BACKGROUND:It remains unclear whether the tumor mutation burden (TMB) or a TMB-related signature could be prognostic indicators in ovarian cancer (OC), as potential correlations with immune infiltrates and immunotherapy responsiveness remains poorly understood.METHODS:Data of 941 OC patients were collected from three datasets, including 587, 260, and 94 patients from The Cancer Genome Atlas (TCGA), GSE32062, and the International Cancer Genome Consortium (ICGC), respectively. TMB was calculated and correlations with clinical outcomes, immune infiltrates, and immunotherapy responsiveness were investigated in the TCGA OC cohort. Weighted gene co-expression network analysis was performed to identify TMB-related genes. A TMB-related signature was constructed and validated.RESULTS:Higher TMB was associated with better survival in the TCGA and ICGC OC cohorts. The high-TMB group had higher CD8+ T-cell infiltration than the low-TMB group. No significant correlation was found between TMB and immunotherapy response. Furthermore, we selected 8 prognostic and TMB-related genes to construct a TMB-related signature that could distinguish between the high- and low-risk patients; its predictive power was validated in the GSE32062 and ICGC datasets. SubMap analysis suggested that patients in the low-risk group might have a better response to anti-PD1 therapy.CONCLUSIONS:We examined the prognostic value of TMB and its potential association with immune cell infiltration and immunotherapy responsiveness in OC. A TMB-related prognostic signature consisting of 8 genes was developed and verified, which might be a promising prognostic signature for the prognosis of OC patients.

Propranolol has a significant anti-cancer effect towards various cancers. Our study aimed at investigating the underlying mechanism of Propranolol's therapeutic effect towards ovarian cancer. Specifically, Propranolol significantly reduced the viability of human ovarian cancer cell lines SKOV-3 and A2780 in a dose- and time-dependent manner. Flow cytometry analysis revealed that Propranolol induced the cell cycle arrest at G2/M phase therefore leading to apoptosis. Moreover, autophagy inhibitor 3-MA markedly enhanced the Propranolol-induced apoptosis. In addition, reactive oxygen species (ROS) increased dramatically after Propranolol treatment and Propranolol activated the phosphorylation of JNK. What is more, p38 inhibitor SB203580 and JNK inhibitor SP600125 attenuated the upregulated expression of LC3-II and cleaved-caspase-3 by the effect of Propranolol. ROS exclusive inhibitor antioxidant N-acetyl cysteine (NAC) weakens the phosphorylation of JNK proteins induced by Propranolol. In summary, these results suggested that Propranolol induced cell apoptosis and protective autophagy through the ROS/JNK signaling pathway in human ovarian cancer cells.

Abstract Background: Propranolol has a significant anti-cancer effect on various cancers. The present study aimed to investigate the underlying mechanism behind the therapeutic effect of Propranolol on the ovarian cancer.Materials and methods: The effect of Propranolol on cell viability was examined by MTT analysis. Cellular apoptosis was evaluated by flow cytometry analysis. Autophagy was defined by autophagosome observed by confocal microscopy after infected with GFP-LC3 adenovirus. In addition, the expression of marker proteins involved in cell apoptosis, autophagy, and ROS/JNK signaling pathway were estimated by Western Blotting assay.Results: Propranolol significantly reduced the viability of human ovarian cancer cell lines SKOV-3 and A2780 in a dose- and time-dependent manner. Flow cytometry analysis revealed that Propranolol induced the cell cycle arrest at G2/M phase and resulted in apoptosis. Moreover, autophagy inhibitor 3-MA markedly enhanced the Propranolol-induced apoptosis. In addition, reactive oxygen species (ROS) was demonstrated dramatically increased after Propranolol treatment and Propranolol activated the phosphorylation of JNK. What is more, p38 inhibitor SB203580 and JNK inhibitor SP600125 attenuated the upregulated expression of LC3-II and cleaved-caspase-3 by the effect of Propranolol. ROS exclusive inhibitor antioxidant N-acetyl cysteine (NAC) weaken the phosphorylation of JNK proteins induced by Propranolol.Conclusions：In summary, our results suggested that Propranolol induced cell apoptosis and protective autophagy through the ROS/JNK signaling pathway in human ovarian cancer cells.

