title: Expression of the miR-302/367 cluster in glioblastoma cells suppresses tumorigenic gene expression patterns and abolishes transformation related phenotypes.
abstract: Cellular transformation is initiated by the activation of oncogenes and a closely associated developmental reprogramming of the epigenetic landscape. Transcription factors, regulators of chromatin states and microRNAs influence cell fates in development and stabilize the phenotypes of normal, differentiated cells and of cancer cells. The miR-302/367 cluster, predominantly expressed in human embryonic stem cells (hESs), can promote the cellular reprogramming of human and mouse cells and contribute to the generation of iPSC. We have used the epigenetic reprogramming potential of the miR-302/367 cluster to "de-program" tumor cells, that is, hift their gene expression pattern towards an alternative program associated with more benign cellular phenotypes. Induction of the miR-302/367 cluster in extensively mutated U87MG glioblastoma cells drastically suppressed the expression of transformation related proteins, for example, the reprogramming factors OCT3/4, SOX2, KLF4 and c-MYC, and the transcription factors POU3F2, SALL2 and OLIG2, required for the maintenance of glioblastoma stem-like tumor propagating cells. It also diminished PI3K/AKT and STAT3 signaling, impeded colony formation in soft agar and cell migration and suppressed pro-inflammatory cytokine secretion. At the same time, the miR-302/367 cluster restored the expression of neuronal markers of differentiation. Most notably, miR-302/367 cluster expressing cells lose their ability to form tumors and to establish liver metastasis in nude mice. The induction of the miR-302/367 cluster in U87MG glioblastoma cells suppresses the expression of multiple transformation related genes, abolishes the tumor and metastasis formation potential of these cells and can potentially become a new approach for cancer therapy.
authors.affiliation: Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt Am Main, D-60596, Germany.
authors.forename: Chul Min
authors.identifier: http://orcid.org/0000-0001-9123-9954
authors.initials: CM
authors.lastname: Yang
authors.affiliation: Department of Pathology, Kyorin University School of Medicine, Mitaka, Tokyo, 181-08-611, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt Am Main, D-60596, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Brill
authors.affiliation: Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt Am Main, D-60596, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Delis
authors.affiliation: Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt Am Main, D-60596, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: von Manstein
authors.affiliation: Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt Am Main, D-60596, Germany.
authors.forename: Vida
authors.initials: V
authors.lastname: Vafaizadeh
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt Am Main, D-60590, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.affiliation: Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt Am Main, D-60596, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Groner
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D065150:Cellular Reprogramming; D016207:Cytokines / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D016207:Cytokines; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C532169:MIRN302A microRNA, human; C568081:MIRN367 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors
keywords: epigenetic regulation of the tumor cell state; miR-302/367 regulated gene expression; tumor suppression