ECE2020 Oral Communications Young Investigators (12 abstracts)
Dysregulation of splicing factor 3B SUBUNIT 1 (SF3B1) is associated with the pathological transformation of the liver: Pharmacological inhibition with pladienolide-B as novel therapeutic tool in liver disease
Juan Manuel Jiménez Vacas1 ,2,3,4 , Juan L López-Cánovas 1,2,3,4 , Mercedes Del Rio-Moreno 1,2,3,4 , Helena García-Fernandez 1,2,3,4 , Marina E Sánchez-Frias 1,3 , Victor Amado 5,6,7 , Fernando L-López 1,2,3,4 , Marcos F Fondevila 4,8 , Ruben Ciria 5,9 , Javier Briceño 5,9 , Rubén Nogueiras 4,8 , Manuel De la Mata 5,6,7 , Justo P Castaño 2,3,4,10 , Manuel Rodriguez-Perálvarez 5,6,7 , Raúl M Luque 1,2,3,4 & Manuel D Gahete 1,2,3,4
1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), OncObesity and Metabolism, Cordoba, Spain; 2University of Cordoba, Department of Cell Biology, Physiology and Immunology, Córdoba, Spain; 3Reina Sofia University Hospital, Cordoba, Spain; 4CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Spain; 5Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain; 6Reina Sofia University Hospital, Hepatology and Liver Transplantation, Cordoba, Spain; 7CIBER Hepatic and Digestive Diseases (CIBERehd), Cordoba, Spain; 8University of Santiago de Compostela-Instituto de Investigación Sanitaria, Department of Physiology, Santiago de Compostela, Spain; 9University Hospital Reina Sofia, Unit of Hepatobiliary Surgery and Liver Transplantation, Cordoba, Spain; 10Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Hormones and Cancer, Cordoba, Spain
Development and progression of liver diseases, from non-alcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH), and hepatocellular carcinoma (HCC), seem to be accompanied by a dysregulation of the expression of alternative splicing variants (SVs) and appearance of aberrant SVs. The splicing factor 3B subunit 1 (SF3B1) represents a crucial player for the functional assembly of the spliceosome, the core machinery that controls the splicing process, and its activity can be specifically blocked using pladienolide-B. Here, we explored the putative dysregulation and pathophysiological role of SF3B1 and the potential therapeutic utility of pladienolide-B in liver disease. To this end, SF3B1 expression (mRNA and protein levels) and clinical implications were assessed in patients with liver diseases from two retrospective (n = 154 and n = 172) cohorts, and five in silico cohorts of HCC patients [TCGA (n = 369), Wurmbach (n = 45), Roessler (n = 43), Roessler 2 (n = 445) and Mas (n = 57)]. Functional and molecular consequences of SF3B1 silencing (using specific siRNAs) and/or pharmacological blockade (using pladienolide-B) were evaluated in normal-like hepatocyte-derived (THLE-2) and liver cancer (HepG2, Hep3b and SNU-387) cell lines. In addition, Hep3b-induced xenograft tumors treated with pladienolide-B were developed in vivo. Results showed that SF3B1 expression levels were consistently elevated (at mRNA and protein levels) in transformed livers (NASH/HCC) compared to normal liver in all cohorts studied. Moreover, SF3B1 expression levels were associated with clinical (histologic differentiation, overall survival) and molecular parameters of aggressiveness (expression of oncogenic SVs, including KLF6-SV1, BCL-XL, etc). Furthermore, SF3B1 silencing in vitro resulted in reduced proliferation and migration capacity of liver cancer cell lines. Consistently, pladienolide-B strongly inhibited proliferation, migration, as well as tumorsphere- and colony-formation in liver cancer cells, whereas its effects on the proliferation of normal-like liver cells (THLE-2) were negligible. Remarkably, intratumor injection of pladienolide-B was able to markedly reduce the growth rate of xenograft tumors. Finally, silencing and blockade of SF3B1 both in vitro and in vivo clearly modulated the expression levels of cancer-associated genes (e.g. CDK4, CD24) and oncogenic SVs (e.g. KLF6-SV1). Altogether, these results demonstrate that SF3B1 expression increases with the pathological transformation of the liver and that its pharmacological inhibition using pladienolide-B may represent a promising novel therapeutic approach worth to be explored through randomized controlled trials, alone or in combination with existing therapies.
Fundings: ISCIII [CP15/00156, PI17-02287, PI16/00264], MINECO/MECD (BFU2016-80360-R), Junta de Andalucía (BIO-0139), and CIBERobn.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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