: The relevant data were retrospectively collected via our electronic medical record system and were analyzed statistically. MEASUREMENTS AND MAIN RESULTS: Vaginal length was assessed using a 3-cm-diameter mold. The Chinese version of the Female Sexual Function Index questionnaire was used to evaluate sexual function. The Chinese version of the modified body image scale was applied to evaluate body image. The median follow-up time was 57 months (range, 13-91 months). Granulomatous polyps in the neovagina were the most common postoperative complication (7 of 42, 16.7%). Patients with MRKH syndrome can achieve long-term satisfactory outcomes both anatomically and functionally after vaginoplasty with ADM, comparable with those of healthy control women. The vaginal length in the MRKH group was comparable to that in the control group ( 8.04 ± 0.51 cm vs. 8.15 ± 0.46 cm, respectively). The FSFI scores were similar between the MRKH (26.54 ± 3.44) and control (26.80 ± 2.23) groups. The modified body image scale score was significantly decreased after vaginoplasty with ADM. CONCLUSION: Vaginoplasty with ADM is a minimally invasive and effective procedure for patients with MRKH syndrome.
Subject(s)
46, XX Disorders of Sex Development , Acellular Dermis , Congenital Abnormalities , Female , Humans , Aged , Retrospective Studies , Body Image , Vagina/surgery , 46, XX Disorders of Sex Development/surgery , Mullerian Ducts/surgery , Congenital Abnormalities/surgeryABSTRACT
BACKGROUND: Radiotherapy is widely used in treating cervical cancer patients, however, radioresistance unavoidably occurs and seriously affects the treatment effect. It is well known that hypoxia plays an important role in promoting radioresistance in tumor microenvironment, yet our understanding of the effect of small extracellular vesicles miRNA on cervical cancer radiosensitivity in hypoxic environment is still limited. METHODS: Small extracellular vesicles extracted from hypoxic and normoxic cultured cervical cancer cells were evaluated for their effects on radioresistance. miR-152-3p was found to be a potential effector in hypoxia-derived extracellular vesicles by searching the GEO database. Its downstream substrate was confirmed by double luciferase report, which was KLF15. The role of miR-152-3p and KLF15 in regulating cervical cancer radioresistance was detected by cell activity assays. The findings were confirmed in vivo by animal models. The expression of miR-152-3p was quantified by qRT-PCR and its prognostic significance was evaluated. RESULTS: Hypoxic environment promoted the secretion of small extracellular vesicles, and reduced the apoptosis and DNA damage caused by radiation, accompanied by increased expression of small extracellular vesicles miR-152-3p from hypoxic cervical cancer cells. Furthermore, small extracellular vesicles miR-152-3p promoted Hela xenograft growth and reduced the radiosensitivity vivo. Mechanism studies revealed that KLF15 protein was the downstream target of miR-152-3p in regulating radioresistance. CONCLUSION: Our findings suggest that small extracellular vesicles miR-152-3p affects the therapeutic effect of radiotherapy and holds potential as a biomarker or therapeutic target for cervical cancer prognosis and improving radiotherapy.
Subject(s)
MicroRNAs , Uterine Cervical Neoplasms , Female , Animals , Humans , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/radiotherapy , Uterine Cervical Neoplasms/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Apoptosis/genetics , HeLa Cells , Hypoxia/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Cell Proliferation/genetics , Tumor Microenvironment , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolismABSTRACT
Radioresistance is the major obstacle that affects the efficacy of radiotherapy which is an important treatment for cervical cancer. By analyzing the databases, we found that aldolase A (ALDOA), which is a key enzyme in metabolic reprogramming, has a higher expression in cervical cancer patients and is associated with poor prognosis. We detected the expression of ALDOA in the constructed cervical cancer radioresistance (RR) cells by repetitive irradiation and found that it was upregulated compared to the control cells. Functional assays were conducted and the results showed that the knockdown of ALDOA in cervical cancer RR cells inhibited the proliferation, migration, and clonogenic abilities by regulating the cell glycolysis. In addition, downregulation of ALDOA enhanced radiation-induced apoptosis and DNA damage by causing G2/M phase arrest and further promoted radiosensitivity of cervical cancer cells. The functions of ALDOA in regulating tumor radiosensitivity were also verified by the mouse tumor transplantation model in vivo. Therefore, our study provides new insights into the functions of ALDOA in regulating the efficacy of radiotherapy and indicates that ALDOA might be a promising target for enhancing radiosensitivity in treating cervical cancer patients.
