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

Tomoaki Takai, Takuya Tsujino, Yuki Yoshikawa, Teruo Inamoto, Nobuhiko Sugito, Yuki Kuranaga, Kazuki Heishima, Tomoyoshi Soga, Kotaro Hayashi, Kanjiro Miyata, Kazunori Kataoka, Haruhito Azuma, Yukihiro Akao

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
JournalMolecular Therapy
DOIs
Publication statusPublished - 2019 Jan 1

    Fingerprint

Keywords

  • autophagy
  • cancer specific metabolism
  • K-RAS
  • renal cell cancer
  • synthetic miR-143

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Takai, T., Tsujino, T., Yoshikawa, Y., Inamoto, T., Sugito, N., Kuranaga, Y., Heishima, K., Soga, T., Hayashi, K., Miyata, K., Kataoka, K., Azuma, H., & Akao, Y. (2019). 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. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2019.03.004