Effect of different metastasis patterns on the prognosis of patients with stage III high-grade serous ovarian cancer.

To investigate the effect of different metastatic patterns of stage III high-grade serous ovarian cancer on the patient prognosis. The clinical data of 134 patients with Stage III, high-grade serous ovarian cancer diagnosed in The Affiliated Hospital of Qingdao University from January 2018 to April 2020 were retrospectively collected, and the patients were grouped according to metastasis mode. Patients with simple lymph node metastasis (SLNM) were included in the SLNM group, and patients with simple abdominal implantation alone and patients with abdominal metastasis combined with lymph node metastasis were all in the abdominal metastasis (AM) group. The prognosis of the two groups was analyzed. Of the 134 enrolled patients, complete datasets from 128 were successfully collected. There were 20 cases of SLNM (15.63%) and 108 cases of AM (84.37%). Initial CA125, initial HE4, and whether neoadjuvant chemotherapy was used were compared between the two groups (P < 0.05). According to the chemotherapy results, patients was divided into two groups: chemotherapy remission and uncontrolled, including 111 patients with chemotherapy remission and 17 patients with uncontrolled chemotherapy. According to the criteria of relapse after complete completion of chemotherapy and clinical remission, 91 cases relapsed, 20 cases did not relapse, of which 78 cases were platinum-sensitive, and 13 were platinum-resistant relapses. There were 4 recurrence cases in SLNM group (4.40%) and 87 recurrence cases (95.60%) in AM group (P < 0.05). The recurrence sites of 91 patients were analyzed, including 52 cases (57.14%) in the peritoneum, 11 cases (12.09%) in distant regions, 9 cases (9.89%) in lymph nodes, 19 cases (20.88%) in the peritoneum and lymph nodes. Significant differences were noted in the two groups' peritoneum, lymph node, and distance (P < 0.05). The two groups had significant differences in progression-free survival, overall survival, and 3-year survival (all P < 0.05). Initial HE4 levels, chemotherapy sensitivity, and SLNM are independent prognostic factors for Stage III high-grade serous ovarian cancer patients. Initial HE4 level < 233.7 pmol/l and chemotherapy sensitivity were protective factors, indicating a good prognosis. Patients in the SLNM group had lower initial CA125 and HE4 levels and higher survival rates. Initial HE4 levels and chemotherapy sensitivity are independent factors affecting prognosis in Stage III high-grade serous ovarian cancer patients.

Comprehensive analysis of novel prognosis-related proteomic signature effectively improve risk stratification and precision treatment for patients with cervical cancer.

OBJECTIVE: Cervical cancer (CC) is one of the most common types of malignant female cancer, and its incidence and mortality are not optimistic. Protein panels can be a powerful prognostic factor for many types of cancer. The purpose of our study was to investigate a proteomic panel to predict the survival of patients with common CC. METHODS AND RESULTS: The protein expression and clinicopathological data of CC were downloaded from The Cancer Proteome Atlas and The Cancer Genome Atlas database, respectively. We selected the prognosis-related proteins (PRPs) by univariate Cox regression analysis and found that the results of functional enrichment analysis were mainly related to apoptosis. We used Kaplan-Meier analysis and multivariable Cox regression analysis further to screen PRPs to establish a prognostic model, including BCL2, SMAD3, and 4EBP1-pT70. The signature was verified to be independent predictors of OS by Cox regression analysis and the area under curves. Nomogram and subgroup classification were established based on the signature to verify its clinical application. Furthermore, we looked for the co-expressed proteins of three-protein panel as potential prognostic proteins. CONCLUSION: A proteomic signature independently predicted OS of CC patients, and the predictive ability was better than the clinicopathological characteristics. This signature can help improve prediction for clinical outcome and provides new targets for CC treatment.

Radiomics nomogram for preoperative differentiation of early-stage serous borderline ovarian tumors and serous malignant ovarian tumors.

