Oct4 and Nanog are key regulatory genes that maintain the pluripotency and self-renewal properties of embryonic stem cells. We previously reported that the two stemness markers were tightly associated with cancer progression and poor outcomes of hepatocellular carcinoma. In this study, we demonstrate that coexpression of Oct4/Nanog modulates activation of signal transducer and activator of transcription 3 (Stat3), an oncogenic transcription factor that is activated in many human malignancies including hepatocellular carcinoma (HCC), as well as the expression of Snail, a key regulator implicated in epithelial-mesenchymal transition and tumor metastasis. Oct4 and Nanog were ectopic expressed in MHCC97-L cell lines via lentiviral gene transfection. The stemness characteristics including self-renewal, proliferation, chemoresistance, and tumorigenicity were assessed. The effect of coexpression of Oct4 and Nanog on epithelial-mesenchymal transition change, and the underlying molecular signaling was investigated. Ectopic coexpression of Oct4 and Nanog empowered MHCC97-L cells with cancer stem cell (CSC) properties, including self-renewal, extensive proliferation, drug resistance, and high tumorigenic capacity. Significantly, Oct4 and Nanog encouraged epithelial-mesenchymal transition change contributing to tumor migration, invasion/metastasis in vitro and in vivo. Following molecular mechanism investigation indicated Oct4/Nanog-regulated epithelial-mesenchymal transition change through Stat3-dependent Snail activation. Moreover, silencing Stat3 abrogates Oct4/Nanog-mediated epithelial-mesenchymal transition (EMT) change and invasion/metastasis in HCC. We delineate Oct4 and Nanog initiate stem cell characteristics in hepatocellular carcinoma and promote epithelial-mesenchymal transition through activation of Stat3/Snail signaling. Our findings propose Stat3/Snail pathway as a novel therapeutic target for the treatment of progression and metastasis of HCC with CSC-like signatures and epithelial-mesenchymal transition phenotype.

Background: Although transarterial chemoembolization (TACE) has been used extensively for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT), no consensus has been reached and an evidence base for practice is lacking. This meta-analysis evaluated the efficacy and safety of TACE for treatment of HCC with PVTT. Methods: Ovid Medline, EMBASE, Web of Knowledge, and Cochrane library databases were searched up to August 2012 for controlled trials assessing TACE in patients with PVTT. Data concerning the study design, characteristics of trials, and outcomes were extracted. Hazard ratio (HR) and 95% confidence interval (CI) were calculated using random effects models. Results: Eight controlled trials involving 1601 HCC patients were included. TACE significantly improved the 6-month (HR, 0.41; 95% CI: 0.32–0.53; z, 6.28; p = 0.000) and 1-year (HR, 0.44; 95% CI: 0.34–0.57; z, 6.22; p = 0.000) overall survival of patients with PVTT compared with conservative treatment. Subgroup analyses showed that TACE was significantly effective in HCC patients whether with main portal vein (MPV) obstruction or with segmental PVTT. Fatal complications were rare, even in patients with MPV obstruction. Temporary liver decompensation and postembolization syndrome occurred frequently. However, they could be treated successfully with conservative treatment. Conclusions: TACE, as a safe treatment, has potential for incurring a survival benefit for advanced HCC with PVTT, even with MPV obstruction. Further large randomized controlled trials may be needed to confirm this result.

Background Intrahepatic cholangiocarcinoma (ICC) is a highly mortal malignancy with limited therapeutic options. Immunotherapies targeting PD-1/PD-L1 pathway represent a promising treatment for ICC. However, PD-L1 expression and microsatellite instability are not common in ICC. This study aimed to investigate whether HHLA2, a newly identified B7 family immune checkpoint for T cells, could be a therapeutic target next to PD-L1 in ICC. Methods Expression levels of PD-L1 and HHLA2 as well as infiltrations of CD3+, CD8+, CD4 + Foxp3+, CD68+, CD163+ and CD20+ cells were evaluated by immunohistochemistry in 153 resected ICC samples. Comprehensive comparisons were made between PD-L1 and HHLA2 in terms of the expression rates, clinicopathological features and infiltrations of different immune cells. The expression level and prognostic significance of HHLA2 were further validated in an independent cohort. Results Expression of HHLA2 is more frequent than PD-L1 in ICC (49.0% vs 28.1%). Co-expression of both immune checkpoints was infrequent (13.1%) and 50% PD-L1 negative cases were with elevated HHLA2. HHLA2 overexpression was associated with sparser CD3+ tumor infiltrating lymphocytes (TILs), CD8+ TILs and a higher CD4 + Foxp3+/CD8+ TIL ratio, whereas PD-L1 expression was associated with prominent T cells and CD163+ tumor associated macrophages infiltrations. PD-L1 failed to stratify overall survival (OS) but HHLA2 was identified as an independent prognostic indicator for OS in two independent cohorts. Conclusions Compared with PD-L1, HHLA2 is more prevalent and possesses more explicit prognostic significance, which confer the rationale for HHLA2 as a potential immunotherapeutic target next to PD-L1 for ICC patients.

Pilot studies have evaluated the correlation between hypoxia-inducible factor-1α (HIF-1α) overexpression and clinical outcome in hepatocellular carcinoma (HCC) patients. However, the results remain inconclusive. To comprehensively and quantitatively summarize the evidence on the suitability of HIF-1α to predict the prognosis of patients with HCC, a meta-analysis was carried out. Systematic literature searches were applied to PubMed, Elsevier and Web of Science databases until Feb. 2013. Seven studies (953 patients) were included in this meta-analysis. Pooled measure was calculated from the available data to evaluate the association between tissue -based HIF-1α level and overall survival (OS) and disease-free survival (DFS) in HCC patients. The relation between HIF-1α expression and vascular invasion was also assessed. Data were synthesized with fixed or random effect model, hazard ration (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. The combined data suggested that HIF-1α overexpression in HCC correlated with poor OS [HR = 1.65 (95% (CI): 1.38, 1.97)] and DFS [HR = 2.14 (95% CI: 1.39, 3.29)]. And high HIF-1α expression tended to be associated with vascular invasion [OR = 2.21 (95% CI: 1.06, 4.57)]. HIF-1α overexpression indicates a poor prognosis for patients with HCC, it may also have predictive potential for HCC invasion and metastasis.

Backgrounds: There have been conflicting reports about serum golgi protein 73 (GP73) as one of the most promising serum markers for the diagnosis of hepatocellular carcinoma (HCC). This study was to make a systematic review about the diagnostic accuracy of serum GP73 versus alpha-fetoprotein (AFP) for HCC. Methods: After a systematic review of related studies, sensitivity, specificity and other measures about the accuracy of serum GP73 and AFP in the diagnosis of HCC were pooled using random-effects models. Summary receiver operating characteristic curve analysis was used to summarize the overall test performance. Results: Eight studies were included in our meta-analysis. The summary estimates for serum GP73 and AFP in diagnosing HCC in the studies included were as follows: sensitivity, 76% (95% confidence interval (CI) 51-91%) vs. 70% (47-86%); specificity, 86% (95%CI 65-95%) vs. 89% (69-96%); diagnostic odds ratio (DOR), 18.59 (95%CI 5.33-64.91) vs. 18.00(9.41-34.46); and area under sROC, 0.88 (95%CI 0.77-0.99) vs. 0.86 (95%CI 0.84-0.87). Conclusions: The current evidence indicates that serum GP73 has a comparable accuracy to AFP for the diagnosis of HCC, while the value of serum GP73 in combination with AFP for HCC detection deserves further investigation.