Abstract
MicroRNAs (miRs) regulate a variety of cellular processes, and their impaired expression is involved in cancer. Silencing of tumor-suppressive miRs in cancer can occur through epigenetic modifications, including DNA methylation and histone deacetylation. We performed comparative miR profiling on cultured lung cancer cells before and after treatment with 5'aza-deoxycytidine plus Trichostatin A to reverse DNA methylation and histone deacetylation, respectively. Several tens of miRs were strongly induced by such 'epigenetic therapy'. Two representatives, miR-512-5p (miR-512) and miR-373, were selected for further analysis. Both miRs were secreted in exosomes. Re-expression of both miRs augmented cisplatin-induced apoptosis and inhibited cell migration; miR-512 also reduced cell proliferation. TEAD4 mRNA was confirmed as a direct target of miR-512; likewise, miR-373 was found to target RelA and PIK3CA mRNA directly. Our results imply that miR-512 and miR-373 exert cell-autonomous and non-autonomous tumor-suppressive effects in lung cancer cells, where their re-expression may benefit epigenetic cancer therapy.
MeSH 主题词
Animals
Cell Cycle
Cell Line
Cell Proliferation/drug effects,genetics
Cisplatin/pharmacology
DNA Methylation/drug effects,genetics
DNA-Binding Proteins/genetics,metabolism
Epigenesis, Genetic/drug effects,genetics
HCT116 Cells
HeLa Cells
Hep G2 Cells
Humans
Hydroxamic Acids/pharmacology
Male
Mice
Mice, Nude
MicroRNAs/genetics,metabolism
Muscle Proteins/genetics,metabolism
Phosphatidylinositol 3-Kinases/genetics,metabolism
TEA Domain Transcription Factors
Transcription Factor RelA/genetics,metabolism
Transcription Factors/genetics,metabolism
化学物质
DNA-Binding Proteins
Hydroxamic Acids
MIRN373 microRNA, human
MIRN512 microRNA, human
MicroRNAs
Muscle Proteins
TEA Domain Transcription Factors
TEAD4 protein, human
Transcription Factor RelA
Transcription Factors
trichostatin A
Cisplatin
作者与单位
共 14 位作者，点击展开单位 / ORCID
Adi Harel S
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Bossel Ben-Moshe N
Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel.
Aylon Y
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Bublik D R
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Moskovits N
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Toperoff G
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Azaiza D
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Biagoni F
Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
Fuchs G
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Wilder S
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Hellman A
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Blandino G
Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
Domany E
Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel.
Oren M
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
