The splicing factor WBP11 mediates MCM7 intron retention to promote the malignant progression of ovarian cancer.

Accumulating studies suggest that splicing factors play important roles in many diseases including human cancers. Our study revealed that WBP11, a core splicing factor, is highly expressed in ovarian cancer (OC) tissues and associated with a poor prognosis. WBP11 inhibition significantly impaired the proliferation and mobility of ovarian cancer cells in vitro and in vivo. Furthermore, FOXM1 transcriptionally activated WBP11 expression by directly binding to its promoter in OC cells. Importantly, RNA-seq and alternative splicing event analysis revealed that WBP11 silencing decreased the expression of MCM7 by regulating intron 4 retention. MCM7 inhibition attenuated the increase in malignant behaviors of WBP11-overexpressing OC cells. Overall, WBP11 was identified as an oncogenic splicing factor that contributes to malignant progression by repressing intron 4 retention of MCM7 in OC cells. Thus, WBP11 is an oncogenic splicing factor with potential therapeutic and prognostic implications in OC.

STING inhibitors sensitize platinum chemotherapy in ovarian cancer by inhibiting the CGAS-STING pathway in cancer-associated fibroblasts (CAFs).

Chemotherapy resistance in ovarian cancer hampers cure rates, with cancer-associated fibroblasts (CAFs) playing a pivotal role. Despite their known impact on cancer progression and chemotherapy resistance, the specific mechanism by which CAFs regulate the tumor inflammatory environment remains unclear. This study reveals that cisplatin facilitates DNA transfer from ovarian cancer cells to CAFs, activating the CGAS-STING-IFNB1 pathway in CAFs and promoting IFNB1 release. Consequently, this reinforces cancer cell resistance to platinum drugs. High STING expression in the tumor stroma was associated with a poor prognosis, while inhibiting STING expression enhanced ovarian cancer sensitivity. Understanding the relevance of the CGAS-STING pathway in CAFs for platinum resistance suggests targeting STING as a promising combination therapy for ovarian cancer, providing potential avenues for improved treatment outcomes.

Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer.

Ovarian cancer is resistant to immune checkpoint blockade (ICB) treatment. Combination of targeted therapy and immunotherapy is a promising strategy for ovarian cancer treatment benefit from an improved immune microenvironment. In this study, Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) cohorts were used to screen prognosis and cytotoxic lymphocyte infiltration-associated genes in upregulated genes of ovarian cancer, tissue microarrays were built for further verification. In vitro experiments and mouse (C57/BL6) ovarian tumor (ID8) models were built to evaluate the synergistic effect of the combination of SF3B1 inhibitor and PD-L1 antibody in the treatment of ovarian cancer. The results show that SF3B1 is shown to be overexpressed and related to low cytotoxic immune cell infiltration in ovarian cancer. Inhibition of SF3B1 induces pyroptosis in ovarian cancer cells and releases mitochondrial DNA (mtDNA), which is englobed by macrophages and subsequently activates them (polarization to M1). Moreover, pladienolide B increases cytotoxic immune cell infiltration in the ID8 mouse model as a SF3B1 inhibitor and increases the expression of PD-L1 which can enhance the antitumor effect of αPDL1 in ovarian cancer. The data suggests that inhibition of SF3B1 improves the immune microenvironment of ovarian cancer and synergizes ICB immunotherapy, which provides preclinical evidence for the combination of SF3B1 inhibitor and ICB to ovarian cancer treatment.

Radiomics-based fertility-sparing treatment in endometrial carcinoma: a review.

In recent years, with the increasing incidence of endometrial carcinoma in women of child-bearing age, to decision of whether to preserve patients' fertility during treatment has become increasingly complex, presenting a formidable challenge for both physicians and patients. Non-fertility-sparing treatment can remove lesions more thoroughly than fertility-sparing treatment. However, patients will permanently lose their fertility. In contrast, fertility-sparing treatment can treat tumors without impairing fertility, but the risk of disease progression is high as compared with non-fertility-sparing treatment. Therefore, it is extremely important to accurately identify patients who are suitable for fertility-sparing treatments. The evaluation of prognostic factors, including myometrial invasion, the presence of lymph node metastases, and histopathological type, is vital for determining whether a patient can receive fertility-sparing treatment. As a non-invasive and quantitative approach, radiomics has the potential to assist radiologists and other clinicians in determining more precise judgments with regard to the above factors by extracting imaging features and establishing predictive models. In this review, we summarized currently available fertility-sparing strategies and reviewed the performance of radiomics in predicting risk factors associated with fertility-sparing treatment. This review aims to assist clinicians in identifying patients suitable for fertility-sparing treatment more accurately and comprehensively and informs more appropriate and rigorous treatment decisions for endometrial cancer patients of child-bearing age.Critical relevance statement: Radiomics is a promising tool that may assist clinicians identify risk factors about fertility-sparing more accurately and comprehensively.

