N6-methyladenosine-modified circPLPP4 sustains cisplatin resistance in ovarian cancer cells via PIK3R1 upregulation.

BACKGROUND: Cisplatin (CDDP) is the first-line chemotherapeutic strategy to treat patients with ovarian cancer (OC). The development of CDDP resistance remains an unsurmountable obstacle in OC treatment and frequently induces tumor recurrence. Circular RNAs (circRNAs) are noncoding RNAs with important functions in cancer progression. Whether circRNAs function in CDDP resistance of OC is unclear. METHODS: Platinum-resistant circRNAs were screened via circRNA deep sequencing and examined using in situ hybridization (ISH) in OC. The role of circPLPP4 in CDDP resistance was assessed by clone formation and Annexin V assays in vitro, and by OC patient-derived xenografts and intraperitoneal tumor models in vivo. The mechanism underlying circPLPP4-mediated activation of miR-136/PIK3R1 signaling was examined by luciferase reporter assay, RNA pull-down, RIP, MeRIP and ISH. RESULTS: circPLPP4 was remarkably upregulated in platinum resistant OC. circPLPP4 overexpression significantly enhanced, whereas circPLPP4 silencing reduced, OC cell chemoresistance. Mechanistically, circPLPP4 acts as a microRNA sponge to sequester miR-136, thus competitively upregulating PIK3R1 expression and conferring CDDP resistance. The increased circPLPP4 level in CDDP-resistant cells was caused by increased RNA stability, mediated by increased N6-methyladenosine (m6A) modification of circPLPP4. In vivo delivery of an antisense oligonucleotide targeting circPLPP4 significantly enhanced CDDP efficacy in a tumor model. CONCLUSIONS: Our study reveals a plausible mechanism by which the m6A -induced circPLPP4/ miR-136/ PIK3R1 axis mediated CDDP resistance in OC, suggesting that circPLPP4 may serve as a promising therapeutic target against CDDP resistant OC. A circPLPP4-targeted drug in combination with CDDP might represent a rational regimen in OC.

A Novel Platinum Resistance-Related Immune Gene Signature for Overall Survival Prediction in Patients with Ovarian Cancer.

Ovarian cancer (OV) is a highly heterogeneous gynecological tumor that makes the prognostic prediction challenging. Resistance to platinum-based chemotherapy is associated with a poor prognosis in OV. There seems to be an overlap between molecular mechanisms responsible for platinum resistance and immunogenicity in OV. However, the predictive role of platinum resistance-related immune genes for OV prognosis needs to be further explored. In our study, the mRNA expression data of OV patients with corresponding clinical information were collected from The Cancer Genome Atlas (TCGA) cohort and International Cancer Genome Consortium (ICGC) cohort. A multigene signature was constructed for OV patients in the TCGA cohort using the least absolute shrinkage and selection operator (LASSO) Cox regression model according to the optimal value of λ and was validated in the ICGC cohort. Furthermore, we performed functional analysis to explore the immune status between low- and high-risk groups based on the median value of the risk score for the multigene signature. Our data showed that there were 41.1% of the platinum resistance-related genes which differentially expressed between immune score low- and high-OV patients in the TCGA cohort. Univariate Cox regression analysis identified 30 differentially expressed genes (DEGs) associated with overall survival (OS) (P < 0.05). 14 genes were identified to construct a novel platinum resistance-related immune model for classifying OV patients into the low- and high- risk groups. Patients in the low-risk group showed significantly higher OS than those in the high-risk group (P < 0.0001 in the both TCGA and ICGC cohort), which was associated with different immune status for the two risk groups. A novel platinum resistance-related immune model can be used for prognostic prediction in OV. Targeting tumor immunity may be a therapeutic alternative for OV with platinum resistance.

Resveratrol reduces lactate production and modifies the ovarian cancer immune microenvironment.

