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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
Show Affiliations
Authors Affiliations
  1. 1. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, 44121, Italy
  2. 2. Department of Basic Sciences, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
  3. 3. Microbiology Department, Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, 11115, Sudan
  4. 4. Department of Medicine DIMED, University of Padova, Padova, 35128, Italy
  5. 5. Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, 11369, Iran
  6. 6. Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Bologna, 40138, Italy
  7. 7. Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, 44121, Italy

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)