The splicing factor SNRPB promotes ovarian cancer progression through regulating aberrant exon skipping of POLA1 and BRCA2.

Splicing factors play a crucial role in the initiation and development of various human cancers. SNRPB, a core spliceosome component, regulates pre-mRNA alternative splicing. However, its function and underlying mechanism in ovarian cancer remain unclear. This study identified SNRPB as a critical driver of ovarian cancer through TCGA and CPTAC database analysis. SNRPB was highly upregulated in fresh frozen ovarian cancer tissues compared with normal fallopian tubes. Immunohistochemistry revealed that SNRPB expression was increased in formalin-fixed, paraffin-embedded ovarian cancer sections and was positively correlated with a poor prognosis for ovarian cancer. Functionally, SNRPB knockdown suppressed ovarian cancer cell proliferation and invasion, and overexpression exerted opposite effects. SNRPB expression increased after cisplatin treatment, and silencing SNRPB sensitized ovarian cancer cells to cisplatin. KEGG pathway analysis revealed that the differentially expressed genes (DEGs) were mainly enriched in DNA replication and homologous recombination, and almost all DEGs related to DNA replication and homologous recombination were downregulated after SNRPB knockdown according to RNA-seq. Exon 3 skipping of the DEGs DNA polymerase alpha 1 (POLA1) and BRCA2 was induced by SNRPB silencing. Exon 3 skipping of POLA1 yielded premature termination codons and led to nonsense-mediated RNA decay (NMD); exon 3 skipping of BRCA2 led to loss of the PALB2 binding domain, which is necessary for homologous recombination, and increased ovarian cancer cell cisplatin sensitivity. POLA1 or BRCA2 knockdown partially impaired the increased malignancy of SNRPB-overexpressing ovarian cancer cells. Moreover, miR-654-5p was found to reduce SNRPB mRNA expression by directly binding to the SNRPB 3'-UTR. Overall, SNRPB was identified as an important oncogenic driver that promotes ovarian cancer progression by repressing exon 3 skipping of POLA1 and BRCA2. Thus, SNRPB is a potential treatment target and prognostic marker for ovarian cancer.

Fertility and prognosis assessment between bleomycin/etoposide/cisplatin and paclitaxel/carboplatin chemotherapy regimens in the conservative treatment of malignant ovarian germ cell tumors: a multicenter and retrospective study.

OBJECTIVE: To evaluate the impact of bleomycin/etoposide/cisplatin (BEP) and paclitaxel/carboplatin (PC) chemotherapy regimens on the fertility and prognostic outcomes in malignant ovarian germ cell tumor (MOGCT) patients who underwent fertility-sparing surgery (FSS). METHODS: A propensity score matching algorithm was performed between the BEP and PC groups. The χ² test and the Kaplan-Meier method were used to compare the fertility outcome, disease-free survival (DFS) and overall survival (OS). The Cox proportional hazards regression analysis was used to identify risk factor of DFS. RESULTS: We included 213 patients, 185 (86.9%) underwent BEP chemotherapy, and 28 (13.1%) underwent PC chemotherapy. The median age was 22 years (range, 8-44 years), and the median follow-up period was 63 months (range, 2-191 months). Fifty-one (29.3%) patients had a pregnancy plan, and 35 (85.4%) delivered successfully. In the before and after propensity score matching cohorts, there were no significant differences in spontaneous abortion, selective termination of pregnancy, during-pregnancy status, and live birth between the BEP and PC groups (p>0.05). Fourteen (6.6%) patients experienced recurrence, including 11 (5.9%) in the BEP group and 3 (10.7%) in the PC group. Four (1.9%) patients in the BEP group died. Kaplan-Meier analysis revealed no significant differences in DFS (p=0.328) and OS (p=0.446) between the BEP and PC groups, and the same survival results were observed in the after matching cohort. CONCLUSION: The PC regimen is as safe as the BEP regimen for MOGCT patients with fertility preservation treatment, and no differences were observed in fertility and clinical prognosis.

Prevalence of human papillomavirus DNA and p16INK4a positivity in vulvar cancer and vulvar intraepithelial neoplasia: a systematic review and meta-analysis.