Tumor cells show deregulated metabolism leading to an enrichment of lactate in the tumor microenvironment (TME). This lactate-rich environment has been reported to impair effector T cells. However, T-regulatory cells (Tregs) show metabolic advantages in lactate-rich TME that maintain a strong suppression of effector T cells, which leads to tumor immune evasion. Therefore, the glycolytic process of tumors could represent a therapeutic target, and agents that modify the energy metabolism of tumor cells have therapeutic potential. Resveratrol is a naturally occurring polyphenol that has been confirmed to suppress tumor cells' glycolytic metabolism. In this study, we show that resveratrol induces metabolic reprogramming in ovarian cancer cells. Resveratrol increases oxidative and decreases glycolysis, in association with decreased lactate production both in vitro and in vivo. Lactate reduction in TME weakens the suppressive function of Tregs, and subsequently restores anti-tumor immunity. Significantly, combined resveratrol and PD-1 blockade promote anti-tumor efficacy. These data suggest that resveratrol's anti-tumor actions in ovarian cancer could be explained, in part, through modification of the anti-tumor immunity, and indicate a novel treatment strategy for improving immune checkpoint blockade therapy using resveratrol.

Clinical significance of circulating tumor cells in predicting disease progression and chemotherapy resistance in patients with gestational choriocarcinoma.

Gestational choriocarcinoma (GC) is a highly aggressive tumor. In our study, we systematically investigated EpCAM/CD147 expression characteristics in patients with GC and assessed the role of circulating tumor cells (CTCs) in predicting chemotherapy response and disease progression. GC tissues were positive for either epithelial cellular adhesion molecule (EpCAM) or CD147, and all samples exhibited strong human chorionic gonadotropin (HCG) expression. Among all the recruited patients (n = 115), 103 had at least 1 CTC in a 7.5-mL peripheral blood sample, and the percentage of patients with ≥4 CTCs in a particular FIGO stage group increased with a higher FIGO stage (p < 0.001). Furthermore, the pretreatment CTC count was related to tumor size (r = 0.225, p = 0.015) and the number of metastases (r = 0.603, p < 0.001). A progression analysis showed that among the 115 included patients who qualified for further examination, 52 of the 64 patients defined as progressive had ≥4 pretreatment CTCs, while only 7 of the 51 non-progressive patients had ≥4 pretreatment CTCs (p < 0.001). In multivariate analysis, CTCs (≥4) remained the strongest predictor of PFS when other prognostic markers, FIGO score and FIGO stage were included. Moreover, based on the chemotherapy response, patients with ≥4 CTCs were more likely to be resistant to chemotherapy than those with <4 CTCs (P < 0.001). These findings demonstrates the feasibility of CTC detection in cases of GC by adopting EpCAM/CD147 antibodies together as capturing antibodies. The CTC count is a promising indicator in the evaluation of biological activities and the chemotherapy response in GC patients.

MiR-216b inhibits cell proliferation by targeting FOXM1 in cervical cancer cells and is associated with better prognosis.

BACKGROUND: Our previous study showed FOXM1 expression was significantly up-regulated in cervical cancer, and was associated with poor prognosis. To clarify miRNAs-FOXM1 modulation pathways, in this study, we investigated the relationships between miR-216b and FOXM1 and the role of miR-216b in cell proliferation and prognosis of cervical cancer patients. METHODS: Western blotting and qPCR were used to determine expression of FOXM1, cell cycle related factors and miR-216b level. MiR-216b overexpression and inhibited cell models were constructed, and siRNA was used for FOXM1 silencing. Cell proliferation was analyzed by MTT and colony formation assay. Dual luciferase reporter assay system was used to clarify the relationships between miR-216b and FOXM1. Kaplan-Meier survival analysis was used to evaluate prognosis. RESULTS: MiR-216b was down-regulated in cervical cancer cells and tissues, and its ectopic expression could decrease cell proliferation. Western blotting analysis showed miR-216b can inhibit cell proliferation by regulating FOXM1-related cell cycle factors, suppressing cyclinD1, c-myc, LEF1 and p-Rb and enhancing p21 expression. Repressing of miR-216b stimulated cervical cancer cell proliferation, whereas silencing FOXM1 expression could reverse this effect. Western blotting and luciferase assay results proved FOXM1 is a direct target of miR-216b. Survival analysis showed higher level of miR-216b was associated with better prognosis in cervical cancer patients. CONCLUSIONS: FOXM1 expression could be suppressed by miR-216b via direct binding to FOXM1 3'-UTR and miR-216b could inhibit cell proliferation by regulating FOXM1 related Wnt/ß-catenin signal pathway. MiR-216b level is related to prognosis in cervical cancer patients and may serve as a potential prognostic marker.

