Transcriptional activation of the IGF-II/IGF-1R axis and inhibition of IGFBP-3 by miR-155 in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is characterized by the aberrant expression of a number of genes that govern crucial signaling pathways. The insulin-like growth factor (IGF) axis is important in this context, and the precise regulation of expression of members of this axis is known to be lost in HCC. miR-155 is a well-established oncogene in numerous types of cancer. However, to the best of our knowledge, its effect on the regulation of the IGF axis has not been investigated to date. The present study aimed to elucidate the interactions between miR-155 and key components of the IGF axis, in addition to examining its effect on HCC development. Reverse transcription-quantitative polymerase chain reaction was used to measure the expression of miR-155 in HCC and cirrhotic tissues, in addition to HCC cell lines. Furthermore, the effect of the induction of miR-155 expression on the expression of three members of the IGF axis [IGF II, IGF type-1 receptor (IGF-1R) and IGF-binding protein 3 (IGFBP-3)], was analyzed. Finally, the effect of miR-155 on HCC cell proliferation, migration and clonogenicity was also examined. Quantification of the expression of miR-155 demonstrated that it is upregulated in HCC. Induction of the expression of miR-155 in HCC cell lines led to the upregulation of IGF-II and IGF-IR, and the downregulation of IGFBP-3. In addition, the proliferation, migration and clonogenicity of HCC was increased following induction of miR-155 expression. miR-155 is an oncomiR, which upregulates the oncogenes, IGF-II and IGF-IR, and downregulates the tumor suppressor, IGFBP-3, thereby resulting in increased HCC cell carcinogenicity. Therefore, miR-155 may be a therapeutic target in HCC.