Krüppel-like factor 8 promotes cancer stem cell-like traits in hepatocellular carcinoma through Wnt/ß-catenin signaling.

Krüppel-like factor 8 (KLF8) is highly expressed in hepatocellular carcinoma (HCC) and contributes to tumor initiation and progression by promoting HCC cell proliferation and invasion. However, the role of KLF8 in liver cancer stem cells (LCSCs) is not known. In the current study, we investigated the role of KLF8 in LCSCs to determine if KLF8 is a novel marker of these cells. We found that KLF8 was highly expressed in primary HCC tumors, distant migrated tissues, and LCSCs. Patients with high KLF8 expression had a poor prognosis. KLF8 promoted stem cell-like features through activation of the Wnt/ß-catenin signaling pathway. Cell apoptosis was significantly increased in HCC cells with knockdown of KLF8 compared with the control cells when treated with the same doses of sorafenib or cisplatin. Taken together, our study shows that KLF8 plays a potent oncogenic role in HCC tumorigenesis by maintaining stem cell-like features through activation of the Wnt/ß-catenin signaling pathway and promoting chemoresistance. Thus, targeting KLF8 may provide an effective therapeutic approach to suppress tumorigenicity of HCC. © 2016 Wiley Periodicals, Inc.

Surgery for hepatocellular carcinoma presenting with variceal bleeding: The eastern experience.

BACKGROUND: Variceal bleeding can be the first manifestation of patients with newly diagnosed hepatocellular carcinoma (HCC), and effective treatments deserve to be explored for these patients. METHODS: A prospectively collected database of HCC patients undergoing hepatectomy identified 75 patients who presented with variceal bleeding. Among them, 31 patients underwent concomitant Hassab's operation. The clinical variables and outcomes were compared between the Hassab and non-Hassab groups. RESULTS: The postoperative morbidity and 90-days mortality were 44.0% and 6.7% respectively. Variceal re-bleeding and tumor recurrence occurred in 28.8% and 52.1% of surviving patients after surgery, and the 1-, 3-, and 5-year overall survival rates were 87.7, 66.8, and 50.3%. There were no significant differences in morbidity, mortality and postoperative recurrence between the Hassab and non-Hassab groups. However, patients in the Hassab group had significantly higher 1-, 3-, and 5-year overall survival rates (P = 0.038), and significantly lower rate of re-bleeding (13.3% vs. 39.5%, P = 0.014) than those in the non-Hassab group. On multivariable analysis, concomitant Hassab's operation was independently predicted longer overall survival. CONCLUSION: Liver resection could safely be performed in selected patients with HCC who presented with variceal bleeding, and concomitant Hassab's operation may improve long-term prognosis for these patients.

TGF-ß regulates hepatocellular carcinoma progression by inducing Treg cell polarization.

BACKGROUND/AIMS: TGF-ß plays a key role in the progression of various tumors. The main objective of our study was to investigate whether TGF-ß is able to regulate N-nitrosodiethylamine (DEN)-induced hepatocellular carcinoma (HCC) progression in a mouse model by inducing Treg cell polarization. METHODS: HCC progression, TGF-ß and Foxp3 expression levels, serum TGF-ß, IL10 and GP73 levels as well as percentage of Treg cells were analyzed in healthy, HCC and HCC+SM-16 mouse groups. The effect of TGF-ß on Treg cell polarization in vitro was measured by flow cytometric analysis. The expression of TGF-ß and IL10 was identified by IHC in HCC patients and the correlation between TGF-ß and IL10 was also assessed. RESULTS: TGF-ß expression is up-regulated in a DEN-induced HCC mouse model. TGF-ß can promote the differentiation of Foxp3(+)CD4(+) T cells (Treg cells) in vitro. However, blocking the TGF-ß pathway with a specific TGF-ß receptor inhibitor, SM-16, reduced HCC progression and the percentage of Treg cells in liver tissue. The correlation between TGF-ß and Treg cells was also confirmed in HCC patients and the expression of both TGF-ß and IL-10 was shown to be associated with HCC progression. CONCLUSION: TGF-ß is necessary for HCC progression, acting by inducing Treg cell polarization.