Suppression of actopaxin impairs hepatocellular carcinoma metastasis through modulation of cell migration and invasion.

UNLABELLED: Early reports suggested that actopaxin, a member of the focal adhesion proteins, regulates cell migration. Here we investigated whether actopaxin is involved in hepatocellular carcinoma (HCC) progression and metastasis. We examined actopaxin expression in human HCC samples using immunohistochemistry and western blotting. The functional and molecular effect of actopaxin was studied in vitro by overexpression in a nonmetastatic HCC cell line, as well as repression in a metastatic cell line. The in vivo effect of actopaxin repression was studied in nonobese diabetic and severe combined immunodeficient mice. We found that actopaxin was frequently overexpressed in human HCC patients and its overexpression positively correlated with tumor size, stage, and metastasis. Actopaxin expression also correlated with the metastatic potential of HCC cell lines. Actopaxin overexpression induced the invasion and migration ability of nonmetastatic HCC cells, whereas down-regulation of actopaxin reverted the invasive phenotypes and metastatic potential of metastatic HCC cells through regulating the protein expression of certain focal adhesion proteins including ILK, PINCH, paxillin, and cdc42, as well as regulating the epithelial-mesenchymal transition pathway. Furthermore, there was a close association between actopaxin and CD29. HCC cells with stronger CD29 expression showed a higher actopaxin level, whereas actopaxin repression attenuated CD29 activity. Finally, actopaxin down-regulation enhanced the chemosensitivity of HCC cells towards oxaliplatin treatment by way of a collective result of suppression of survivin protein, ß-catenin, and mammalian target of rapamycin pathways and up-regulation of p53. CONCLUSION: This study provides concrete evidence of a significant role of actopaxin in HCC progression and metastasis, by way of regulation of cell invasiveness and motility, an epithelial-mesenchymal transition process, and chemosensitivity to cytotoxic drugs.

Immediate and long-term outcomes of hepatectomy for hepatolithiasis.

OBJECTIVE: The aim of this study was to evaluate the perioperative and long-term results of hepatectomy for hepatolithiasis. PATIENTS AND METHODS: Immediate and long-term outcomes of 103 consecutive patients with hepatolithiasis who underwent hepatectomy from 1989 to 2001 were analyzed. Immediate outcomes included stone clearance rate, operative morbidity, and mortality. Long-term results included stone recurrence rate and survival. RESULTS: The immediate stone clearance rate was 90%, and the final stone clearance rate was 98% after subsequent choledochoscopic lithotripsy by cutaneous stoma or T-tube route. The operative morbidity and hospital mortality rates were 28% and 2%, respectively. Multivariate analysis showed that right hepatectomy (P=.006) and preoperative hyperbilirubinemia (P=.038) were predictive of postoperative complications. Ten patients (10%) had associated cholangiocarcinoma (four known preoperatively) at the time of hepatectomy. With a median follow-up of 56 months (range 6-158), recurrent stones developed in eight patients and cholangiocarcinoma developed in three patients (range: 7-30 months postoperatively). Sixteen patients had died during the follow-up period, none of recurrent cholangitis. Cholangiocarcinoma was the only significant prognostic factor of long-term survival by Cox regression analysis. CONCLUSIONS: Hepatectomy is a safe and effective treatment for hepatolithiasis, with a high immediate stone clearance rate and a low long-term stone recurrence rate. The presence of associated cholangiocarcinoma is the main factor compromising long-term survival in patients with hepatolithiasis.