BACKGROUND: Human papillomavirus (HPV) DNA and p16INK4a positivity have crucial roles in the pathogenesis of vulvar cancer and vulvar intraepithelial neoplasia. We aimed to examine the pooled prevalence of HPV DNA and p16INK4a positivity in vulvar cancer and vulvar intraepithelial neoplasia worldwide. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, and the Cochrane Library databases for studies published between Jan 1, 1986, and May 6, 2022, that reported the prevalence of HPV DNA, or p16INK4a positivity, or both, in histologically verified vulvar cancer or vulvar intraepithelial neoplasia. Studies on a minimum of five cases were included. Study-level data were extracted from the published studies. Random effect models were used to examine the pooled prevalence of HPV DNA and p16INK4a positivity in both vulvar cancer and vulvar intraepithelial neoplasia, which were further investigated using stratified analyses by histological subtype, geographical region, HPV DNA or p16INK4a detection method, tissue sample type, HPV genotype, publication year, and age at diagnosis. Additionally, meta-regression was applied to explore sources of heterogeneity. FINDINGS: We retrieved 6393 search results, of which 6233 were excluded for being duplicates or after application of our inclusion and exclusion criteria. We also identified two studies from manual searches of references lists. 162 studies were eligible for inclusion in the systematic review and meta-analysis. The prevalence of HPV in vulvar cancer (91 studies; n=8200) was 39·1% (95% CI 35·3-42·9) and in vulvar intraepithelial neoplasia (60 studies; n=3140) was 76·1% (70·7-81·1). The most predominant HPV genotype in vulvar cancer was HPV16 (78·1% [95% CI 73·5-82·3]), followed by HPV33 (7·5% [4·9-10·7]). Similarly, HPV16 (80·8% [95% CI 75·9-85·2]) and HPV33 (6·3% [3·9-9·2]) were also the most two predominant HPV genotypes in vulvar intraepithelial neoplasia. The distribution of type-specific HPV genotypes in vulvar cancer among geographical regions was different, with HPV16 varying between regions, showing a high prevalence in Oceania (89·0% [95% CI 67·6-99·5]) and a low prevalence in South America (54·3% [30·2-77·4]). The prevalence of p16INK4a positivity in patients with vulvar cancer was 34·1% (95% CI 30·9-37·4; 52 studies; n=6352), and it was 65·7% (52·5-77·7; 23 studies; n=896) in patients with vulvar intraepithelial neoplasia. Furthermore, among patients with HPV-positive vulvar cancer, p16INK4a positivity prevalence was 73·3% (95% CI 64·7-81·2), compared with 13·8% (10·0-18·1) in HPV-negative vulvar cancer. The prevalence of double positivity for HPV and p16INK4a was 19·6% (95% CI 16·3-23·0) in vulvar cancer and 44·2% (26·3-62·8) in vulvar intraepithelial neoplasia. Most analyses had large heterogeneity (I2>75%). INTERPRETATION: The high prevalence of HPV16 and HPV33 in vulvar cancer and vulvar intraepithelial neoplasia emphasised the importance of nine-valent HPV vaccination in preventing vulvar neoplasm. Additionally, this study highlighted the potential clinical significance of double positivity for HPV DNA and p16INK4a in vulvar neoplasm. FUNDING: Taishan Scholar Youth Project of Shandong Province, China.

Assessment of prognostic and reproductive outcomes of omentectomy for patients with clinically apparent early-stage (I, II) malignant ovarian germ cell tumours: A multicentre retrospective study.

OBJECTIVE: This study assessed the effect of omentectomy on the prognosis and fertility in patients with clinically early-stage (I, II) malignant ovarian germ cell tumours (MOGCT). DESIGN: A retrospective multicentre study. SETTING: Four university teaching hospitals in China. POPULATION: A total of 268 patients with clinically apparent early-stage (I, II) MOGCT. METHODS: Data were obtained from the medical records. Additionally, the propensity score matching (PSM) algorithm was adopted. MAIN OUTCOME MEASURES: Prognostic outcomes were disease-free survival (DFS) and overall survival (OS). Fertility outcomes were pregnancy and live birth rates. RESULTS: A total of 187 (69.8%) patients underwent omentectomy. Kaplan-Meier analysis showed no significant differences in DFS and OS between the omentectomy and non-omentectomy groups before and after PSM (p > 0.05). Additionally, subgroup analysis stratified by age (<18 and ≥18 years) showed similar results. International Federation of Gynecology and Obstetrics (FIGO) stage was the only risk factor associated with DFS (hazard ratio [HR] 14.71, 95% confidence interval [CI] 4.47-48.38, p < 0.001) and OS (HR 37.36, 95% CI 3.87-361.16, p = 0.002). Pregnancy and live birth rates in the total population were 80.3% and 66.7%, respectively. There were no significant differences between the two groups before and after PSM. CONCLUSIONS: Omentectomy did not improve survival or affect fertility in patients with clinically apparent early-stage (I, II) MOGCT, regardless of the age. The clinical FIGO stage was an independent risk factor for recurrence and death.