Background: Ovarian cancer (OC) is a disease characterized by late-stage presentation and poor prognosis. Our aim was to identify a DNA methylation signature for predicting progression-free survival (PFS) of patients with advanced-stage OC. Methods: A bioinformatics analysis was performed to identify methylation sites that are relevant to PFS and develop a DNA methylation signature. A total of 501 patients with advanced-stage OC who were identified from the Cancer Genome Atlas (TCGA) were enrolled as a training cohort, and 108 patients with advanced-stage OC from GSE65820 were used as a validation cohort. Results: A DNA methylation signature was constructed on the basis of five methylation sites. We found that patients with OC in the training and validation cohorts could be stratified, based on the DNA methylation signature, into high- and low-risk groups with distinct prognosis. Different cancer-related pathways were enriched between these two groups. Finally, a nomogram that integrated the methylation signature risk score and clinical stage was established, and the nomogram performed well. Conclusions: The DNA methylation signature provides a promising prognostic biomarker for patients with advanced-stage OC and may help to optimize clinical management.

PURPOSE/AIM OF THE STUDY:Colposcopy-directed cervical biopsy has played a major role in diagnosing cervical lesions. The precision of colposcopy-guided biopsy has been questioned. We analyzed several factors that may be correlated with the accuracy of biopsy. METHODS:PubMed, EMBASE were searched from January 1, 1998 to March 1, 2020. Odds ratio with 95% confidence intervals (CIs) were calculated. SELECTION CRITERIA:Included studies evaluated factors correlated with the accuracy of biopsy and patients' final diagnosis was established by histological examination of the specimen obtained by conization, loop electrosurgical excision procedure (LEEP), or colpohysterectomy. RESULTS:A total of 10 studies were selected for the systematic review and meta-analysis. The pooled analysis indicated that the diagnostic inaccuracies of colposcopy-directed cervical biopsy were magnified in women who were 50 years of age or older. Postmenopausal status and transformation zone 3 type were also associated with the diagnostic inaccuracies of colposcopy-directed biopsy. High-grade squamous intraepithelial lesions had better concordance rates than low-grade squamous intraepithelial lesions. The number of vaginal deliveries, number of biopsies, and HPV type were associated with biopsy underdiagnosis and biopsy overestimation. CONCLUSIONS:This meta-analysis found that the correlation between the histological findings at biopsy and after surgical treatment was influenced by women's age, menopausal status, and the transformation zone type. The diagnostic efficacy was also better for high-grade squamous intraepithelial lesions than for low-grade squamous intraepithelial lesions. Further large-scale randomized clinical trials are required to analyze the factors correlated with biopsy underdiagnosis and biopsy overestimation.

Background: A growing number of studies have identified that circular RNAs (circRNAs) play a vital role in the progression of various tumors. However, the underlying functions and mechanisms of circRNAs in cervical cancer have not been clarified. Methods: qRT-PCR was used to detect the level of circGSE1 in cervical cancer tissues and matched normal tissues. In vitro cell wound healing, transwell migration and invasion assays were employed to assess the effects of circGSE1 on cell mobility. The pull-down, luciferase reporter, RIP and rescue assays were performed to evaluate the interaction between circGSE1and miR-138-5p and the regulation of miR-138-5p on Vimentin. Results: We found that circGSE1 was significantly higher in cervical cancer tissues than that in matched normal tissues. Further analyses revealed that the level of circGSE1 was positively correlated with tumor differentiation, FIGUREO stage, depth of stromal invasion, lymph node metastasis and infiltration of parauterine organ. Kaplan-Meier survival analysis showed that high circGSE1 predicted worse overall survival and disease-free survival. Down-regulated circGSE1 evidently inhibited cell migration and metastasis of cervical cancer, while up-regulated circGSE1 significantly promoted cell migration and metastasis. The pull-down, luciferase reporter and RIP assays revealed that circGSE1 directly bound to and sponge miR-138-5p. MiR-138-5p inhibited the expression of Vimentin through directly binding to 3'UTR of Vimentin mRNA. In addition, miR-138-5p suppressed cell migration and invasion through inhibiting Vimentin expression, and circGSE1 promoted cell migration and invasion through sponging miR-138-5p and enhancing Vimentin expression. Conclusion: CircGSE1 promotes the progression and may act as a novel diagnostic biomarker for disease progression of cervical cancer.

