PMID- 28099924 OWN - NLM STAT- MEDLINE DCOM- 20170920 LR - 20181113 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 8 IP - 8 DP - 2017 Feb 21 TI - MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6. PG - 13872-13885 LID - 10.18632/oncotarget.14681 [doi] AB - 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. FAU - Yoshida, Akiyo AU - Yoshida A AD - Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. AD - Deperment of Cellular Transplantation Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan. FAU - Kitajima, Shunsuke AU - Kitajima S AD - Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA02215, USA. FAU - Li, Fengkai AU - Li F AD - Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. FAU - Cheng, Chaoyang AU - Cheng C AD - DNAFORM Precision Gene Technologies, Yokohama, Kanagawa, 230-0046, Japan. FAU - Takegami, Yujiro AU - Takegami Y AD - DNAFORM Precision Gene Technologies, Yokohama, Kanagawa, 230-0046, Japan. FAU - Kohno, Susumu AU - Kohno S AD - Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. FAU - Wan, Yuan Song AU - Wan YS AD - Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. FAU - Hayashi, Naoyuki AU - Hayashi N AD - Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. AD - Department of Health and Nutrition, Faculty of Human Health Science, Kanazawa Gakuin University, Kanazawa, Ishikawa, 920-1302, Japan. FAU - Muranaka, Hayato AU - Muranaka H AD - Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. FAU - Nishimoto, Yuuki AU - Nishimoto Y AD - Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. FAU - Nagatani, Naoko AU - Nagatani N AD - Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. FAU - Nishiuchi, Takumi AU - Nishiuchi T AD - Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan. FAU - Thai, Tran C AU - Thai TC AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA02215, USA. FAU - Suzuki, Sawako AU - Suzuki S AD - Deperment of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8670 Japan. FAU - Nakao, Shinji AU - Nakao S AD - Deperment of Cellular Transplantation Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan. FAU - Tanaka, Tomoaki AU - Tanaka T AD - Deperment of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8670 Japan. FAU - Hirose, Osamu AU - Hirose O AD - Division of Electrical Engineering and Computer Science, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. FAU - Barbie, David A AU - Barbie DA AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA02215, USA. FAU - Takahashi, Chiaki AU - Takahashi C AD - Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. LA - eng PT - Journal Article PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (Interleukin-6) RN - 0 (MIRN140 microRNA, mouse) RN - 0 (MicroRNAs) RN - 0 (Mirn140 microRNA, human) RN - 0 (Retinoblastoma Protein) SB - IM MH - Animals MH - Cell Line, Tumor MH - Gene Expression Regulation, Neoplastic/*physiology MH - Humans MH - Immunoblotting MH - Interleukin-6/*metabolism MH - Mice MH - Mice, Knockout MH - MicroRNAs/genetics/*metabolism MH - Neoplasms/genetics/*pathology MH - Neoplastic Stem Cells/*pathology MH - Oligonucleotide Array Sequence Analysis MH - Polymerase Chain Reaction MH - Retinoblastoma Protein/genetics/*metabolism MH - Transcriptome PMC - PMC5355146 OTO - NOTNLM OT - RB OT - cancer OT - cancer stem cells OT - interleukin-6 OT - mir-140 COIS- CONFLICTS OF INTEREST The authors declare no conflicts of interest. EDAT- 2017/01/19 06:00 MHDA- 2017/09/21 06:00 PMCR- 2017/02/21 CRDT- 2017/01/19 06:00 PHST- 2016/06/29 00:00 [received] PHST- 2017/01/03 00:00 [accepted] PHST- 2017/01/19 06:00 [pubmed] PHST- 2017/09/21 06:00 [medline] PHST- 2017/01/19 06:00 [entrez] PHST- 2017/02/21 00:00 [pmc-release] AID - 14681 [pii] AID - 10.18632/oncotarget.14681 [doi] PST - ppublish SO - Oncotarget. 2017 Feb 21;8(8):13872-13885. doi: 10.18632/oncotarget.14681.