Voltage-Gated Sodium Channels as Potential Biomarkers and Therapeutic Targets for Epithelial Ovarian Cancer

Abnormal ion channel expression distinguishes several types of carcinoma. Here, we explore the relationship between voltage-gated sodium channels (VGSC) and epithelial ovarian cancer (EOC). We find that EOC cell lines express most VGSC, but at lower levels than fallopian tube secretory epithelial cells (the cells of origin for most EOC) or control fibroblasts. Among patient tumor samples, lower SCN8A expression was associated with improved overall survival (OS) (median 111 vs. 52 months; HR 2.04 95% CI: 1.21–3.44; p = 0.007), while lower SCN1B expression was associated with poorer OS (median 45 vs. 56 months; HR 0.69 95% CI 0.54–0.87; p = 0.002). VGSC blockade using either anti-epileptic drugs or local anesthetics (LA) decreased the proliferation of cancer cells. LA increased cell line sensitivity to platinum and taxane chemotherapies. While lidocaine had similar additive effects with chemotherapy among EOC cells and fibroblasts, bupivacaine showed a more pronounced impact on EOC than fibroblasts when combined with either carboplatin (ΔAUC −37% vs. −16%, p = 0.003) or paclitaxel (ΔAUC −37% vs. −22%, p = 0.02). Together, these data suggest VGSC are prognostic biomarkers in EOC and may inform new targets for therapy

A természetes ölősejtek szerepe az anyai-magzati immunhomeostasis fenntartásában

A sikeres fogantatás, beágyazódás és terhesség komplex és szervezett kommunikációt igényel az embrió (allograft) és az anya (gazda) immunrendszere között. A különböző leukocyta-alcsoportok fontos szerepet játszanak az immunválasz szervezésében a magzati-anyai határfelületen. Vannak bizonyos hasonlóságok a tumorsejteknek az immunrendszert kijátszó kóros és az embrionális eredetű trophoblastsejteknek az anyai deciduába irányuló fiziológiás inváziója között. A decidualis vagy uterinalis természetes ölősejtek a természetes ölősejtek speciális részhalmaza, és a macrophagokkal és a dendritikus sejtekkel együtt a veleszületett immunrendszer részét képezik, ezért ők az első immunsejtek, amelyek kapcsolatba lépnek bármely behatolóval, legyen az daganat vagy embrionális szövet. Érdekes módon a decidualis természetes ölősejtek nemcsak nem támadják meg az invazív trophoblastsejteket, hanem kifejezetten elősegítik azok progresszióját. Angiogenikus aktivitásuk megkönnyíti és koordinálja a kialakuló méhlepény helyi vascularis átalakulását. Dolgozatunkban áttekintjük a trophoblastsejtek és a decidualis természetes ölősejtek kölcsönhatásait, a decidualis természetes ölősejtek szerepét a decidua vascularisatiójában és immunháztartásában

Characterization of MicroRNA-200 pathway in ovarian cancer and serous intraepithelial carcinoma of fallopian tube

Abstract Background Ovarian cancer is the leading cause of death among gynecologic diseases in Western countries. We have previously identified a miR-200-E-cadherin axis that plays an important role in ovarian inclusion cyst formation and tumor invasion. The purpose of this study was to determine if the miR-200 pathway is involved in the early stages of ovarian cancer pathogenesis by studying the expression levels of the pathway components in a panel of clinical ovarian tissues, and fallopian tube tissues harboring serous tubal intraepithelial carcinomas (STICs), a suggested precursor lesion for high-grade serous tumors. Methods RNA prepared from ovarian and fallopian tube epithelial and stromal fibroblasts was subjected to quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) to determine the expression of miR-200 families, target and effector genes and analyzed for clinical association. The effects of exogenous miR-200 on marker expression in normal cells were determined by qRT-PCR and fluorescence imaging after transfection of miR-200 precursors. Results Ovarian epithelial tumor cells showed concurrent up-regulation of miR-200, down-regulation of the four target genes (ZEB1, ZEB2, TGFβ1 and TGFβ2), and up-regulation of effector genes that were negatively regulated by the target genes. STIC tumor cells showed a similar trend of expression patterns, although the effects did not reach significance because of small sample sizes. Transfection of synthetic miR-200 precursors into normal ovarian surface epithelial (OSE) and fallopian tube epithelial (FTE) cells confirmed reduced expression of the target genes and elevated levels of the effector genes CDH1, CRB3 and EpCAM in both normal OSE and FTE cells. However, only FTE cells had a specific induction of CA125 after miR-200 precursor transfection. Conclusions The activation of the miR-200 pathway may be an early event that renders the OSE and FTE cells more susceptible to oncogenic mutations and histologic differentiation. As high-grade serous ovarian carcinomas (HGSOC) usually express high levels of CA125, the induction of CA125 expression in FTE cells by miR-200 precursor transfection is consistent with the notion that HGSOC has an origin in the distal fallopian tube

Additional file 1: of Characterization of MicroRNA-200 pathway in ovarian cancer and serous intraepithelial carcinoma of fallopian tube

Fig. S1. Western blot analysis to show negligible expression of CA125 (MUC16) in OSE and FTE primary cultures. Table S1. Correlation analyses for the relationship between expression levels of miR-200 family and miR-205 and target genes. Table S2. Correlation analyses for the expression relationship between miR-200 family and miR-205 and effector genes. Table S3. Differential expression of effector gene MUC16 in different subtypes of ovarian tumors. Table S4. Effects of microRNA on target gene expression in OSE and FTE cells. Table S5. Effects of microRNA on effector gene expression in OSE and FTE (PDF 445 kb

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

non present