HMGB1 promotes progression of intrahepatic cholangiocarcinoma through regulating Erk1/2, Cyclin D1 and MMP14 proteins

Abstract

Objective To explore the effect and the mechanism of high mobility group box1 (HMGB1) in the progression of intrahepatic cholangiocarcinoma (ICC). Methods The expression of HMGB1 in ICC specimens obtained from 75 patients was examined by immunohistochemistry (IHC). The correlation between HMGB1 expression level and clinicopathologic characteristics was analyzed. In in vitro study, ICC cells were treated with exogenous HMGB1 and siRNA, then the effect of HMGB1 on ICC cells malignant biological behavior was assessed using CCK-8 assay, cell migration and invasion assay. Western blot analysis was used to detect intracellular proteins. Results IHC results showed that overexpression of HMGB1 was found in 54.6% (41/75) ICCs. The overexpression of HMGB1 was significantly correlated with tumor differentiation grade (P=0.019), TNM stage (P=0.017) and vessel invasion (P=0.033). CCK-8 assay showed that exogenous HMGB1 promoted the proliferation of HuCCT-1 cells (P < 0.05). Cell migration assay indicated that exogenous HMGB1 treatment promoted cell migration by 1.85±0.28 fold (P < 0.01), and siRNA treatment reduced cell migration by 0.48±0.04 fold (P < 0.01). Similarly, exogenous HMGB1 increased invasion of HuCCT-1 cells by 1.46±0.05 fold (P < 0.01) through matrigel layer, and siRNA treatment reduced cell invasion by 0.67±0.07 (P < 0.01). Western blotting indicated that the expression of Erk1/2, Cyclin D1 and MMP14 were up-regulated in the cells treated with exogenous HMGB1. Moreover, Western blot results showed that suppression of HMGB1 by siRNA induced the down-regulation of MMP14. Conclusion HMGB1 plays a role in the progression of ICC, and the mechanism may be involved in the regulation of Erk1/2, Cyclin D1 and MMP14 proteins.

Keywords

• intrahepatic cholangiocarcinoma
• high mobility group box1
• extracellular signal regulated kinase
• cyclin d1
• matrix metalloproteinases 14