ABSTRACT
Liver cancer stem cells (CSCs) contribute to tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver CSCs remains unclear. Herein, we observed low expression of miR-194 in chemoresistant HCC cells. A remarkable decrease of miR-194 was detected in EpCAM or CD133-positive liver CSCs and CSC-enriched hepatoma spheres. Interference miR-194 facilitated liver CSCs expansion by enhancing the self-renewal of liver CSCs. While up-regulating miR-194 inhibited liver CSCs expansion by suppressing the self-renewal of liver CSCs. Furthermore, hepatoma cells with miR-194 overexpression performed more sensitivity to sorafenib treatment. Mechanistically, functional studies found that Ras-related C3 botulinum toxin substrate 1 (RAC1) was a direct target of miR-194. Overexpression of miR-194 inhibited the expression of RAC1 in liver CSCs. Special RAC1 siRNA diminished the discrepancy in liver CSC proportion and the self-renewal capacity between miR-194 overexpression hepatoma cells and control cells, which further confirmed that RAC1 was required in miR-194-inhibited liver CSCs expansion. More importantly, downregulated expression of miR-194 was a predictor of poor prognosis of HCC patients.
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , MicroRNAs/genetics , Neoplastic Stem Cells/metabolism , rac1 GTP-Binding Protein/metabolism , Animals , Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Self Renewal , Cells, Cultured , Down-Regulation , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Mice , Mice, Inbred NOD , Mice, SCID , MicroRNAs/metabolism , rac1 GTP-Binding Protein/geneticsABSTRACT
AIM: to determine the efficacy and toxicities of sorafenib in the treatment of patients with multiple recurrences of hepatocellular carcinoma (HCC) after liver transplantation in a Chinese population. METHODS: twenty patients with multiple recurrences of HCC after liver transplantation were retrospectively studied. They received either transarterial chemoembolization (TACE) or TACE combined with sorafenib. RESULTS: the median survival times (MST) after multiple recurrences was 14 months (TACE+sorafenib group) and 6 months (TACE only group). The difference was significant in MST between the two groups (P=0.005). The TACE + sorafenib group had more stable disease (SD) patients than the TACE group. The most frequent adverse events of sorafenib were hand-foot skin reaction and diarrhea. In the univariate analysis, preoperative bilirubin and CHILD grade are found to be significantly associated with tumor-free survival time, the survival time after multiple recurrences and overall survival time. TACE+sorafenib group showed a better outcome than single TACE treatment group. In the multivariate COX regression modeling, the preoperative high CHILD grade was found to be a risk factor of tumor-free survival time. In addition, the preoperative high bilirubin grade was also found to be a risk factor of survival time after recurrence and overall survival time. Furthermore, survival time after recurrence and overall survival time were also associated with therapeutic schedule, which was indicated by the GROUP. CONCLUSION: Treatment with TACE and sorafenib is worthy of further study and may have more extensive application prospects.