Evaluation of the prognostic value of lymphadenectomy for low-grade serous ovarian cancer: A case-control multicenter retrospective study.

BACKGROUND: The prognostic value of lymphadenectomy in low-grade serous ovarian cancer (LGSOC) remains uncertain. MATERIALS AND METHODS: A retrospective analysis of 155 patients with LGSOC who underwent surgery over a ten-year period (2011-2020) was performed. The propensity score matching (PSM) algorithm was performed between the lymphadenectomy and no lymphadenectomy groups, and Kaplan-Meier analyses were conducted to evaluate clinical prognosis. Finally, univariate and multivariate Cox proportional hazards regression analyses were performed to analyze high-risk factors associated with clinical prognosis. RESULTS: In the pre-PSM cohort, 110 (71.0%) patients underwent lymphadenectomy. Of these, 54 (34.8%) experienced recurrence, and 27 (17.4%) died. There were statistical differences in disease-free survival (DFS) (P = 0.018) and overall survival (OS) (P = 0.016) in the post-PSM cohort. In the subgroup analysis, there were no statistically significant differences in DFS (P = 0.449) or OS (P = 0.167) in the FIGO I/II cohort. However, in the FIGO III/IV cohort, DFS (P = 0.011) and OS (P = 0.046) were statistically different between the two groups. Age > 50 years, FIGO stage III/IV, and suboptimal cytoreductive surgery were risk factors associated with prognosis. In the lymphadenectomy group, the histological status of pelvic lymph nodes had no significant effect on DFS (P = 0.205) or OS (P = 0.114). CONCLUSION: Lymphadenectomy was associated with DFS and OS, particularly in patients with advanced LGSOC patients. Age > 50 years, advanced FIGO stage III/IV, and suboptimal cytoreductive surgery were high-risk factors associated with clinical prognosis in patients with LGSOC.

HJURP Promotes Malignant Progression and Mediates Sensitivity to Cisplatin and WEE1-inhibitor in Serous Ovarian Cancer.

Ovarian cancer is the most lethal gynecological malignancy. Recurrence and chemoresistance are tough challenges leading to poor prognosis. HJURP is a molecular chaperone of CENP-A, which is associated with aggressive progression in multiple tumors. However, the function of HJURP in ovarian cancer has not been elucidated. In our study, we found HJURP was over-expressed in ovarian cancer and high expression of HJURP was correlated to unfavorable prognosis. HJURP knockdown could inhibit proliferation, metastasis and induce G0/G1 stagnation of ovarian cancer cells. Besides, next-generation sequencing (NGS) unveiled that WEE1 was down-regulated by silencing HJURP. Further mechanistic research revealed that HJURP regulated WEE1 through MYC, and luciferase assay indicated that MYC was a transcription factor of WEE1. Additionally, we investigated that silencing HJURP increased sensitivity of ovarian cancer cells to cisplatin via MYC/WEE1 axis, and HJURP participated in DNA repair of cisplatin-induced damage. More interestingly, silencing HJURP could enhance sensitivity of ovarian cancer cells to AZD1775 and improve the synergistic effect of cisplatin plus AZD1775 combined therapy. Collectively, our data displays that HJURP promotes tumor progression and chemoresistance of ovarian cancer, and HJURP has potential to be a novel therapeutic target in the combined treatment with cisplatin and AZD1775 in ovarian cancer.

Progress in the management of ovarian granulosa cell tumor: A review.

Ovarian granulosa cell tumor (GCT) is a rare, low-grade malignant tumor that accounts for 70% of the sex cord-stromal tumors. It has two histopathologic types with different clinical and biologic features: adult GCT and juvenile GCT. Most women diagnosed with the adult GCT have a favorable prognosis, with a 5-year survival rate of 97%-98%, but adult GCT has a feature of late relapse; the recurrence time could be more than 20 years after diagnosis. Juvenile GCT has a survival rate of 97% in stage I and a 5-year survival rate of 0%-22% in advanced stage with earlier recurrence than adult GCT. Consequently, the scenario emphasizes the need for early diagnosis, standardized treatment protocols, and long-term follow up. However, there is a lack of consensus regarding accurate diagnosis of GCT and adjuvant treatment. Furthermore, GCT tends to occur in young women, which emphasizes the viability of fertility-sparing surgery. The current review performed a systematic literature review of 60 articles to summarize the latest advances in GCT, with an emphasis on the molecular pathogenesis and survival after fertility-sparing surgery. We found that young women with fertility-sparing surgery had a desirable reproductive and survival outcome compared with those undergoing radical surgery.