title: MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6.
abstract: We established an in vitro cell culture system to determine novel activities of the retinoblastoma (Rb) protein during tumor progression. Rb depletion in p53-null mouse-derived soft tissue sarcoma cells induced a spherogenic phenotype. Cells retrieved from Rb-depleted spheres exhibited slower proliferation and less efficient BrdU incorporation, however, much higher spherogenic activity and aggressive behavior. We discovered six miRNAs, including mmu-miR-18a, -25, -29b, -140, -337, and -1839, whose expression levels correlated tightly with the Rb status and spherogenic activity. Among these, mmu-miR-140 appeared to be positively controlled by Rb and to antagonize the effect of Rb depletion on spherogenesis and tumorigenesis. Furthermore, among genes potentially targeted by mmu-miR-140, Il-6 was upregulated by Rb depletion and downregulated by mmu-mir-140 overexpression. Altogether, we demonstrate the possibility that mmu-mir-140 mediates the Rb function to downregulate Il-6 by targeting its 3'-untranslated region. Finally, we detected the same relationship among RB, hsa-miR-140 and IL-6 in a human breast cancer cell line MCF-7. Because IL-6 is a critical modulator of malignant features of cancer cells and the RB pathway is impaired in the majority of cancers, hsa-miR-140 might be a promising therapeutic tool that disrupts linkage between tumor suppressor inactivation and pro-inflammatory cytokine response.
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.|Deperment of Cellular Transplantation Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Akiyo
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA02215, USA.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kitajima
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Fengkai
authors.initials: F
authors.lastname: Li
authors.affiliation: DNAFORM Precision Gene Technologies, Yokohama, Kanagawa, 230-0046, Japan.
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Cheng
authors.affiliation: DNAFORM Precision Gene Technologies, Yokohama, Kanagawa, 230-0046, Japan.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Takegami
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kohno
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Yuan Song
authors.initials: YS
authors.lastname: Wan
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.|Department of Health and Nutrition, Faculty of Human Health Science, Kanazawa Gakuin University, Kanazawa, Ishikawa, 920-1302, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hayashi
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Muranaka
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Nishimoto
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Nagatani
authors.affiliation: Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Nishiuchi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA02215, USA.
authors.forename: Tran C
authors.initials: TC
authors.lastname: Thai
authors.affiliation: Deperment of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8670 Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Deperment of Cellular Transplantation Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakao
authors.affiliation: Deperment of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8670 Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Division of Electrical Engineering and Computer Science, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Hirose
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA02215, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D015850:Interleukin-6; C547828:MIRN140 microRNA, mouse; D035683:MicroRNAs; C544302:Mirn140 microRNA, human; D016160:Retinoblastoma Protein
keywords: RB; cancer; cancer stem cells; interleukin-6; mir-140