Subject(s)
Fructose-Bisphosphate Aldolase , Uterine Cervical Neoplasms , Animals , Female , Humans , Mice , Cell Line, Tumor , Cell Proliferation/genetics , DNA Damage , Fructose-Bisphosphate Aldolase/genetics , Fructose-Bisphosphate Aldolase/metabolism , Gene Expression Regulation, Neoplastic , Glycolysis , Radiation Tolerance/genetics , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/radiotherapy , Uterine Cervical Neoplasms/pathologyABSTRACT
BACKGROUND: To summarise the application of minimally invasive surgery for female primary pelvic retroperitoneal tumours (PPRTs). METHODS: The clinical data of PPRT in a hospital between January 2017 and August 2022 were retrospectively collected. Surgical outcomes for cystic and solid tumours and two minimally invasive techniques were compared. RESULTS: 99 patients were included. Cystic tumours had fewer intraoperative injuries (4.0% vs. 28.0%, p < 0.001) than solid tumours. Robot-assisted laparoscopy (RALS) seemed to have fewer intraoperative complications (8.3% vs. 35.1%, p = 0.156) than conventional laparoscopy (CLS) in solid tumours. For cystic tumours, RALS included larger tumour sizes and longer operative times (p < 0.05), but intraoperative injury was comparable to CLS. RALS exhibited a higher cost than CLS in all tumours. CONCLUSIONS: Minimally invasive surgery for solid PPRTs tends to be more difficult than for cystic tumours, and RALS has a slight advantage over CLS with respect to short-term PPRT outcomes.
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BACKGROUND: Caesarean scar pregnancy (CSP) is a special type of ectopic pregnancy with a high risk of massive haemorrhage. Few studies have focused on the efficacy of prophylactic abdominal aortic balloon occlusion as a minimally invasive method in caesarean section. This study aimed to evaluate the effectiveness and safety of prophylactic abdominal aortic balloon occlusion for patients with type III CSP. METHODS: This was a prospective cohort study. Patients with type III CSP in the First Affiliated Hospital of Zhengzhou University from January 2020 to June 2022 were enrolled. Eligible patients received prophylactic abdominal aortic balloon occlusion (defined as the AABO group) or uterine artery embolization (defined as the UAE group) before laparoscopic surgery. Clinical outcomes included intraoperative blood loss, body surface radiation dose, hospitalization expenses, and time to serum ß-hCG normalization, and safety were also assessed. RESULTS: A total of 68 patients met the criteria for the study, of whom 34 patients were in the AABO group and 34 patients were in the UAE group. The median intraoperative blood loss in the AABO and UAE groups was 17.5 (interquartile ranges [IQR]: 10, 45) and 10 (IQR: 6.25, 20) mL, respectively (P = 0.264). The body surface radiation dose of the AABO group was much lower than that of the UAE group (5.22 ± 0.44 vs. 1441.85 ± 11.59 mGy, P < 0.001). The AABO group also had lower hospitalization expenses than the UAE group (2.42 ± 0.51 vs. 3.42 ± 0.85 *10^5 yuan, P < 0.001). The average time to serum ß-hCG normalization in the AABO group was 28.9 ± 3.21 d, which was similar to that in the UAE group (30.3 ± 3.72 d, P = 0.099). In addition, the incidence of adverse events in the AABO group was lower than that in the UAE group (5.9% vs. 58.8%, P < 0.001). CONCLUSION: Prophylactic AABO was equally as effective as UAE in patients with type III CSP but was safer than UAE during and after the operation.