Objectives: This study aimed to construct a radiomics nomogram and validate its performance in the preoperative differentiation between early-stage (I and II) serous borderline ovarian tumors (SBOTs) and serous malignant ovarian tumors (SMOTs). Methods: Data were collected from 80 patients with early-stage SBOTs and 102 with early-stage SMOTs (training set: n = 127; validation set: n = 55). Univariate and multivariate analyses were performed to identify the independent clinicoradiological factors. A radiomics signature model was constructed using radiomics features extracted from multidetector computed tomography images of the venous phase, in which the least absolute shrinkage and selection operator regression was employed to lessen the dimensionality of the data and choose the radiomics features. A nomogram model was established by combining independent clinicoradiological factors with the radiomics signature. The performance of nomogram calibration, discrimination, and clinical usefulness was evaluated using training and validation sets. Results: In terms of clinicoradiological characteristics, age (p = 0.001), the diameter of the solid component (p = 0.009), and human epididymis protein 4 level (p < 0.001) were identified as the independent risk factors of SMOT, for which the area under the curves (AUCs) were calculated to be 0.850 and 0.836 in the training and validation sets, respectively. Nine features were finally selected to construct the radiomics signature model, which exhibited AUCs of 0.879 and 0.826 for the training and validation sets, respectively. The nomogram model demonstrated considerable calibration and discrimination with AUCs of 0.940 and 0.909 for the training and validation sets, respectively. The nomogram model displayed more prominent clinical usefulness than the clinicoradiological and radiomics signature models according to the decision curve analysis. Conclusions: The nomogram model can be employed as an individualized preoperative non-invasive tool for differentiating early-stage SBOTs from SMOTs.

MDCT-Based Radiomics Features for the Differentiation of Serous Borderline Ovarian Tumors and Serous Malignant Ovarian Tumors.

OBJECTIVE: To investigate whether multidetector computed tomography (MDCT)-based radiomics features can discriminate between serous borderline ovarian tumors (SBOTs) and serous malignant ovarian tumors (SMOTs). PATIENTS AND METHODS: Eighty patients with SBOTs and 102 patients with SMOTs, confirmed by pathology (training set: n = 127; validation set: n = 55) from December 2017 to June 2020, were enrolled in this study. The interclass correlation coefficient (ICC) and least absolute shrinkage and selection operator (LASSO) regression were applied to select radiomics parameters derived from MDCT images on the arterial phase (AP), venous phase (VP), and equilibrium phase (EP). Receiver operating characteristic (ROC) analysis of each selected parameter was carried out. Heat maps were created to illustrate the distribution of the radiomics parameters. Three models incorporating selected radiomics parameters generated by support vector machine (SVM) classifiers in each phase were analyzed by ROC and compared using the DeLong test. RESULTS: The most predictive features selected by ICC and LASSO regression between SBOTs and SMOTs included 9 radiomics parameters on AP, VP, and EP each. Three models on AP, VP, and EP incorporating the selected features generated by SVM classifiers produced AUCs of 0.80 (accuracy, 0.75; sensitivity, 0.74; specificity, 0.75), 0.86 (accuracy, 0.78; sensitivity, 0.80; specificity, 0.75), and 0.73 (accuracy, 0.69; sensitivity, 0.71; specificity, 0.67), respectively. There were no significant differences in the AUCs among the three models (AP vs. VP, P = 0.199; AP vs. EP, P = 0.260; VP vs. EP, P = 0.793). CONCLUSION: MDCT-based radiomics features could be used as biomarkers for the differentiation of SBOTs and SMOTs.

Knockdown of MIR4435-2HG Suppresses the Proliferation, Migration and Invasion of Cervical Cancer Cells via Regulating the miR-128-3p/MSI2 Axis in vitro.

