TY - JOUR A1 - Lacombe, Amanda Meneses Ferreira A1 - Soares, Iberê Cauduro A1 - Mariani, Beatriz Marinho de Paula A1 - Nishi, Mirian Yumie A1 - Bezerra-Neto, João Evangelista A1 - Charchar, Helaine da Silva A1 - Brondani, Vania Balderrama A1 - Tanno, Fabio A1 - Srougi, Victor A1 - Chambo, José Luiz A1 - Costa de Freitas, Ricardo Miguel A1 - Mendonca, Berenice Bilharinho A1 - Hoff, Ana O. A1 - Almeida, Madson Q. A1 - Weigand, Isabel A1 - Kroiss, Matthias A1 - Zerbini, Maria Claudia Nogueira A1 - Fragoso, Maria Candida Barisson Villares T1 - Sterol O-acyl transferase 1 as a prognostic marker of adrenocortical carcinoma JF - Cancers N2 - Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis. Despite the poor prognosis in the majority of patients, no improvements in treatment strategies have been achieved. Therefore, the discovery of new prognostic biomarkers is of enormous interest. Sterol-O-acyl transferase 1 (SOAT1) is involved in cholesterol esterification and lipid droplet formation. Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC. To date, no studies have addressed the impact of SOAT1 expression on ACC prognosis and clinical outcomes. We evaluated SOAT1 expression by quantitative real-time polymerase chain reaction and immunohistochemistry in a tissue microarray of 112 ACCs (Weiss score ≥ 3) from adults treated in a single tertiary center in Brazil. Two independent pathologists evaluated the immunohistochemistry results through a semiquantitative approach (0–4). We aimed to evaluate the correlation between SOAT1 expression and clinical, biochemical and anatomopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). SOAT1 protein expression was heterogeneous in this cohort, 37.5% of the ACCs demonstrated a strong SOAT1 protein expression (score > 2), while 62.5% demonstrated a weak or absent protein expression (score ≤ 2). Strong SOAT1 protein expression correlated with features of high aggressiveness in ACC, such as excessive tumor cortisol secretion (p = 0.01), an advanced disease stage [European Network for the Study of Adrenal Tumors (ENSAT) staging system 3 and 4 (p = 0.011)] and a high Ki67 index (p = 0.002). In multivariate analysis, strong SOAT1 protein expression was an independent predictor of a reduced OS (hazard ratio (HR) 2.15, confidence interval (CI) 95% 1.26–3.66; p = 0.005) in all patients (n = 112), and a reduced RFS (HR 2.1, CI 95% 1.09–4.06; p = 0.027) in patients with localized disease at diagnosis (n = 83). Our findings demonstrated that SOAT1 protein expression has prognostic value in ACC and reinforced the importance of investigating SOAT1 as a possible therapeutic target for patients with ACC. KW - adrenocortical carcinoma KW - prognostic factors KW - SOAT1 KW - target therapies Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200857 SN - 2072-6694 VL - 12 IS - 1 ER - TY - JOUR A1 - Löhr, Mario A1 - Härtig, Wolfgang A1 - Schulze, Almut A1 - Kroiß, Matthias A1 - Sbiera, Silviu A1 - Lapa, Constantin A1 - Mages, Bianca A1 - Strobel, Sabrina A1 - Hundt, Jennifer Elisabeth A1 - Bohnert, Simone A1 - Kircher, Stefan A1 - Janaki-Raman, Sudha A1 - Monoranu, Camelia-Maria T1 - SOAT1: A suitable target for therapy in high-grade astrocytic glioma? JF - International Journal of Molecular Sciences N2 - Targeting molecular alterations as an effective treatment for isocitrate dehydrogenase-wildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and IDH-mutant astrocytoma, CNS WHO grade 4 (HGA), and assessed the distribution of LD in these tumors. Twenty-seven GBM and three HGA specimens were evaluated by multiple GFAP, Iba1, IDH1 R132H, and SOAT1 immunofluorescence labeling as well as Oil Red O staining. To a small extent SOAT1 was expressed by tumor cells in both tumor entities. In contrast, strong expression was observed in glioma-associated macrophages. Triple immunofluorescence labeling revealed, for the first time, evidence for SOAT1 colocalization with Iba1 and IDH1 R132H, respectively. Furthermore, a notable difference in the amount of LD between GBM and HGA was observed. Therefore, SOAT1 suppression might be a therapeutic option to target GBM and HGA growth and invasiveness. In addition, the high expression in cells related to neuroinflammation could be beneficial for a concomitant suppression of protumoral microglia/macrophages. KW - SOAT1 KW - glioblastoma KW - astrocytoma KW - IDH1/2 KW - lipid droplets KW - mitotane KW - targeted therapy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284178 SN - 1422-0067 VL - 23 IS - 7 ER - TY - JOUR A1 - Eckhardt, Carolin A1 - Sbiera, Iuliu A1 - Krebs, Markus A1 - Sbiera, Silviu A1 - Spahn, Martin A1 - Kneitz, Burkhard A1 - Joniau, Steven A1 - Fassnacht, Martin A1 - Kübler, Hubert A1 - Weigand, Isabel A1 - Kroiss, Matthias T1 - High expression of Sterol-O-Acyl transferase 1 (SOAT1), an enzyme involved in cholesterol metabolism, is associated with earlier biochemical recurrence in high risk prostate cancer JF - Prostate Cancer and Prostatic Diseases N2 - Background Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans. Objective To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa. Patients and Methods Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards modeling were used to compare outcome. Main Outcome Measure Biochemical recurrence (BCR) free survival. Results SOAT1 expression was high in 73 (25%) and low in 219 (75%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14%) and at low levels in 249 (86%) samples (not evaluable: 16). By Kaplan-Meier analysis, we found significantly shorter median BCR free survival of 93 months (95% confidence interval 23.6-123.1) in patients with high SOAT1 vs. 134 months (112.6-220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95% CI 1.57-3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression CONCLUSIONS: SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target. KW - prostate cancer KW - SOAT1 KW - cholesterol metabolism Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271819 SN - 1476-5608 VL - 25 IS - 3 ER - TY - THES A1 - Finkl, Sophia T1 - Untersuchungen zur Funktion und Expression von miR-200b im Prostatakarzinom unter besonderer Beachtung von miR-200b als Prognosemarker bei Hochrisiko-Erkrankten und des Enzyms SOAT1 als Zielstruktur von miR-200b T1 - Studies on the function and expression of miR-200b in prostate carcinoma with special attention to miR-200b as a prognostic marker in high-risk disease patients and the enzyme SOAT1 as a target of miR-200b N2 - Die miR-200b zeigte sich in zwei unabhängigen Prostatakarzinomkollektiven herabreguliert und in dem verwendeten Hochrisiko Kollektiv erwies sich miR-200b zudem in uni- und multivariaten Analysen in einem retrospektiven Versuchsansatz als geeigneter Marker zur Abschätzung der Prognose des Prostatakarzinoms. Mittels in vitro Experimenten konnten tumorsuppressive Funktionen von miR-200b bestätigt werden, da miR-200b überexprimierende Prostatakarzinom Zelllinien eine geringere Proliferation und eine geringere Autophagie zeigten. Zusätzlich konnte auf funktioneller Ebene, SOAT1 als Zielgen von miR-200b definiert werden. Die funktionelle Bedeutung der miR-200b vermittelten Regulation der SOAT1 Expression konnte in weiteren Experimenten bestätigt werden, indem eine Sensitivierung gegenüber der antiproliferativen Wirkung von SOAT1 Inhibitoren in miR-200b überexprimierenden Prostatakarzinom-Zellen beobachtet werden konnte. Mit diesen Ergebnissen konnte ein Model entwickelt werden, welches einen möglichen Erklärungsansatz der Bedeutung, der von miR-200b vermittelten SOAT1 Regulation für den Fettstoffwechsel des Prostatakarzinoms liefern könnte. N2 - The miR-200b was shown to be downregulated in two independent prostate cancer collectives and in the high-risk collective, miR-200b was also found to be a suitable marker to estimate the prognosis of prostate cancer in univariate and multivariate analyses in a retrospective experimental approach. Using in vitro experiments, tumor suppressive functions of miR-200b could be confirmed, as miR-200b overexpressing prostate carcinoma cell lines showed lower proliferation and autophagy. In addition, at the functional level, SOAT1 could be defined as a target gene of miR-200b. The functional significance of miR-200b mediated regulation of SOAT1 expression was confirmed in further experiments by observing sensitivity to the antiproliferative effect of SOAT1 inhibitors in miR-200b overexpressing prostate carcinoma cells. With these results, a model could be developed that could provide a possible explanation of the importance of SOAT1 regulation mediated by miR-200b for lipid metabolism in prostate carcinoma. KW - Prostatakrebs KW - Prostatakarzinom KW - miR-200b KW - SOAT1 KW - prostate cancer KW - lipid metabolism Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257418 ER -