Experimental Tumor Pathology, Institute of Pathology, University Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain.
Int J Mol Sci. 2023 Jan 20;24(3):2055. 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.
肝细胞癌 (HCC) 是一种原发性肝脏肿瘤，具有高致死率和全球范围内发病率不断上升的特点。虽然肿瘤切除术或肝移植在疾病早期是有效的，但晚期 HCC 的治疗选择仍然有限，且疗效是暂时的。因此，迫切需要针对这种致命癌症的新治疗靶点和更有效的治疗方法。在这里，我们研究了真核起始因子 4A1 (eIF4A1) 在这种肿瘤类型中的发病机制和治疗作用。我们观察到 HCC 病变中与非肿瘤周围肝组织相比，eIF4A1 持续上调。此外，水平与 HCC 患者的预后呈负相关。在 HCC 系中，暴露于各种 eIF4A 抑制剂会显著降低增殖并增加细胞凋亡，同时抑制几种致癌途径。重要的是，eIF4A1 抑制剂的纳摩尔浓度即可实现抗生长作用，并且通过同时施用 pan mTOR 抑制剂 Rapalink-1 进一步增加。总之，我们的结果强调了 eIF4A1 在 HCC 中的发病机制相关性，并建议进一步评估基于 eIF4A 和 mTOR 抑制剂的药物组合在治疗这种侵袭性肿瘤方面的潜在有用性。