PURPOSE: Long non-coding RNAs (lncRNAs) play major roles in the development of several cancers, including cervical cancer (CC). The purpose of the present study is to explore the regulatory mechanism of MIR4435-2HG on CC in vitro. PATIENTS AND METHODS: Fifty-nine pairs of CC tissues and adjacent normal tissues were collected from 59 patients by resection. The expression of lncRNA MIR4435-2HG, microRNA (miR)-128-3p and Musashi 2 (MSI2) in CC tissues and cells was detected by quantitative reverse-transcription PCR (qRT-PCR). The viability of CC cells was detected by 3-(4, 5-Dimethyl-2-Thiazolyl)-2, 5-Diphenyl-2-H-Tetrazolium Bromide (MTT) assay. The ability of migration and invasion in CC cells was measured by wound healing assay and transwell invasion assay, respectively. Starbase software and Targetscan software were utilized to predict the relationship between miR-128 and MIR4435-2HG/MSI2, respectively. The dual-luciferase reporter assay was used to confirm these interactions. RESULTS: LncRNA MIR4435-2HG expression was significantly up-regulated in CC tissues (P < 0.001) and cells (P < 0.01). Knockdown of MIR4435-2HG inhibited the proliferation, migration and invasion of CC cells (P < 0.01). MiR-128-3p was a target of MIR4435-2HG and was negatively modulated by MIR4435-2HG (P < 0.0001, r = -0.6331). Up-regulation of miR-128-3p suppressed the proliferation, migration and invasion of CC cells (P < 0.01). In addition, MSI2 was the target gene of miR-128-3p and negatively regulated by miR-128-3p (P < 0.0001, r = -0.4775). Both down-regulation of miR-128-3p and up-regulation of MSI2 reversed the inhibitory effects of MIR4435-2HG knockdown on the proliferation, migration and invasion of CC cells (P < 0.05). CONCLUSION: MIR4435-2HG knockdown suppresses the proliferation, migration and invasion of CC cells through regulating the miR-128-3p/MSI2 axis, providing a possible therapeutic strategy for CC.

Evaluation of Ovarian Tumors with Multidetector Computed Tomography and Tumor Markers: Differentiation of Stage I Serous Borderline Tumors and Stage I Serous Malignant Tumors Presenting as Solid-Cystic Mass.

BACKGROUND The aim of this study was to determine multidetector computed tomography (MDCT) features and tumor markers for differentiating stage I serous borderline ovarian tumors (SBOTs) from stage I serous malignant ovarian tumors (SMOTs). MATERIAL AND METHODS In total, 48 patients with stage I SBOTs and 54 patients with stage I SMOTs who underwent MDCT and tumor markers analysis were analyzed. MDCT features included location, shape, margins, texture, papillary projections, vascular abnormalities, size, and attenuation value. Tumor markers included serum cancer antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and human epididymis protein 4 (HE4). Parameters of clinical characteristic, MDCT features, and tumor markers were compared using a chi-square test and Mann-Whitney U tests. A binary logistic regression analysis was performed to detect predictors for SMOTs. A receiver operating characteristic (ROC) curve analysis was used to assess the potential diagnostic value of the quantitative parameters. Kappa and intraclass correlation coefficients were used to evaluate interobserver reproducibility for MDCT features. RESULTS Median ages between patients with SBOTs and SMOTs were significantly different. Compared with SBOTs, vascular abnormalities were significantly more common in SMOTs. CA125, HE4, the maximum thickness of the wall, the maximum thickness of the septa, and the maximum diameter of the solid portions were significantly higher in patients with SMOTs. A binary logistic regression analysis revealed that age, vascular abnormalities, and the maximum diameter of the solid portion were independent factors of SMOTs. ROC analysis was used to assess the potential diagnostic value for predicting SMOTs. Moderate or good interobserver reproducibility for MDCT features were identified. CONCLUSIONS Age, vascular abnormalities, and the maximum diameter of the solid portion were independent factors for differentiating SBOTs from SMOTs. The combined analysis of age, vascular abnormalities, and the maximum diameter of the solid portion may allow better differentiation between SBOTs and SMOTs.

SiRNA-Mediated RRM2 Gene Silencing Combined with Cisplatin in the Treatment of Epithelial Ovarian Cancer In Vivo: An Experimental Study of Nude Mice.