MiR-760 overexpression promotes proliferation in ovarian cancer by downregulation of PHLPP2 expression.

OBJECTIVE: Ovarian cancer is one of the most lethal gynecologic malignancies worldwide and with poor prognosis and survival rate in women. Identifying sensitive and specific molecular in carcinogenesis may improve diagnostic and therapeutic strategies for this malignancy and achieve a better clinical outcome. METHODS: miR-760 expression in ovarian cancer cell lines and patient tissues were determined using Real-time PCR. 145 human ovarian cancer tissue samples were analyzed by RT-PCR to investigate the association between miR-760expression and the clinicopathological characteristics of ovarian cancer patients. Functional assays, such as MTT, anchorage-independent growth, colony formation and BRDU assay were used to determine the oncogenic role of miR-760 in human ovarian cancer progression. Furthermore, western blotting and luciferase assay were used to determine the mechanism of miR-760 promotes proliferation in ovarian cancer cells. RESULT: The expression of miR-760 was markedly upregulated in ovarian cancer cell lines and tissues, and high miR-760 expression was associated with an aggressive phenotype and poor prognosis with ovarian cancer patients. Upregulation of miR-760 promoted, whereas downregulation of miR-760 inhibited the proliferation of ovarian cancer cells in vitro. Additionally, we identified PHLPP2 as a direct target of miR-760, and silencing the expression of PHLPP2 is the essential biological function of miR-760 during ovarian cancer cell proliferation. Finally, we showed a significant correlation between miR-760 and PHLPP2 expression in ovarian cancer tissues. CONCLUSION: Our findings suggest that miR-760 represents a potential onco-miR and participates in ovarian cancer carcinogenesis, which highlight its potential as a target for ovarian cancer therapy.

CPE overexpression is correlated with pelvic lymph node metastasis and poor prognosis in patients with early-stage cervical cancer.

PURPOSE: Elevated carboxypeptidase E (CPE) levels play crucial roles in tumorigenesis and metastasis. This study investigated the expression and clinicopathological significance of CPE in early-stage cervical cancer. METHODS: Elevated carboxypeptidase E expression was analyzed using quantitative polymerase chain reaction and western blotting in normal cervical tissue, cervical cancer cell lines, and in cervical cancer tissues and adjacent noncancerous tissues (ANTs) from the same patient. Immunohistochemistry (IHC) was used to examine CPE expression in tissue samples from 112 patients with early-stage cervical cancer (FIGO stages Ia2-IIa2), 60 patients with cervical intraepithelial neoplasia, and 19 patients with normal cervical tissues (NCTs). Associations between CPE expression and prognostic and diagnostic factors were evaluated statistically. RESULTS: CPE expression was significantly higher in cervical cancer cell lines and tissues than in normal tissues and ANTs. Semi-quantitative analysis of IHC indicated that CPE gradually increased from CIN I to cervical cancer, but was absent in NCTs. CPE expression was seen in 40.2 % (45/112) of the cervical cancer samples. CPE expression was significantly associated with FIGO stage (P = 0.003), tumor size (P = 0.012), stromal invasion (P < 0.001), lymphovascular space invasion (P = 0.016), parametrial infiltration (P = 0.027), vaginal involvement (P = 0.007), postoperative adjuvant therapy (P = 0.024), recurrence (P < 0.001), survival (P < 0.001), and pelvic lymph node metastasis (PLNM) (P < 0.001), and it was significantly higher in tissues from patients with PLNM than without PLNM. Logistic regression analysis identified high-level CPE expression as an independent risk factor for PLNM (P = 0.001). Patients with higher CPE expression had shorter overall survival duration than patients with lower CPE expression. Univariate and multivariate Cox-regression analyses suggested that high-level CPE expression is an independent prognostic factor for overall survival in early-stage cervical cancer. CONCLUSIONS: High-level CPE expression was associated with a poor prognosis in early-stage cervical cancer. CPE may serve as a biomarker for predicting PLNM and survival in these patients.