Subject(s)
Balloon Occlusion , Pregnancy, Ectopic , Pregnancy , Humans , Female , Cesarean Section/adverse effects , Blood Loss, Surgical/prevention & control , Prospective Studies , Cicatrix/etiology , Cicatrix/prevention & control , Cicatrix/surgery , Treatment Outcome , Pregnancy, Ectopic/surgery , Balloon Occlusion/methods , Retrospective StudiesABSTRACT
BACKGROUND: The main symptoms of preeclampsia (PE), a specific ailment that develops during pregnancy, are proteinuria and hypertension. The pathological root of the onset and progression of PE is widely regarded as abnormal placental trophoblast cell function. This study aimed to look into the character and mechanism of Placenta-specific 8 (PLAC8) in trophoblast cell invasion and migration. METHODS: Expressions of PLAC8 and AlkB homologue 5 (ALKBH5) were examined by western blot and quantitative real-time PCR. The m6A level of PLAC8 mRNA was detected by methylated RNA Immunoprecipitation. Using Transwell experiments, cell invasion and migration were examined. The enzyme-linked immunosorbent assay was utilized to analyze the MMP-2 and MMP-9 secretion levels. RNA pull-down and RNA immunoprecipitation were conducted to detect the binding between ALKBH5 and PLAC8. RESULTS: In PE tissue and hypoxia-treated HTR-8/SVneo cells, levels of ALKBH5 and PLAC8 were increased, and PLAC8 m6A methylation levels were decreased. There was a positive correlation between PLAC8 and ALKBH5 expression in clinical tissues. In addition, overexpressing PLAC8 promoted HTR-8/SVneo cell migration and invasion, and so as the levels of MMP-2 and MMP-9; while interference with PLAC8 reduced the migration and invasion of hypoxia-treated HTR-8/SVneo cells, and so as the levels of MMP-2 and MMP-9. Moreover, the PLAC8 mRNA's m6A modification site was GAACU (Position 1449, Site 2). Increased levels of MMP-2 and MMP-9, as well as migration and invasion of HTR-8/SVneo cells exposed to hypoxia, were all facilitated by the m6A Site2 mutation. Furthermore, ALKBH5 could bind to PLAC8, reduce its m6A modification, and promote its expression. CONCLUSION: High-expressed ALKBH5 inhibits the m6A level of PLAC8 mRNA and promotes PLAC8 expression, while PLAC8 overexpression can promote hypoxia-induced invasion and migration of HTR-8/Svneo cells, indicating its potential protective function in PE.
Subject(s)
Matrix Metalloproteinase 2 , Pre-Eclampsia , Humans , Pregnancy , Female , Up-Regulation , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Cell Line , Pre-Eclampsia/genetics , Pre-Eclampsia/metabolism , Pre-Eclampsia/pathology , Trophoblasts/metabolism , Trophoblasts/pathology , Placenta/metabolism , Placenta/pathology , Cell Movement/genetics , RNA , RNA, Messenger/metabolism , Hypoxia/metabolism , Proteins/genetics , Proteins/metabolismABSTRACT
Intrauterine adhesion (IUA), also referred to as Asherman Syndrome (AS), results from uterine trauma in both pregnant and nonpregnant women. The IUA damages the endometrial bottom layer, causing partial or complete occlusion of the uterine cavity. This leads to irregular menstruation, infertility, or repeated abortions. Transcervical adhesion electroreception (TCRA) is frequently used to treat IUA, which greatly lowers the prevalence of adhesions and increases pregnancy rates. Although surgery aims to disentangle the adhesive tissue, it can exacerbate the development of IUA when the degree of adhesion is severer. Therefore, it is critical to develop innovative therapeutic approaches for the prevention of IUA. Endometrial fibrosis is the essence of IUA, and studies have found that the use of different types of mesenchymal stem cells (MSCs) can reduce the risk of endometrial fibrosis and increase the possibility of pregnancy. Recent research has suggested that exosomes derived from MSCs can overcome the limitations of MSCs, such as immunogenicity and tumorigenicity risks, thereby providing new directions for IUA treatment. Moreover, the hydrogel drug delivery system can significantly ameliorate the recurrence rate of adhesions and the intrauterine pregnancy rate of patients, and its potential mechanism in the treatment of IUA has also been studied. It has been shown that the combination of two or more therapeutic schemes has broader application prospects; therefore, this article reviews the pathophysiology of IUA and current treatment strategies, focusing on exosomes combined with hydrogels in the treatment of IUA. Although the use of exosomes and hydrogels has certain challenges in treating IUA, they still provide new promising directions in this field.