Introduction: We aimed to explore small interfering (si)RNA silencing of ribonucleotide reductase M2 (RRM2) gene combined with cisplatin for the treatment of human ovarian cancer in nude mice models of subcutaneous transplantation of tumor cells. Methods: After conventional cultivation of human ovarian cancer cell line SKOV3 in vitro, SKOV3 cells were injected into the right back of nude mice by subcutaneous injection to establish the subcutaneous tumor models. Twenty-four tumor-burdened rats were randomly divided into four groups (n=6): siRNA group, siRNA in combination with cisplatin group, cisplatin group, and control group. Intraperitoneal injection of cisplatin and subcutaneous injection of siRNA were performed weekly. Tumor volume was measured, and tumor growth inhibition rate was calculated. RRM2 expression at the mRNA and protein levels was detected by reverse transcription-polymerase chain reaction and immunohistochemistry. Results: In the siRNA group, the tumor volume and tumor growth inhibition rate were 249.60±20.46 mm³ and 36.39%, respectively. The tumor growth inhibition rate and tumor volume were significantly different between the siRNA and control groups (p<0.05). In the cisplatin group, the tumor volume and tumor growth inhibition rate were 249.86±12.46 mm³ and 41.10%, respectively. The tumor growth inhibition rate and tumor volume were significantly different between the cisplatin and control groups (p<0.05). In the siRNA + cisplatin group, the tumor volume reduced to 180.84±16.25 mm³ and the tumor growth inhibition rate was increased to 64.33%, which were significantly different compared with the control group (p<0.01). Significant downregulation of RRM2 mRNA and protein expression in the tumor tissues was detected by reverse transcription polymerase chain reaction and immunohistochemistry assay (p<0.05). Discussion: siRNA alone or combined with cisplatin can effectively inhibit the growth of human ovarian cancer in nude mice models of subcutaneous transplantation of tumor cells. RRM2 gene silencing may be a potential treatment regimen for ovarian cancer in future.

Long non­coding RNA plasmacytoma variant translocation 1 gene promotes the development of cervical cancer via the NF­κB pathway.

The long noncoding RNA plasmacytoma variant translocation 1 gene (LncRNA PVT1) has an important role in tumor occurrence and development, yet the role and underlying molecular mechanisms of this RNA in cervical cancer have not yet been elucidated. In the present study, three cervical cancer cell lines (HeLa, Ca Ski and SiHa) were used to verify how LncRNA PVT1 mediates cervical cancer development, and the H8 cell line was used as a control. A LncRNA PVT1 overexpression vector or small interfering RNAs targeting LncRNA PVT1 were transfected into cervical cancer cells to generate LncRNA PVT1 overexpression and silencing in these cells. LncRNA PVT1 overexpression accelerated the growth of cervical cancer cells by advancing the cell cycle and inhibiting cellular apoptosis; increases in Cyclin D1 (CCND1) mRNA and activated Bcl­2 protein expression levels also supported this finding. Furthermore, NF­κB activation and expression was increased by LncRNA PVT1 overexpression. In addition, NF­κB activation or inhibition induced changes in cell viability, accompanied by changes in CCND1 and Bcl­2 expression. Increases or decreases in microRNA­16 (miR­16) expression (using miR mimics and inhibitors) also corresponded to changes in LncRNA PVT1 expression, in vitro. miR­16 mimics and inhibitor had opposite effects to those of NF­κB activity, and miR­16 was demonstrated to directly interact with the NF­κB gene as measured using the dual­luciferase assay. In summary, LncRNA PVT1 inhibits the effect of miR­16, promoting the cell cycle and inhibiting cellular apoptosis of cervical cancer cells, potentially via the NF­κB pathway. The data from the present study will contribute to the current knowledge surrounding the theoretical basis of cervical cancer and provide a new perspective for the treatment of cervical cancer.

Expression of microRNA-145, OCT4, and SOX2 in double primary endometrioid endometrial and ovarian carcinomas.