Astrocyte elevated gene-1(AEG-1) induces epithelial-mesenchymal transition in lung cancer through activating Wnt/ß-catenin signaling.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a highly metastatic cancer with limited therapeutic options, so development of novel therapies that target NSCLC is needed. During the early stage of metastasis, the cancer cells undergo an epithelial-mesenchymal transition (EMT), a phase in which Wnt/ß-catenin signaling is known to be involved. Simultaneously, AEG-1 has been demonstrated to activate Wnt-mediated signaling in some malignant tumors. METHODS: Human NSCLC cell lines and xenograft of NSCLC cells in nude mice were used to investigate the effects of AEG-1 on EMT. EMT or Wnt/ß-catenin pathway-related proteins were characterized by western blot, immunofluorescence and immunohistochemistry. RESULTS: In the present study, we demonstrated that astrocyte elevated gene-1(AEG-1) ectopic overexpression promoted EMT, which resulted from the down-regulation of E-cadherin and up-regulation of Vimentin in lung cancer cell lines and clinical lung cancer specimens. Using an orthotopic xenograft-mouse model, we also observed that AEG-1 overexpression in human carcinoma cells led to the development of multiple lymph node metastases and elevated mesenchymal markers such as Vimentin, which is a characteristic of cells in EMT. Furthermore, AEG-1 functioned as a critical protein in the regulation of EMT by directly targeting multiple positive regulators of the Wnt/ß-catenin signaling cascade, including GSK-3ß and CKIδ. Notably, overexpression of AEG-1 in metastatic cancer tissues was closely associated with poor survival of NSCLC patients. CONCLUSIONS: These results reveal the critical role of AEG-1 in EMT and suggest that AEG-1 may be a prognostic biomarker and its targeted inhibition may be utilized as a novel therapy for NSCLC.

Single-Cell Atlas of Human Ovaries Reveals The Role Of The Pyroptotic Macrophage in Ovarian Aging.

Female fecundity declines in a nonlinear manner with age during the reproductive years, even as ovulatory cycles continue, which reduces female fertility, disrupts metabolic homeostasis, and eventually induces various chronic diseases. Despite this, the aging-related cellular and molecular changes in human ovaries that occur during these reproductive years have not been elucidated. Here, single-cell RNA sequencing (scRNA-seq) of human ovaries is performed from different childbearing ages and reveals that the activation of the pyroptosis pathway increased with age, mainly in macrophages. The enrichment of pyroptotic macrophages leads to a switch from a tissue-resident macrophage (TRM)-involve immunoregulatory microenvironment in young ovaries to a pyroptotic monocyte-derived macrophage (MDM)-involved proinflammatory microenvironment in middle-aged ovaries. This remolded ovarian immuno-microenvironment further promotes stromal cell senescence and accelerated reproductive decline. This hypothesis is validated in a series of cell and animal experiments using GSDMD-KO mice. In conclusion, the work expands the current understanding of the ovarian aging process by illustrating a pyroptotic macrophage-involved immune mechanism, which has important implications for the development of novel strategies to delay senescence and promote reproductive health.

FOXM1 promotes tumor cell invasion and correlates with poor prognosis in early-stage cervical cancer.