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Background: Endometrial carcinoma (EC) is a disease that predominantly affects peri- and post-menopausal women and its incidence has continued to rise over recent years. Since the gold standard for EC diagnosis-hysteroscopic biopsy-is invasive, expensive, and unsuitable for wide use, there is an urgent need for a non-invasive method that exhibits both high sensitivity and high specificity. We therefore investigated the efficacy of UterCAD (the uterine exfoliated cell chromosomal aneuploidy detector) using tampon-collected specimens for the early detection of EC. Methods: We prospectively recruited 51 patients with a history of abnormal bleeding and who planned to undergo hysteroscopic examination or hysterectomy between March 2020 and January 2021. Before executing an invasive procedure, a tampon was inserted into the patient's vagina for 6 h to collect exfoliated cells from the uterine cavity. Total DNA was extracted and low-coverage whole-genome sequencing was performed on an Illumina HiSeq X10, and we analyzed the differences in chromosomal status between women with EC and those bearing benign lesions using UterCAD. Results: Thirty EC patients-including 26 with endometrioid carcinoma (EEC) and four with uterine serous carcinoma (USC), as well as 14 benign cases-were enrolled in our final analysis. Copy-number variations (CNVs) were detected in tampon specimens collected from 26 EC patients (83.3%), including 21 with EEC (80.7%) and four with USC (100%). In the benign group, only one woman with focal atypical hyperplasia presented with a 10q chromosomal gain (P < 0.001). In the EC group, the most common CNVs were copy gains of 8q (N = 14), 2q (N = 4), and 10q (N = 3); and copy losses of 2q (N = 3) and 17p (N = 2). When we stratified by FIGO stage, the CNV rates in stages IA, IB, and II/III were 83.3% (15/18), 85.7% (6/7), and 80.0% (4/5), respectively. At the optimal cutoff (|Z| ≥ 2.3), UterCAD discriminated 83.3% of EC cases from benign cases, with a specificity of 92.9%. Conclusions: We initially reported that UterCAD could serve as a non-invasive method for the early detection of EC, especially in the rare and aggressive USC subtype. The use of UterCAD might thus avoid unnecessary invasive procedures and thereby reduce the treatment burden on patients.
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OBJECTIVE: Our study aims to evaluate programmed cell death ligand-1 (PD-L1) expression and its prognostic significance in cervical cancer (CC), endometrial cancer (EC) and ovarian cancer (OC). METHODS: Several electronic databases were searched. Fixed effects models or random effects models were employed to calculate the pooled prevalence of PD-L1 positivity and pooled hazard ratios (HRs) as appropriate. Heterogeneity and publication bias were also assessed. RESULTS: The pooled prevalence of PD-L1 positivity was 58.1%, 33.8% and 37.5% for CC, EC and OC patients, respectively. There were significant differences in the pooled estimates after stratification by PD-L1-positive assessment criteria and antibody clones. PD-L1 positivity was associated with worse OS in CC and EC patients and poorer progression-free survival (PFS) in CC patients. CONCLUSIONS: The prevalence of PD-L1-positive expression was considerably high in CC and modestly high in EC and OC patients. PD-L1 expression has the potential to be a prognostic biomarker for predicting the clinical outcomes of patients with CC and EC but not OC.
Subject(s)
Endometrial Neoplasms , Ovarian Neoplasms , Uterine Cervical Neoplasms , Female , Humans , Prognosis , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Prevalence , Proportional Hazards ModelsABSTRACT
OBJECTIVE: This study aimed to determine the prognostic significance of positive peritoneal cytology (PC) on endometrial carcinoma (EC) patients under the ESGO/ESTRO/ESP risk classification. METHODS: This study retrospectively analyzed EC patients from 27 medical centers in China from 2000 to 2019. Patients were divided into three ESGO risk groups: low-risk, intermediate-risk and high-intermediate risk, and high-risk groups. The covariates were balanced by using the propensity score-based inverse probability of treatment weighting (PS-IPTW). The prognostic significance of PC was assessed by Kaplan-Meier curves and multivariate Cox regression analysis. RESULTS: A total of 6313 EC patients with PC results were included and positive PC was reported in 384 women (6.1%). The multivariate Cox analysis in all patients showed the positive PC was significantly associated with decreased PFS (hazard ratio [HR] 2.20, 95% confidence interval [CI] 1.55-3.13, P < 0.001) and OS (HR 2.25, 95% CI 1.49-3.40, P < 0.001),and the Kaplan-Meier curves also showed a poor survival in the intermediate and high-intermediate risk group (5-year PFS: 75.5% vs. 93.0%, P < 0.001; 5-year OS: 78.3% vs. 96.4%, P < 0.001); While in the low-risk group, there were no significant differences in PFS and OS between different PC status (5-year PFS: 93.1% vs. 97.3%, P = 0.124; 5-year OS: 98.6% vs. 98.2%, P = 0.823); in the high-risk group, significant difference was only found in PFS (5-year PFS: 62.5% vs. 77.9%, P = 0.033). CONCLUSION: Positive PC was an adverse prognostic factor for EC, especially in the intermediate and high-intermediate risk patients. Gynecologic oncologists should reconsider the effect of positive PC on different ESGO risk groups.
