Work

MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6

Year: 2017

Type: article

Abstract: // Akiyo Yoshida 1, 2 , Shunsuke Kitajima 1, 3 , Fengkai Li 1 , Chaoyang Cheng 4 , Yujiro Takegami 4 , Susumu Kohno 1 , Yuan Song Wan 1 , Naoyuki Hayashi 1, 5 , Hayato Muranaka 1 , Yuuki Nishimoto 1 , Naoko Nagatani 1 , Takumi Nishiuchi 6 , Tran C Thai 3 , Sawako Suzuki 7 , Shinji Nakao 2 , Tomoaki Tanaka 7 , Osamu Hirose 8 , David A. Barbie 3 , Chiaki Takahashi 1 1 Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan 2 Deperment of Cellular Transplantation Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA02215, USA 4 DNAFORM Precision Gene Technologies, Yokohama, Kanagawa, 230-0046, Japan 5 Department of Health and Nutrition, Faculty of Human Health Science, Kanazawa Gakuin University, Kanazawa, Ishikawa, 920-1302, Japan 6 Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan 7 Deperment of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8670 Japan 8 Division of Electrical Engineering and Computer Science, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan Correspondence to: Chiaki Takahashi, email: [email protected],.ac.jp Shunsuke Kitajima, email: [email protected] Keywords: cancer, cancer stem cells, RB, mir-140, interleukin-6 Received: June 29, 2016 Accepted: January 03, 2017 Published: January 16, 2017 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.14681