OBJECTIVE: The forkhead box M1 (FOXM1) transcription factor plays crucial roles in regulating the proliferation, differentiation, and transformation of cells. Overexpression of FOXM1 is associated with a variety of aggressive solid carcinomas, including cervical cancer. However, the precise role and molecular mechanism responsible for the aggressive action of FOXM1 in cervical cancer remain unclear. This study investigated the cellular and molecular aggressive function of FOXM1 in cervical cancer. METHODS: The FOXM1 gene and protein expression profiles were determined by quantitative polymerase chain reaction, Western blotting and immunohistochemical staining, and other cellular and molecular approaches including gene transfection, short hairpin RNA interference (RNAi), and wound-healing, migration, and invasion assays. RESULTS: FOXM1 expression was significantly up-regulated at both mRNA and protein levels in early-stage cervical cancer, compared to cervical intraepithelial neoplasia and normal cervical tissues. High levels of FOXM1 expression were significantly associated with aggression in cervical cancer, and were an independent prognostic factor for poor survival in early-stage cervical cancer patients. Moreover, enforced expression of FOXM1 increased migration and invasion of cancer cells, whereas RNAi-mediated knockdown of FOXM1 had the opposite effect. In addition, up-regulation of FOXM1 increased the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 in vitro and in vivo, and activated the Akt/glycogen synthase kinase-3ß/Snail pathway, resulting in the promotion of migration and invasion of cervical cancer cells. CONCLUSIONS: These results suggest that FOXM1 up-regulation is associated with poor prognosis in early-stage cervical cancer, and therefore it may act as a prognostic marker and a new potential target for cervical cancer treatment.

Successful management of mucinous ovarian cancer by conservative surgery in week 6 of pregnancy: case report and literature review.

PURPOSE: The management of ovarian cancer during pregnancy is still a big challenge, mostly due to the reciprocal impacts between cancer and pregnancy. The objective of this article is to present a rare case of maternal ovarian adenocarcinoma and review published similar cases about this clinical condition. MATERIALS AND METHODS: Here we report a rare case of maternal ovarian adenocarcinoma detected during gestational week 6, with good pregnancy outcome treated with conservative surgery. RESULTS AND DISCUSSION: A case of maternal ovarian adenocarcinoma (stage I) was detected in week 6 of pregnancy receiving conservative surgery without chemotherapy. In week 39 of pregnancy, due to relapse of the cancer, the patient underwent excision of the isolated tumor, and gave birth to a healthy baby through cesarian section. After that, the patient received cytoreductive surgery associated with six chemotherapy. The patient was finally diagnosed as epithelial ovarian cancer stage IIIC, and had survived more than 5 years without relapse. The successful experience from this case suggested that pregnancy complicated with early ovarian cancer receiving conservative surgery could continue to pregnancy and the effect of cesarian section followed with cytoreductive surgery associated with six chemotherapy at full term was still satisfied.

[Retracted] MicroRNA­1297 inhibits metastasis and epithelial­mesenchymal transition by targeting AEG­1 in cervical cancer.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the immunohistochemical data shown in Fig. 4C and the cell migration assay data shown in Fig. 3B and D and Fig. 7B and D were strikingly similar to data that had appeared in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 38: 3121­3129, 2017; DOI: 10.3892/or.2017.5979].

Family with sequence similarity 46 member a confers chemo-resistance to ovarian carcinoma via TGF-ß/Smad2 signaling.

Ovarian cancer is the most lethal malignancy with depressive 5-year survival rate, mainly due to patients with advanced stages experience tumor recurrence and resistance to the current chemotherapeutic agents. Thus, exploring the underlying molecular mechanisms involved in chemo-resistance is crucial for management of treatment to improve therapeutic outcomes. In the current study, we found overexpression of FAM46A in ovarian cancer patients demonstrated an aggressive phenotype and poor outcome. Furthermore, FAM46A overexpression in ovarian cancer cells induces higher CDDP resistance. However, inhibition of FAM46A sensitized ovarian cancer cell lines to CDDP cytotoxicity both in vitro and in vivo. Mechanically, upregulation of FAM46A activated transforming growth factor-ß (TGF-ß)/Smad signaling and upregulated the levels of nuclear Smad2. Taken together, our results highlight the important oncogenic role of FAM46A in ovarian cancer progression and might provide a potential clinical target for patients with chemo resistant ovarian cancer.

The value of first-trimester platelet parameters in predicting gestational diabetes mellitus.

