New Tumor Suppressor MicroRNAs Target Glypican-3 in Human Liver Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 May 6

PMID 28476031

Citations 18

Authors

Flora Cartier

Emilie Indersie

Sarah Lesjean

Justine Charpentier

Katarzyna B Hooks

Amani Ghousein

Angelique Desplat

Nathalie Dugot-Senant

Veronique Trezeguet

Francis Sagliocco

Martin Hagedorn

Christophe F Grosset

Affiliations

Soon will be listed here.

Abstract

Glypican-3 (GPC3) is an oncogene, frequently upregulated in liver malignancies such as hepatocellular carcinoma (HCC) and hepatoblastoma and constitutes a potential molecular target for therapy in liver cancer. Using a functional screening system, we identified 10 new microRNAs controlling GPC3 expression in malignant liver cells, five of them e.g. miR-4510, miR-203a-3p, miR-548aa, miR-376b-3p and miR-548v reduce GPC3 expression. These 5 microRNAs were significantly downregulated in tumoral compared to non-tumoral liver and inhibited tumor cell proliferation. Interestingly, miR-4510 inversely correlated with GPC3 mRNA and protein in HCC samples. This microRNA also induced apoptosis of hepatoma cells and blocked tumor growth in vivo in the chick chorioallantoic membrane model. We further show that the tumor suppressive effect of miR-4510 is mediated through direct targeting of GPC3 mRNA and inactivation of Wnt/β-catenin transcriptional activity and signaling pathway. Moreover, miR-4510 up-regulated the expression of several tumor suppressor genes while reducing the expression of other pro-oncogenes. In summary, we uncovered several new microRNAs targeting the oncogenic functions of GPC3. We provided strong molecular, cellular and in vivo evidences for the tumor suppressive activities of miR-4510 bringing to the fore the potential value of this microRNA in HCC therapy.

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