CHST11/13 Regulate the Metastasis and Chemosensitivity of Human Hepatocellular Carcinoma Cells Via Mitogen-Activated Protein Kinase Pathway

Carbohydrate sulfotransferases 11–13 (CHST11–13), that catalyze the transfer of sulfate to position 4 of the GalNAc residue of chondroitin, have been implicated in various diseases. This study aimed to clarify the association of CHST11–13 expression with metastasis and drug sensitivity in hepatocellular carcinoma (HCC) cells. We measured the levels of CHST11 and CHST13 in a series of HCC cells using real-time PCR and Western blotting. After RNAi and forced expression treatment of CHST11 and CHST13 in MHCC97L and MHCC97H cells, metastatic potential and drug sensitivity of the two cells were investigated with ECM invasion assay, drug sensitivity assay, and in vivo antitumor activity assay. By real-time PCR and Western blotting, we explored the possible impacts of these two genes on mitogen-activated protein kinase (MAPK) signal pathway. MAPK pathway was blocked by PD98059 or SP600125 to elucidate the effects of MAPK pathway on metastasis and chemosensitivity. Significantly reduced levels of CHST11 and CHST13 were observed in highly invasive MHCC97H cells compared with those of MHCC97L cell line with low metastatic potential. Decreased or forced expression of CHST11 and CHST13 altered metastatic potential and drug sensitivity of MHCC97L and MHCC97H cells. Remarkable alteration of MAPK activity was shown in two HCC cells with genetic manipulation. Conversely, pharmacologic inhibition of the MAPK pathway suppressed invasive potential and rescued drug sensitivity of MHCC97H cells. Our results have demonstrated that CHST11 and CHST13 negatively modulate metastasis and drug resistance of HCC cells probably via oncogenic MAPK signal pathway.