Double primary endometrioid endometrial and ovarian carcinomas (DPEEOCs) are the most common multiple gynecological carcinomas. In recent years, gene sequential comparison analysis has strongly supported the opinion that sporadic double endometrioid endometrial and ovarian cancers (DEEOCs) are clonally related in both primary and metastatic tumors. In order to find more clonal evidence for DPEEOC, we investigated cancer stem cells (CSCs). SOX2 and OCT4 are two common factors in CSCs. MicroRNA (miRNA)-145, a small non-coding RNA, has effects in regulating gene expression and tumorigenesis in CSCs. The aim of this study was to assess the involvements of SOX2, OCT4, and miRNA-145 in the tumorigenesis of DPEEOCs. In our study, twenty DPEEOC patients were chosen. Metastatic DEEOCs and normal endometrial and ovarian tissues were also included. The expression of miRNA-145 was detected by real-time quantitative PCR. Immunohistochemical staining was used to measure the expression of OCT4 and SOX2. The results showed that miRNA-145 expression was lower in DPEEOC endometrial tissues and higher in DPEEOC ovarian tissues compared to the corresponding normal tissues. Both SOX2 and OCT4 were over-expressed in cancer tissues compared with that in normal tissues. MiRNA-145, SOX2, and OCT4 were expressed at similar levels in two cancer sites of a given DPEEOC or metastatic DEEOC sample. Besides, metastatic DEEOC sections expressed a higher level of SOX2 and OCT4 compared to the corresponding DPEEOC tissues. Together, these results support the clonality of DPEEOCs. Moreover, SOX2 and OCT4 may have some implication in DPEEOC and metastatic DEEOC diagnosis.

Effects of neoadjuvant chemotherapy on patients with primary vaginal squamous cell carcinoma.

Vaginal cancer is a rare gynecological malignancy, mainly treated by radiotherapy and surgery. However, the effect of neoadjuvant chemotherapy on patients with vaginal cancer has not been extensively evaluated. The aim of the present study was to assess the feasibility and efficacy of irinotecan and cisplatin in the management of patients with vaginal squamous cell cancer (SCC). Two patients with International Federation of Obstetrics and Gynecology (FIGO) stage I and one patient with FIGO stage II vaginal SCC were treated with irinotecan (240 mg) and cisplatin (100 mg) every 3-4 weeks. The effect of chemotherapy after 2-4 courses was assessed and the next step of treatment was determined according to the outcome. In the present study, all 3 patients had complete remission after 2-4 courses of chemotherapy. In case 1, the patient received a total of 6 courses of chemotherapy and had no recurrence after 45 months of follow-up. In case 2, the patient received 4 courses of chemotherapy and partial vaginal resection, and had no recurrence after 48 months of follow-up. In case 3, the patient underwent laparoscopic radical surgery and peritoneal vaginoplasty after 2 courses of chemotherapy, and no residual tumors were identified in the resected tissues on postoperative pathological examination. Effective neoadjuvant chemotherapy may decrease the size of the tumor, induce tumor regression, or even achieve pathologically-confirmed complete tumor eradication. Thus, neoadjuvant chemotherapy with irinotecan combined with cisplatin is a feasible treatment for patients with early-stage vaginal SCC. In the present study, all the patients achieved good therapeutic results following chemotherapy.

MicroRNA-186 induces sensitivity of ovarian cancer cells to paclitaxel and cisplatin by targeting ABCB1.

BACKGROUND: Recent studies have shown that microRNAs may regulate the ABCB1 gene (ATP-binding cassette, sub-family B [MDR/TAP], member 1). Computational programs have predicted that the 3'-untranslated region (3'-UTR) of ABCB1 contains a potential miRNA-binding site for miR-186. Here, we investigated the role of miR-186 in sensitizing ovarian cancer cells to paclitaxel and cisplatin. RESULTS: Human ovarian carcinoma cell lines OVCAR3, A2780, A2780/DDP, and A2780/Taxol were exposed to paclitaxel or cisplatin with or without miR-186 transfection, and cell viability was determined by MTT assay. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis were used to assess the MDR1, GST-π, and MRP1 expression levels. Dual-luciferase reporter assay was used to reveal the correlation between miR-186 and ABCB1. Lower miR-186 while higher MDR1 and GST-π mRNA expression levels were found in the A2780/Taxol and A2780/DDP cells than in the A2780 cells. After miR-186 transfection, all the cell lines showed increased sensitivity to paclitaxel and cisplatin. MiR-186 transfection induced apoptosis while anti-miR-186 transfection reduced apoptosis. The dual-luciferase reporter assay verified that that miR-186 combined with the 3'-untranslated region (UTR) of ABCB1. MDR1 and GST-π mRNA and protein expression levels were downregulated after transfection with miR-186 but upregulated following anti-miR-186 transfection compared to the mock and negative control cancer cells; however, the MRP1 expression levels did not significantly differ among the groups. CONCLUSION: Our results are the first to demonstrate that miR-186 may sensitize ovarian cancer cell to paclitaxel and cisplatin by targeting ABCB1 and modulating the expression of GST-π.

