eIF4A1 Is a Prognostic Marker and Actionable Target in Human Hepatocellular Carcinoma

• Published in: International journal of molecular sciences 2023-01, Vol.24 (3), p.2055
• Main Authors: Steinmann, Sara M, Sánchez-Martín, Anabel, Tanzer, Elisabeth, Cigliano, Antonio, Pes, Giovanni M, Simile, Maria M, Desaubry, Laurent, Marin, Jose J G, Evert, Matthias, Calvisi, Diego F
• Format: Article
• Language: English
• Subjects: Apoptosis; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; Cell Proliferation; Esophagus; Eukaryotic Initiation Factor-4A - genetics; Eukaryotic Initiation Factor-4A - metabolism; Gene expression; Hepatocellular carcinoma; Human health and pathology; Humans; Inhibitors; Initiation factor eIF-4A; Life Sciences; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Medical prognosis; Metastasis; Prognosis; Proteins; Therapeutic targets; TOR protein; Transplantation; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24032055

Hepatocellular carcinoma (HCC) is a primary liver tumor with high lethality and increasing incidence worldwide. While tumor resection or liver transplantation is effective in the early stages of the disease, the therapeutic options for advanced HCC remain limited and the benefits are temporary. Thus, novel therapeutic targets and more efficacious treatments against this deadly cancer are urgently needed. Here, we investigated the pathogenetic and therapeutic role of eukaryotic initiation factor 4A1 (eIF4A1) in this tumor type. We observed consistent eIF4A1 upregulation in HCC lesions compared with non-tumorous surrounding liver tissues. In addition, levels were negatively correlated with the prognosis of HCC patients. In HCC lines, the exposure to various eIF4A inhibitors triggered a remarkable decline in proliferation and augmented apoptosis, paralleled by the inhibition of several oncogenic pathways. Significantly, anti-growth effects were achieved at nanomolar concentrations of the eIF4A1 inhibitors and were further increased by the simultaneous administration of the pan mTOR inhibitor, Rapalink-1. In conclusion, our results highlight the pathogenetic relevance of eIF4A1 in HCC and recommend further evaluation of the potential usefulness of pharmacological combinations based on eIF4A and mTOR inhibitors in treating this aggressive tumor.