OBJECTIVE: To explore the potential clinical value of platelet parameters in early pregnancy in predicting gestational diabetes mellitus (GDM). METHODS: A total of 1188 singleton pregnant women were included in the regular antenatal examination and delivered in the First Affiliated Hospital of Sun Yat-Sen University from January 2016 to December 2018, who had no pre-pregnancy diabetes, no factors leading to elevated blood glucose level, no medical complications and no other obstetrical complications. Blood routine examination was performed at the 11-13+6 gestational weeks. All pregnant women underwent 75 g OGTT directly at the 24-28th gestational weeks. And they were divided into GDM group (n = 192) and non-GDM group (n = 996). Binomial Logistic regression analysis and receiver operating characteristic (ROC) curve were used to evaluate the ability of first-trimester platelet parameters to predict GDM, that is the sensitivity and specificity of platelet parameters at the optimal critical value. RESULTS: There were significant differences in platelet count (PLT), platelet distribution width (PDW), mean platelet volume (MPV), and plateletcrit (PCT) between the GDM group and the normal group (p＜.05). After adjusting for the related factors such as maternal age, parity and pregestational body mass index (BMI), the MPV and PCT were correlated with the incidence of GDM (p＜.05). The area under the curve (AUC) of MPV was 0.577; 95% confidence interval (CI) 0.533-0.621 and that of PCT was 0.628. 95%CI 0.582-0.674. PLT and PDW were not correlated with GDM. CONCLUSION: MPV and PCT in early pregnancy are potential indicators in predicting gestational diabetes mellitus.

Tumor antigen-pulsed CD8α(+) dendritic cells induce T cell-mediated graft-versus-tumor effect in vitro.

The graft-versus-tumor (GVT) effect of T cells induced by tumor antigen-pulsed CD8α(+) dendritic cells (DCs) in vitro was investigated in this study. Immature CD8α(+) DCs were prepared from C57BL/6 (H-2(b)) bone marrow cells by using a cytokine cocktail. On the 3rd day of culture, CD8α(+) DCs were pulsed by allogeneic (Balb/c, H-2(d)) EL9611 leukemia antigen, or RM-1 syngeneic prostate cancer antigen, with the concentration series of 0, 2.5, 5.0, 10.0, 20.0 µg/mL, respectively, then antigen-loaded immature CD8α(+) DCs were co-cultured with syngeneic T cells according to the DC/T ratio of 1:1, 2:1 and 4:1. T cell proliferation was measured by MTT assay. Cytokines including interferon gamma (IFN-γ) and interleukin-10 (IL-10) in CD8α(+) DCs and T co-culture supernatant were detected by using ELISA. Cytotoxic effect of antigen-specific T cells was tested by LDH release assay. Conventional mature DCs (mDCs) induced from C57BL/6 (H-2(b)) bone marrow cells by using granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) served as a control. The results showed that the proliferative activity of T cells stimulated by CD8α(+) DCs loaded with allogeneic or syngeneic tumor antigen was augmented with the CD8α(+) DC/T ratio increased (P<0.05). When antigen concentration ≤ 5 µg/mL and CD8α(+) DC/T ratio ≤ 2:1, the ability of CD8α(+) DCs to stimulate T cell proliferation was higher than mDC control in allogeneic tumor antigen-pulsed groups (P<0.05), but not in syngeneic tumor antigen-pulsed groups (P>0.05). The level of IFN-γ and IL-10 in CD8α(+) DCs and T cell co-culture supernatant were increased in both allogeneic and syngeneic antigen-pulsed groups (P<0.05), and the cytokine level was higher in allogeneic antigen-pulsed groups than in syngeneic antigen groups when the CD8α(+) DC/T was 1:1 or 2:1 (P<0.05). There existed a negative correlation between the level of IL-10 and T cell proliferation. T cell cytotoxicity assay showed that when CD8α(+) DCs were pulsed with allogeneic tumor antigen, the maximal T cell killing efficiency could reach (100±7.7)%, whereas syngeneic tumor antigen-pulsed group had only (65.0±3.4)%. It was concluded that syngeneic and allogeneic tumor antigen-pulsed immature CD8α(+) DCs could stimulate T cells to exert the GVT effect in vitro, and the GVT effect was more obvious with allogeneic tumor antigen than with syngeneic tumor antigen. The optimal condition was low allogeneic tumor antigen pulsation (≤ 5 µg/mL) and low CD8α(+) DC/T ratio (1:1 and 2:1).