MicroRNA-133b targets glutathione S-transferase π expression to increase ovarian cancer cell sensitivity to chemotherapy drugs.

BACKGROUND: Accumulating studies reveal that aberrant microRNA (miRNA) expression can affect the development of chemotherapy drug resistance by modulating the expression of relevant target proteins. The aim of this study was to investigate the role of miR-133b in the development of drug resistance in ovarian cancer cells. METHODS: We examined the levels of miR-133b expression in ovarian carcinoma tissues and the human ovarian carcinoma cell lines (A2780, A2780/DDP and A2780/Taxol, respectively). We determined the cell viability of these cell lines treated with cisplatin or paclitaxel in the presence or absence of miR-133b or anti-miR-133b transfection using the MTT assay. Reverse transcription polymerase chain reaction and Western blotting were used to assess the mRNA and protein expression levels of two drug-resistance-related genes: glutathione S-transferase (GST)-π and multidrug resistance protein 1 (MDR1). The dual-luciferase reporter assay was used to detect the promoter activity of GST-π in the presence and absence of miR-133b. RESULTS: The expression of miR-133b was significantly lower in primary resistant ovarian carcinomas than in the chemotherapy-sensitive carcinomas (P<0.05), and the same results were found in primary resistant ovarian cell lines (A2780/Taxol and A2780/DDP) compared to the chemotherapy-sensitive cell line (A2780; P<0.05). Following miR-133b transfection, four cell lines showed increased sensitivity to paclitaxel and cisplatin, while anti-miR-133b transfection reduced cell sensitivity to paclitaxel and cisplatin. Dual-luciferase reporter assay showed that miR-133b interacted with the 3'-untranslated region of GST-π. Compared to controls, the mRNA and protein levels of MDR1 and GST-π were downregulated after miR-133b transfection and upregulated after anti-miR-133b transfection. CONCLUSION: MicroRNA-133b may reduce ovarian cancer drug resistance by silencing the expression of the drug-resistance-related proteins, GST-π and MDR1. In future, the combination of miR-133b with chemotherapy agents may prevent the development of drug resistance in ovarian cancers.

Tanshinone IIA acts via p38 MAPK to induce apoptosis and the down-regulation of ERCC1 and lung-resistance protein in cisplatin-resistant ovarian cancer cells.

Tanshinone IIA is known to induce apoptosis in several types of cancer cells. However, little is known about its activity in chemoresistant cells. The aim of this study was to investigate the anticancer properties of tanshinone IIA in cisplatin-resistant human ovarian cancer COC1/DDP cells in vitro. We used a variety of methods to measure cell viability, the resistance index (RI) of cisplatin, cellular apoptosis, p38 mitogen-activated protein kinase (MAPK) expression and phosphorylation, and the mRNA expression of several genes implicated in drug resistance including survivin, Caspase-3, excision repair cross-complementing gene 1 (ERCC1), multidrug resistance (MDR), lung resistance protein (LRP) and glutathione-S-transferase-π (GST-π). We found that tanshinone IIA time- and dose-dependently inhibited the proliferation of COC1/DDP cells and caused significant apoptosis. Western blotting revealed that tanshinone IIA also increased phospho-p38 MAPK in a time- and dose-dependent manner. After treatment by tanshinone IIA for 48 h, the RI of cisplatin and the mRNA expression of survivin, ERCC1 and LRP were all significantly decreased. Furthermore, blockade of p38 signal transduction decreased apoptotic cell rates and dramatically elevated the mRNA expression of the survivin, ERCC1 and LRP genes. We therefore conclude that tanshinone IIA induces apoptosis and reduces cisplatin resistance in COC1/DDP cells and thus causes significant growth inhibitory effects. This mechanism appears to involve p38-mediated downregulation of survivin, ERCC1 and LRP mRNA expression.