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.

miR-199a-3p Modulates MTOR and PAK4 Pathways and Inhibits Tumor Growth in a Hepatocellular Carcinoma Transgenic Mouse Model

Callegari, Elisa
Primo
;
D'Abundo, Lucilla;Guerriero, Paola;Simioni, Carolina;Cani, Alice;Bassi, Cristian;Zagatti, Barbara;Moshiri, Farzaneh;Ultimo, Simona;Frassoldati, Antonio;Neri, Luca Maria;Sabbioni, Silvia;Negrini, Massimo
Ultimo
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
Callegari, Elisa; D'Abundo, Lucilla; Guerriero, Paola; Simioni, Carolina; Elamin, Bahaeldin K.; Russo, Marta; Cani, Alice; Bassi, Cristian; Zagatti, Barbara; Giacomelli, Luciano; Blandamura, Stella; Moshiri, Farzaneh; Ultimo, Simona; Frassoldati, Antonio; Altavilla, Giuseppe; Gramantieri, Laura; Neri, Luca Maria; Sabbioni, Silvia; Negrini, Massimo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2390358
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