Hepatocellular carcinoma (HCC) cells invade interstitial connective tissue and proliferate. Suppression of this invasion and proliferation could serve as a novel molecular therapy. Since insulin-like growth factor-I receptor (IGF-IR) interacts with components of interstitial tissue, we focused on the inhibition of IGF-IR, analyzing HLE and HLF, poorly-differentiated HCC cells, as well as PLC/PRF/5 and Huh-7, well-differentiated HCC cells. Cell numbers were counted under serum starvation. Western blot analysis showed that all cell lines clearly expressed IGF-IR. Either a neutralizing antibody of IGF-IR or picropodophyllin (PPP), a specific inhibitor of IGF-IR, were used, with MTS assay, to analyze changes in cell number or, with wound assay, to analyze invasion. HLF significantly proliferated without serum while the cell numbers of the other cell lines did not. IGF-IR antibody did not affect HLF cell number, while PPP decreased it. Wound assay clearly indicated that PPP inhibited the invasion of HLF. H&E staining showed that apoptosis caused the inhibition of proliferation and metastasis. In conclusion, IGF-IR was involved in the proliferation and invasion of HCC cells in interstitial connective tissue. It was proposed that an inhibitor of IGF-IR, PPP, would be a good candidate for molecular therapy for HCC via the suppression of proliferation/invasion in interstitial connective tissue.

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