PARP inhibitors in breast and ovarian cancer with BRCA mutations: a meta-analysis of survival.

OBJECTIVE: To evaluate the efficacy of poly ADP ribose polymerase (PARP) inhibitors (PARPis) in breast and ovarian cancer with BRCA (BReast CAncer susceptibility gene) mutation (BRCAm). METHODS: We conducted a meta-analysis of randomized controlled, phase II or III trials by searching of electronic databases from inception to September 1, 2020. The efficacy of PARPis measured by hazard ratios (HRs) and 95% confidence intervals (95% CIs) for progression free survival (PFS) and overall survival (OS) of patients. RESULTS: By addition of PARPis to conventional therapy, breast or ovarian cancer patients carrying BRCAm significantly benefited PFS (breast cancer: HR 0.64, 95% CI=0.55-0.75, P<0.001; ovarian cancer: HR 0.33, 95% CI=0.27-0.42, P<0.001), but OS of patients did not increase significantly in these two cancer types (breast cancer: HR 0.87, 95% CI=0.76-1.01, P=0.065; ovarian cancer: HR 0.78, 95% CI=0.61-1.01, P=0.058). For ovarian cancer patients carrying BRCAm, the use of therapy with PARPis yielded longer PFS at the stage of newly diagnosed than the stage of recurrence (22.5 months vs 9.6 months). CONCLUSION: PARPis were beneficial to all with BRCAm, but they were "most" beneficial to the ovarian cancer subset when administered early after diagnosis, rather than after recurrence.

FAM83B inhibits ovarian cancer cisplatin resistance through inhibiting Wnt pathway.

Cisplatin resistance is frequently occurred in ovarian cancer therapy, understanding its regulatory mechanisms is critical for developing novel treatment methods and drugs. Here, we found ovarian cancer patients with low FAM83B levels had shorter survival time, tissues with cisplatin resistance also had low FAM83B levels, suggesting FAM83B might inhibit cisplatin resistance. FAM83B overexpression inhibits cisplatin resistance showed in increased ovarian cancer cell proliferation and growth rate, and reduced apoptosis rate, while FAM83B knockdown promotes cisplatin resistance. Mechanism analysis showed FAM83B interacted with APC to inhibit Wnt pathway activity, causing ovarian cancer cisplatin resistance. We also found FAM83B levels were negative with Wnt pathway activity in clinic samples, confirming FAM83B inhibited Wnt pathway activity. In summary, we found FAM83B inhibits ovarian cancer cisplatin resistance through inhibiting Wnt pathway, providing a new target for ovarian cancer therapy.

Overexpression of glycosyltransferase 8 domain containing 2 confers ovarian cancer to CDDP resistance by activating FGFR/PI3K signalling axis.

It has been reported that chemotherapy resistance mainly contributed to treatment failure and poor survival in patients with ovarian cancer. Therefore, clarifying the molecular mechanism and identifying effective strategies to overcome drug resistance may play an important clinical impact on this malignant tumor. In our study, we found that the expression of Glycosyltransferase 8 domain containing 2 (GLT8D2) was significantly upregulated in ovarian cancer samples with CDDP (Cis-dichlorodiammine-platinum) resistance. Biological experiment demonstrate that GLT8D2 overexpression confers CDDP resistance on ovarian cancer cells; however, inhibition of GLT8D2 sensitized ovarian cancer cell lines to CDDP cytotoxicity both in vitro and in vivo. By using affinity purification/mass spectrometry (IP/MS) and reciprocal co-immunoprecipitation (co-IP) analyses, we found that GLT8D2 interacts with fibroblast growth factor receptor 1(FGFR1) in ovarian cancer cells. Furthermore, overexpression of GLT8D2 activated FGFR/PI3K signaling axis and upregulated the phosphorylation levels of FRS2a and AKT (AKT serine/threonine kinase). Importantly, pharmacological inhibition of FGFR and PI3K (phosphatidylinositol 3-kinase) signaling pathway significantly counteracted GLT8D2-induced chemoresistance and enhanced platinum's therapeutic efficacy in ovarian cancer. Therefore, our findings suggest that GLT8D2 is a potential therapeutic target for the treatment of ovarian cancer; targeting GLT8D2/FGFR/PI3K/AKT signaling axis may represent a promising strategy to enhance platinum response in patients with chemoresistant ovarian cancer.

