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Mir-199A-3P Modulates Mtor and Pak4 Pathways and Inhibits Tumor Growth in a Hepatocellular Carcinoma Transgenic Mouse Model Publisher



Callegari E1 ; Dabundo L1 ; Guerriero P1 ; Simioni C1 ; Elamin BK2, 3 ; Russo M1 ; Cani A1 ; Bassi C1 ; Zagatti B1 ; Giacomelli L4 ; Blandamura S4 ; Moshiri F1, 5 ; Ultimo S1 ; Frassoldati A1 Show All Authors
Authors
  1. Callegari E1
  2. Dabundo L1
  3. Guerriero P1
  4. Simioni C1
  5. Elamin BK2, 3
  6. Russo M1
  7. Cani A1
  8. Bassi C1
  9. Zagatti B1
  10. Giacomelli L4
  11. Blandamura S4
  12. Moshiri F1, 5
  13. Ultimo S1
  14. Frassoldati A1
  15. Altavilla G4
  16. Gramantieri L6
  17. Neri LM1
  18. Sabbioni S7
  19. Negrini M1

Source: Molecular Therapy Nucleic Acids Published:2018


Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Prognosis is poor, and therapeutic options are limited. MicroRNAs (miRNAs) have emerged as potential therapeutic molecules against cancer. Here, we investigated the therapeutic efficacy of miR-199a-3p, an miRNA highly expressed in normal liver and downregulated in virtually all HCCs. The therapeutic value of miR-199a-3p mimic molecules was assayed in the TG221 mouse, a transgenic model highly predisposed to the development of liver cancer. Administration of miR-199a-3p mimics in the TG221 transgenic mouse showing liver cancer led to a significant reduction of number and size of tumor nodules compared to control animals. In vivo delivery confirmed protein downregulation of the miR-199a-3p direct targets, mechanistic target of rapamycin (MTOR) and p21 activated kinase 4 (PAK4), ultimately leading to the repression of FOXM1. Remarkably, the anti-tumor activity of miR-199a-3p mimics was comparable to that obtained with sorafenib. These results suggested that miR-199a-3p may be considered a promising HCC therapeutic option. © 2018 The Author(s)
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