PMID- 31406139 OWN - NLM STAT- MEDLINE DCOM- 20201026 LR - 20211204 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 9 IP - 1 DP - 2019 Aug 12 TI - Vitamin D reverts resistance to the mTOR inhibitor everolimus in hepatocellular carcinoma through the activation of a miR-375/oncogenes circuit. PG - 11695 LID - 10.1038/s41598-019-48081-9 [doi] LID - 11695 AB - Primary or acquired resistant mechanisms prevent the employment of individualized therapy with target drugs like the mTOR inhibitor everolimus (EVE) in hepatocellular carcinoma (HCC). The current study evaluated the effect of 1,25(OH)(2)Vitamin D (VitD) treatment on EVE sensitivity in established models of HCC cell lines resistant to everolimus (EveR). DNA content and colony formation assays, which measure the proliferative index, revealed that VitD pre-treatment re-sensitizes EveR cells to EVE treatment. The evaluation of epithelial and mesenchymal markers by western blot and immunofluorescence showed that VitD restored an epithelial phenotype in EveR cells, in which prolonged EVE treatment induced transition to mesenchymal phenotype. Moreover, VitD treatment prompted hepatic miRNAs regulation, evaluated by liver miRNA finder qPCR array. In particular, miR-375 expression was up-regulated by VitD in EveR cells, in which miR-375 was down-regulated compared to parental cells, with consequent inhibition of oncogenes involved in drug resistance and epithelial-mesenchymal transition (EMT) such as MTDH, YAP-1 and c-MYC. In conclusion, the results of the current study demonstrated that VitD can re-sensitize HCC cells resistant to EVE treatment triggering miR-375 up-regulation and consequently down-regulating several oncogenes responsible of EMT and drug resistance. FAU - Provvisiero, Donatella Paola AU - Provvisiero DP AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. FAU - Negri, Mariarosaria AU - Negri M AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. FAU - de Angelis, Cristina AU - de Angelis C AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. AD - Dipartimento di Sanita Pubblica, Universita Federico II di Napoli, Naples, Italy. FAU - Di Gennaro, Gilda AU - Di Gennaro G AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. FAU - Patalano, Roberta AU - Patalano R AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. AD - Dipartimento di Sanita Pubblica, Universita Federico II di Napoli, Naples, Italy. FAU - Simeoli, Chiara AU - Simeoli C AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. FAU - Papa, Fortuna AU - Papa F AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. FAU - Ferrigno, Rosario AU - Ferrigno R AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. FAU - Auriemma, Renata Simona AU - Auriemma RS AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. FAU - De Martino, Maria Cristina AU - De Martino MC AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. FAU - Colao, Annamaria AU - Colao A AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. FAU - Pivonello, Rosario AU - Pivonello R AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. FAU - Pivonello, Claudia AU - Pivonello C AD - Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy. claudia.pivonello@unina.it. LA - eng PT - Journal Article DEP - 20190812 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Antineoplastic Agents) RN - 0 (MIRN375 microRNA, human) RN - 0 (MTDH protein, human) RN - 0 (MYC protein, human) RN - 0 (Membrane Proteins) RN - 0 (MicroRNAs) RN - 0 (Proto-Oncogene Proteins c-myc) RN - 0 (RNA-Binding Proteins) RN - 0 (Transcription Factors) RN - 0 (YAP-Signaling Proteins) RN - 0 (YAP1 protein, human) RN - 1406-16-2 (Vitamin D) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Adaptor Proteins, Signal Transducing/genetics/metabolism MH - Antineoplastic Agents/*pharmacology MH - Cell Line, Tumor MH - Cell Movement/drug effects MH - Cell Proliferation/drug effects MH - Drug Resistance, Neoplasm/*drug effects/genetics MH - Epithelial-Mesenchymal Transition/drug effects/genetics MH - Everolimus/*pharmacology MH - *Gene Expression Regulation, Neoplastic MH - Hep G2 Cells MH - Humans MH - Membrane Proteins/genetics/metabolism MH - MicroRNAs/agonists/*genetics/metabolism MH - Proto-Oncogene Proteins c-myc/genetics/metabolism MH - RNA-Binding Proteins/genetics/metabolism MH - Signal Transduction MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/*genetics/metabolism MH - Transcription Factors/genetics/metabolism MH - Vitamin D/*pharmacology MH - YAP-Signaling Proteins PMC - PMC6690984 COIS- The authors declare no competing interests. EDAT- 2019/08/14 06:00 MHDA- 2020/10/27 06:00 PMCR- 2019/08/12 CRDT- 2019/08/14 06:00 PHST- 2019/03/14 00:00 [received] PHST- 2019/07/30 00:00 [accepted] PHST- 2019/08/14 06:00 [entrez] PHST- 2019/08/14 06:00 [pubmed] PHST- 2020/10/27 06:00 [medline] PHST- 2019/08/12 00:00 [pmc-release] AID - 10.1038/s41598-019-48081-9 [pii] AID - 48081 [pii] AID - 10.1038/s41598-019-48081-9 [doi] PST - epublish SO - Sci Rep. 2019 Aug 12;9(1):11695. doi: 10.1038/s41598-019-48081-9.