Hepatocellular carcinoma (HCC) is one of the most prevalent life-threatening human cancers, with a rapidly increasing incidence worldwide. The pathogenesis of HCC is complex and consists of multiple interconnected molecular alterations. Current evidence indicates that altered iron metabolism plays an important role in the development and progression of HCC; however, there is a lack of conclusive information regarding the mechanisms of this dysregulation. In previous studies using different models of rodent carcinogenesis, we demonstrated prominent alterations of intracellular iron metabolism in preneoplastic livers, including changes in gene expression and the level of related proteins involved in the regulation of intracellular hepatic iron metabolism, primarily up-regulation of transferrin receptor 1 (TFRC). In the present study, we investigated the role and underlying mechanisms of the aberrant expression of TFRC, the main receptor controlling cellular iron uptake, in liver carcinogenesis. In both preneoplastic liver tissue from a relevant rat model of human HCC and in human HCC cells, there was a significant increase in the levels of TFRC mRNA and protein. This resulted in a substantial increase in TFRC/ferroportin (FPN) ratio, favoring an accumulation of iron in the HCC cells. The increase in levels of TFRC was attributed to a post-transcriptional microRNA-mediated mechanism. This was demonstrated by a computational analysis and confirmed experimentally by in vitro transfection experiments showing that transfection of human HCC cell lines with has-miR-152 effectively suppressed the expression of TFRC. Additionally, there was a strong inverse correlation between the level of TRFC and the expression of miR-152 in human HCC cells (r = -0.99, p = 4.7×10-9). Finally, the expression of TFRC and miR-152 in human HCC tissues was evaluated using the TCGA database. We observed an over-expression of TFRC in human HCC tissue samples and a markedly decreased level of miR-152 when compared to non-tumor liver tissue. These results demonstrate that dysregulation of cellular iron metabolism in liver carcinogenesis is driven by an up-regulation of TFRC, and indicate that miR-152-specific targeting of TFRC to decrease its levels may provide a selective anticancer therapeutic approach for the treatment of HCC.
Citation Format: Iryna Kindrat, Volodymyr Tryndyak, Aline de Conti, Svitlana Shpyleva, Anna Erstenyuk, Frederick A. Beland, Igor Pogribny. Mechanism of the transferrin receptor 1 dysregulation in hepatocarcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 920. doi:10.1158/1538-7445.AM2015-920