Synthetic miR-143 Exhibited an Anti-Cancer Effect via the Downregulation of K-RAS Networks of Renal Cell Cancer Cells In Vitro and In Vivo

To understand the role of RAS-signaling networks in the pathogenesis of renal cell carcisnoma, we clarified the relationship between miR-143 and RAS. The expression of miR-143 was extremely downregulated in tumor tissues from renal cell carcinoma patients compared with that in the adjacent normal ti...

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Published in:Molecular therapy Vol. 27; no. 5; pp. 1017 - 1027
Main Authors: Takai, Tomoaki, Tsujino, Takuya, Yoshikawa, Yuki, Inamoto, Teruo, Sugito, Nobuhiko, Kuranaga, Yuki, Heishima, Kazuki, Soga, Tomoyoshi, Hayashi, Kotaro, Miyata, Kanjiro, Kataoka, Kazunori, Azuma, Haruhito, Akao, Yukihiro
Format: Journal Article
Language:English
Published: United States Elsevier Inc 08-05-2019
Elsevier Limited
American Society of Gene & Cell Therapy
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Summary:To understand the role of RAS-signaling networks in the pathogenesis of renal cell carcisnoma, we clarified the relationship between miR-143 and RAS. The expression of miR-143 was extremely downregulated in tumor tissues from renal cell carcinoma patients compared with that in the adjacent normal tissues and Caki-1 cells. We developed a synthetic miR-143#12, and we found that the ectopic expression of it inhibited cell growth with autophagy in Caki-1 cells. Also, the expression level of c-Myc was markedly decreased, resulting in the perturbation of cancer-specific energy metabolism by negatively modulating the expression of GLUT1 and the PTBP1/PKMs axis. A partial metabolic shift from glycolysis to oxidative phosphorylation induced autophagy through increasing the intracellular level of reactive oxygen species (ROS). In an in vivo study, the potent anti-tumor activity of polyion complex (PIC)-loaded miR-143#12 (miR-143#12/PIC) was shown by systemic administration of it to Caki-1 cell-xenografted mice. Higher levels of miR-143 were found in both blood and tumor tissues after the systemic administration with miR-143#12/PIC compared to those with lipoplexes in the xenografted mice. These findings indicated that this synthetic miR-143#12 induced a marked growth inhibition by impairing K-RAS-signaling networks in vitro and in vivo. Synthetic miR-143 loaded with a PIC nanocarrier can be delivered specifically to tumor tissue. Also, the miR-143 can induce marked growth inhibition, cell-cycle arrest, and autophagy through impairing K-RAS-signaling networks.
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ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2019.03.004