Subject(s)
Cytology , Endometrial Neoplasms , Female , Humans , Prognosis , Retrospective Studies , Endometrial Neoplasms/pathology , Peritoneum/pathologyABSTRACT
Endometrial cancer (EC) ranks as the sixth most common malignancy in women around the world. Although lowgrade and earlystage EC commonly have an excellent prognosis, ~20% of EC patients experience an unfavorable prognosis. Identifying the pathogenesis and novel therapeutic targets may help address this group of patients. Noncoding (nc)RNAs, such as long noncoding RNAs (lncRNAs), microRNAs and circular RNAs (circRNAs), have been associated with EC occurrence and development. In addition, the aberrant activation of the Wnt/ßcatenin signaling pathway can promote the proliferation, invasion, migration and epithelialtomesenchymal transition (EMT) of EC cells. The network of ncRNAs has also been demonstrated to inhibit or activate the Wnt/ßcatenin signaling pathway. In the present review, ncRNAs, the Wnt/ßcatenin signaling pathway, and their crosstalk in EC were summarized and highlighted. This information is expected to provide novel insights into improving the management of EC using RNA as therapeutics.
Subject(s)
Endometrial Neoplasms , MicroRNAs , RNA, Long Noncoding , Humans , Female , Wnt Signaling Pathway/genetics , Cell Proliferation/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Endometrial Neoplasms/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Gene Expression Regulation, Neoplastic , Cell Line, Tumor , beta Catenin/genetics , beta Catenin/metabolismABSTRACT
Histone acetyltransferase human males absent on the first (hMOF) is a member of MYST family which participates in posttranslational chromatin modification by controlling the acetylation level of histone H4K16. Abnormal activity of hMOF occurs in multiple cancers and biological alteration of hMOF expression can affect diverse cellular functions including cell proliferation, cell cycle progression and embryonic stem cells (ESCs) self-renewal. The relationship between hMOF and cisplatin resistance was investigated in The Cancer Genome Atlas (TCGA) and Genomics of Drug Sensitivity in Cancer (GDSC) database. Lentiviral-mediated hMOF-overexpressed cells or hMOF-knockdown cells were established to investigate its role on cisplatin-based chemotherapy resistance in vitro ovarian cancer cells and animal models. Furthermore, a whole transcriptome analysis with RNA sequencing was used to explore the underlying molecular mechanism of hMOF affecting cisplatin-resistance in ovarian cancer. The data from TCGA analysis and IHC identification demonstrated that hMOF expression was closely associated with cisplatin-resistance in ovarian cancer. The expression of hMOF and cell stemness characteristics increased significantly in cisplatin-resistant OVCAR3/DDP cells. In the low hMOF expressing ovarian cancer OVCAR3 cells, overexpression of hMOF improved the stemness characteristics, inhibited cisplatin-induced apoptosis and mitochondrial membrane potential impairment, as well as reduced the sensitivity of OVCAR3 cells to cisplatin treatment. Moreover, overexpression of hMOF diminished tumor sensitivity to cisplatin in a mouse xenograft tumor model, accompanied by decrease in the proportion of cisplatin-induced apoptosis and alteration of mitochondrial apoptosis proteins. In addition, opposite phenotype and protein alterations were observed when knockdown of hMOF in the high hMOF expressing ovarian cancer A2780 cells. Transcriptomic profiling analysis and biological experimental verification orientated that MDM2-p53 apoptosis pathway was related to hMOF-modulated cisplatin resistance of OVCAR3 cells. Furthermore, hMOF reduced cisplatin-induced p53 accumulation by stabilizing MDM2 expression. Mechanistically, the increased stability of MDM2 was due to the inhibition of ubiquitinated degradation, which resulted by increased of MDM2 acetylation levels by its direct interaction with hMOF. Finally, genetic inhibition MDM2 could reverse hMOF-mediated cisplatin resistance in OVCAR3 cells with up-regulated hMOF expression. Meanwhile, treatment with adenovirus expressing shRNA of hMOF improved OVCAR3/DDP cell xenograft sensitivity to cisplatin in mouse. Collectively, the results of the study confirm that MDM2 as a novel non-histone substrate of hMOF, participates in promoting hMOF-modulated cisplatin chemoresistance in ovarian cancer cells. hMOF/MDM2 axis might be a potential target for the treatment of chemotherapy-resistant ovarian cancer.
