1. miR-92b-3p is significantly lower in exosomes derived from ovarian cancer cells than that derived from normal ovarian epithelial cells. 2. Exosomes with overexpressed miR-92b-3p can inhibit the angiogenesis of ovarian cancer. 3. DSPE-PEG2K-RGD modified engineered exosomes loaded with miR-92b-3p can produce a combined antitumor and anti-angiogenic effect with Apatinib in nude mice abdominal tumor models.

RNA methylation has recently emerged as an important category of epigenetic modifications, which plays diverse physiopathological roles in various cancers. Recent studies have confirmed the presence of 5-methylcytosine (m5C) modification on mammalian mRNAs, mainly modified by NOP2/Sun RNA methyltransferase family member 2 (NSUN2), but little is known about the underlying functions of m5C. Gynecologic cancers are malignancies starting from women’s reproductive organs. The prevalence of gynecologic cancers leads to a massive economic burden and public health concern. In this study, we investigated the potential biological functions of NSUN2 in common gynecologic cancers including cervical cancer, ovarian cancer, and endometrial cancer. Remarkably, distinct scenarios were found. The levels of NSUN2 did not show alteration in endometrial cancer, and in ovarian cancer, depletion of upregulated NSUN2 did not reduce carcinogenesis in cancer cells, suggesting that the upregulated NSUN2 might be an incidental effect. On the contrary, NSUN2 played a role in tumorigenesis of cervical cancer; depletion of upregulated NSUN2 notably inhibited migration and invasion of cancer cells, and only wild-type but not catalytically inactive NSUN2 rescued these malignant phenotypes of cancer cells. Mechanistically, NSUN2 promoted migration and invasion by leading to m5C methylation on keratin 13 (KRT13) transcripts, and methylated KRT13 transcripts would be recognized and stabilized by an m5C reader, Y-box binding protein 1 (YBX1). Collectively, these results not only displayed the nature of diversity among human malignancies, but also demonstrated a novel NSUN2-dependent m5C-YBX1-KRT13 oncogenic regulatory pathway.

Wide metastasis contributes to a high death rate in ovarian cancer, and understanding of the molecular mechanism helps to find effective targets for metastatic ovarian cancer therapy. It has been found that phospholipase A2-activating protein (PLAA) is inactivated in some cancers, but its role in cancer metastasis remains unknown. Here, we found that PLAA was significantly downregulated in ovarian cancer highly metastatic cell lines and patients, and the low expression of PLAA was associated with poorer prognosis and high-risk clinicopathological features of patients. PLAA inhibited the migration and invasion of ovarian cancer cells and metastasis of transplanted tumor in the orthotopic xenograft mouse model. Meanwhile, PLAA inhibited metastasis of ovarian cancer by inhibiting transient receptor potential channel canonical 3 (TRPC3)-mediated the intracellular Ca2+ level. Mechanistically, PLAA inhibited methyltransferase-like 3 (METTL3) expression through the ubiquitin-mediated degradation, and METTL3 stabilized TRPC3 mRNA expression via N6-methyladenosine (m6A) modification. Our study verified the function and mechanism of the PLAA-METTL3-TRPC3 axis involved in ovarian cancer metastasis, with a view to providing a potential therapeutic approach for ovarian cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors are efficacious in treating platinum-sensitive ovarian cancer (OC), but demonstrate limited efficiency in patients with platinum-resistant OC. Thus, further investigations into combined strategies that enhance the response to PARP inhibitors (PARPi) in platinum-resistant OC are required. The present study aimed to investigate the combined therapy of arsenic trioxide (ATO) with olaparib, a common PARPi, and determine how this synergistic cytotoxicity works in platinum-resistant OC cells. Functional assays demonstrated that the combined treatment of olaparib with ATO significantly suppressed cell proliferation and colony formation, and enhanced DNA damage as well as cell apoptosis in A2780-CIS and SKOV3-CIS cell lines. Results of the present study also demonstrated that a combination of olaparib with ATO increased lipid peroxidation and eventually triggered ferroptosis. Consistently, the combined treatment synergistically suppressed tumor growth in mice xenograft models. Mechanistically, ATO in combination with olaparib activated the AMPK α pathway and suppressed the expression levels of stearoyl-CoA desaturase 1 (SCD1). Collectively, results of the present study demonstrated that treatment with ATO enhanced the effects of olaparib in platinum-resistant OC.

Background: Patients with late-stage ovarian cancer still have a very poor prognosis due to chemotherapy resistance. Curcumin has been shown to synergistically enhance the therapeutic effects of multiple chemotherapeutic agents, but the potential involvement of curcumin in ovarian cancer is largely unknown. This study aimed to investigate whether curcumin has synergistic anti-cancer effects with paclitaxel in ovarian cancer and its underlying mechanism.Methods: Ovarian cancer cell lines (SKOV3 and A2780) were treated with curcumin, alone or combined with paclitaxel. Cell viability, colony formation, EdU incorporation assays, and flow cytometry were used to assess cell proliferation, apoptosis, and cell cycle progression. The cytotoxic synergistic effect of curcumin and paclitaxel was detected by Calcusyn software. RNA immunoprecipitation assay was used to verify the interaction between miR-9-5p and BRCA1. qRT-PCR and Western blot were performed to detect gene and protein expression.Results: We found that curcumin and paclitaxel synergistically inhibited proliferation and promoted apoptosis in ovarian cancer cells. Furthermore, curcumin and paclitaxel combination resulted in decreased miR-9-5p expression and increased BRCA1 expression. Functionally, miR-9-5p overexpression counteracted the synergistic effect of curcumin and paclitaxel on cell proliferation and apoptosis by targeting BRCA1. Meanwhile, in vivo experiments revealed that curcumin and paclitaxel combination dramatically suppressed the growth of transplanted tumors, while miR-9-5p mimics eliminated the growth inhibition of xenografts induced by the combined treatment.Conclusion: Curcumin enhanced the anti-cancer efficacy of paclitaxel in ovarian cancer by regulating the miR-9-5p/BRCA1 axis. These findings provide strong evidence for clinical investigation of curcumin and paclitaxel combination as a novel strategy for ovarian cancer patients, and identify miR-9-5p and BRCA1 as key targets for regulating sensitivity to this therapy.