As a new class of non-coding RNA, circular RNAs (circRNAs) play crucial roles in the development and progression of various cancers. However, the detailed functions of circRNAs in cervical cancer have seldom been reported. In this study, circRNA sequence was applied to detect the differentially expressed circRNAs between cervical cancer tissues and adjacent normal tissues. The relationships between circCLK3 level with clinicopathological characteristics and prognosis were analyzed. In vitro CCK-8, cell count, cell colony, cell wound healing, transwell migration and invasion, and in vivo tumorigenesis and lung metastasis models were performed to evaluate the functions of circCLK3. The pull-down, RNA immunoprecipitation (RIP), luciferase reporter and rescue assays were employed to clarify the interaction between circCLK3 and miR-320a and the regulation of miR-320a on FoxM1. We found that the level of circCLK3 was remarkably higher in cervical cancer tissues than in adjacent normal tissues, and closely associated with tumor differentiation, FIGO stage and depth of stromal invasion. Down-regulated circCLK3 evidently inhibited cell growth and metastasis of cervical cancer in vitro and in vivo, while up-regulated circCLK3 significantly promoted cell growth and metastasis in vitro and in vivo. The pull-down, luciferase reporter and RIP assays demonstrated that circCLK3 directly bound to and sponge miR-320a. MiR-320a suppressed the expression of FoxM1 through directly binding to 3′UTR of FoxM1 mRNA. In addition, FoxM1 promoted cell proliferation, migration, and invasion of cervical cancer, while miR-320a suppressed cell proliferation, migration, and invasion through suppressing FoxM1, and circCLK3 enhanced cell proliferation, migration and invasion through sponging miR-320a and promoting FoxM1 expression. In summary, circCLK3 may serve as a novel diagnostic biomarker for disease progression and a promising molecular target for early diagnoses and treatments of cervical cancer.

目的:检测宫颈浸润癌(ICC)和宫颈上皮内瘤变(CIN)中Annexin A2、细胞核因子(NF-κBp65)蛋白的表达,探讨两者在ICC和CIN组织中表达的意义.方法:用免疫组化SP法检测74例ICC、24例CIN及15例正常宫颈上皮中Annexin A2、NF-κBp65蛋白的表达,并分析它与临床病理特征的关系.结果:(1)Annexin A2、NF-κBp65在ICC阳性表达率(71.6%,74.3%)均显著高于CIN(37.5%,33.3%)(P＜0.05)和正常宫颈上皮(13.3%,20%)组(P＜0.05);(2)低分化癌组织中Annexin A2的阳性表达显著高于中、高分化癌组织(P＜0.05),且其表达与年龄、组织类型、病理分级和淋巴结转移呈正相关(P＜0.05).NF-κBp65表达与淋巴结转移呈正相关(P＜0.05);(3)ICC中Annexin A2、NF-κBp65的表达呈正相关(r=0.339,P＜0.05).结论:Annexin A2在宫颈癌中可能充当癌基因的角色;Annexin A2表达可作为诊断宫颈癌的辅助指标;Annexin A2、NF-κBp65可能在宫颈癌的发生发展中起重要作用.