ECE2018 Poster Presentations: Interdisciplinary Endocrinology Nuclear receptors and Signal transduction (3 abstracts)
1,25 dihydroxyvitamin D reverses everolimus resistance in hepatocellular carcinoma activating mesenchymal-epithelial transition and miR-375
Claudia Pivonello 1 , Donatella Paola Provvisiero 1 , Mariarosaria Negri 1 , Gilda Di Gennaro 1 , Cristina de Angelis 1, , Roberta Patalano 1 , Giacomo Galdiero 1 , Chiara Simeoli 1 , Renata Simona Auriemma 1 , Maria Cristina De Martino 1 , Annamaria Colao 1 & Rosario Pivonello 1
1Department of Clinical Medicine and Surgery, University of Naples, Naples, Italy; 2I.O.S. & COLEMAN Srl, Naples, Italy.
HCC is a difficult-to-treat-cancer with poor prognosis. EVOLVE-1 trial demonstrated that EVE did not improve overall survival in molecularly and clinically unselected patients with advanced HCC resistant to sorafenib. In selected patients, the well-established antitumor effect of EVE could make this a potential adjuvant therapy. Unfortunately, EVE acquired resistance due to the tumor adaptation to chronic drug use is a current challenge. VitD was deemed as potential regimen to treat several cancers alone or in combination with other drugs. The aim of this study was to explore the role of VitD pre-treatment in the re-sensitization to EVE in two models of HCC cell lines, PLC/PRF/5 and JHH-6 cell lines resistant to EVE (PLC/PRF/5 EveR and JHH-6 EveR). EveR cells were obtained after 4 months of treatment with EVE 10−8M. VitD receptor (VDR) expression was confirmed by RT-qPCR and WB. DNA assay was established to evaluate the proliferation rate in parental and EveR cells after EVE treatment (from 10−14M to 10−8M) alone or in combination with VitD (10−7M). Epithelial–mesenchymal transition (EMT) markers were evaluated by IF in parental and EveR cells, even after VitD treatment. miRNA PCR Arrays were employed to investigate the difference in parental and EveR cells after 12hrs of treatment with VitD. EVE long-term exposure increased mRNA and protein VDR expression in PLC/PRF/5 EveR but not in JHH-6 EveR cells. Contrary to EveR, in parental cells, EVE significantly reduced cell proliferation in a dose-dependent manner after 6 days of treatment where VitD did not improve EVE effect. In both EveR cells 12 and 24hrs of VitD pre-treatment was sufficient to significantly restore EVE efficacy at concentration ranging from 10−14M to 10−8M. In EveR cells, EVE 10−8M chronic treatment increased the protein expression of mesenchymal markers, but VitD prolonged treatment restored epithelial markers protein expression. miRNA expression analysis in EveR cells revealed miR-375 downregulation compared to parental ones, conversely, EveR cells treated with VitD for 12hrs showed miR-375 upregulation compared to EveR cells. Treatment with VitD was able to downregulate metadherin and Yes Associated Protein 1, genes involved in drug resistance and bioinformatically predicted miR-375 target genes, expression in both EveR cells. These data suggested the use of VitD to overcome EVE acquired resistance in HCC reverting EMT and downregulating the expression of genes involved in drug resistance acting trough the regulation of miR-375.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more