PTOV1 promotes cisplatin-induced chemotherapy resistance by activating the nuclear factor kappa B pathway in ovarian cancer.

Chemotherapy resistance is a bottleneck for ovarian cancer treatment; therefore, revealing its regulatory mechanism is critical. In the present study, we found that prostate tumor overexpressed-1 (PTOV1) was upregulated significantly in ovarian cancer cells and tissues. Patients with high PTOV1 levels had a poor outcome. In addition, PTOV1 overexpression increased CDDP (cisplatin) resistance, while PTOV1 knockdown inhibited CDDP resistance, as determined using cell viability assays, apoptosis assays, and an animal model. Mechanistic analysis showed that PTOV1 increased nuclear factor kappa B (NF-κB) pathway activity, reflected by increased nuclear translocation of its p65 subunit and the phosphorylation of inhibitor of nuclear factor kappa-B kinase subunits alpha and beta, which are markers of NF-κB pathway activation. Inhibition of the NF-κB pathway in PTOV1-overexpressing ovarian cancer cells increased CDDP-induced apoptosis, suggesting that PTOV1 promoted chemotherapy resistance by activating the NF-κB pathway. In summary, we identified PTOV1 as a prognostic factor for patients with ovarian cancer. PTOV1 might be a target for inhibition of chemotherapy resistance.

Efficacy and safety of PARP inhibitors as the maintenance therapy in ovarian cancer: a meta-analysis of nine randomized controlled trials.

PURPOSE: Poly ADP ribose polymerase (PARP) inhibitors can effectively kill cancer cells by restraining the activity of DNA repair enzymes and utilizing the characteristics of BRCA mutations. This article evaluates the efficacy and safety of PARP inhibitors (PARPis) in the maintenance treatment of ovarian cancer. METHOD: We searched for clinical trials in electronic databases. PARPis efficacy were evaluated by the hazard ratios (HR) and its 95% confidence intervals (95% CI) of overall survival (OS) and progression-free survival (PFS) between the PARPis groups and placebo groups, while the PARPis' safety was assessed by relative risk (RR) values of adverse events (AEs) between the two arms. RESULTS: The immature OS data manifested that patients with BRCA mutation receiving PARPis therapy versus placebo therapy appeared to have longer OS (HR = 0.78, 95%CI = 0.61-1.01; P = 0.06). Compared with placebo group, PARP group had a significant advantage in PFS in ovarian cancer patients with BRCA wild-type (BRCAwt), BRCA mutation (BRCAm), BRCA status unclassified, BRCA1 mutation subgroup and the BRCA2 mutation subgroup (BRCAwt: HR = 0.53, 95%CI = 0.42-0.68, P < 0.00001; BRCAm: HR = 0.30, 95%CI = 0.26-0.34, P < 0.00001; BRCA status unclassified: HR = 0.52, 95%CI = 0.41-0.66, P < 0.00001; BRCA1m: HR = 0.38, 95%CI = 0.29-0.48, P < 0.00001; BRCA2m: HR = 0.23, 95%CI = 0.10-0.57, P = 0.001). Our analysis revealed the incidence rates for AEs of grade ≥3 (grades 3 to 4) and serious AEs in PARPis group were 55.19% and 26.29%, respectively. CONCLUSION: Our meta-analysis demonstrates that PARPis therapy can significantly improve PFS in ovarian cancer patients, but it has no benefit in OS. However, the therapy is associated with a significant increase in the risk of AEs of grade ≥ 3 and serious AEs.