ABSTRACT
INTRODUCTION: Proliferation, migration and invasion of extravillous trophoblasts (EVTs) play an important role in the progression of preeclampsia (PE). The purpose of this study was to investigate the molecular mechanism by which DNA methylase regulates the transcription level of APLNR and affects the phenotypic function of EVTs. MATERIALS AND METHODS: PE mice model and H/R model in HTR8/Svneo cells were constructed. Clinical samples of normal pregnant women and PE patients were collected. Expression and methylation level of APLNR in vivo and in vitro were detected. ChIP-qPCR was used to detect the binding of DNA methyltransferase at the APLNR promoter. The expression of DNA methyltransferase 1 (DNMT1), NO and eNOS in vitro were detected. EVTs proliferation, migration and invasion in vitro were detected. RESULTS: In placental tissues or HTR8/Svneo cells of the PE model group, the expression of APLNR was reduced and APLNR methylation level was up-regulated. There was no significant difference in the APLNR expression in placental tissues between normal pregnant women and PE patients. H/R conditions only promote the binding of DNMT1 at the APLNR promoter. DNMT1 interference decreased the enrichment degree of DNMT1 in APLNR promoter region and up-regulated the mRNA and protein levels of APLNR in vivo and in vitro. The activation of APLNR by Elabela (ELA) can promote eNOS transcription, thereby promoting cell proliferation and NO level, while eNOS inhibitor can reverse this effect. DNMT1 down-regulation inhibted APLNR methylation level, promoted eNOS transcription, and promoted EVTs proliferation, migration and invasion, which could be revised by the interference of APLNR. DISCUSSION: DNMT1 promotes eNOS transcription by inhibting APLNR methylation level, and promotes EVTs proliferation, migration and invasion, thus providing a new and broad application prospect for PE treatment.
Subject(s)
Placenta , Pre-Eclampsia , Animals , Female , Humans , Mice , Pregnancy , Apelin Receptors/genetics , Apelin Receptors/metabolism , Cell Movement/genetics , Cell Proliferation/genetics , DNA/metabolism , DNA Methylation , Methyltransferases/genetics , Placenta/metabolism , Pre-Eclampsia/metabolism , Trophoblasts/metabolismABSTRACT
Pyroptosis is one of the mechanisms of programmed cell death (PCD) activated by inflammasomes and involved by the caspase family and the gasdermin family. During the oncogenesis and progression of tumors, pyroptosis is crucial, and complex withal. Currently, pyroptosis is the focus topic in the research field of oncology, but there is no single bibliometric analysis systematically studying 'pyroptosis and cancer'. Our study aimed to visualize the research status of pyroptosis in oncology and excavate the hotspots and prospects in this field. Furthermore, in consideration of the professional direction of researchers, we particularly emphasized articles on pyroptosis in gynecology and formed a mini systematic review. This bibliometric work integrated and analyzed all articles from ISI Web of Science: Science Citation Index Expanded (SCI-Expanded) (dated April 25th, 2022), based on quantitative and visual mapping approaches. Systematically reviewing articles on pyroptosis in gynecology helped us complement our analysis of research advancements in this field. Including 634 articles, our study found that the number of articles on pyroptosis in cancer increased exponentially in recent years. These publications came from 45 countries and regions headed by China and the US mainly aiming at the mechanism of pyroptosis in cell biology and biochemistry molecular biology, as well as the role of pyroptosis in the development and therapeutic application of various cancers. The top 20 most cited studies on this topic mostly came from the US, followed by China and England, and half of the articles cited more than 100 times in total were published in Nature. Moreover, as for gynecologic cancer, in vitro and bioinformatics analysis were the main methodology conducting to explore roles of pyroptosis-related genes (PRGs) and formation of inflammasomes in cancer progression and prognosis. Pyroptosis has evolved into a burgeoning research field in oncology. The cellular and molecular pathway mechanism of pyroptosis, as well as the effect of pyroptosis in oncogenesis, progression, and treatment have been the hot topic of the current study and provided us the future direction as the potential opportunities and challenges. We advocate more active cooperation to improve therapeutic strategies for cancer.