Hepatocellular carcinoma (HCC) is a major leading cause of cancer-related death worldwide. Alpha fetoprotein (AFP) is reactivated in a majority of hepatocellular carcinoma (HCC) and associated with poor patient outcomes. Although increasing evidence has shown that AFP can regulate HCC cell growth, the precise functions of AFP in hepatocarcinogenesis and the associated underlying mechanism remain incompletely understood. In this study, we demostrated that depleting AFP significantly suppressed diethylnitrosamine (DEN)-induced liver tumor progression in an AFP gene-deficient mouse model. Similarly, knocking down AFP expression inhibited human HCC cell proliferation and tumor growth by inducing apoptosis. AFP expression level was inversely associated with the apoptotic rate in mouse and human HCC specimens. Investigation of potential cross-talk between AFP and apoptotic signaling revealed that AFP exerted its growth-promoting effect by suppressing the Fas/FADD-mediated extrinsic apoptotic pathway. Mechanistically, AFP bound to the RNA-binding protein HuR, increasing the accumulation of HuR in the cytoplasm and subsequent inhibition of Fas mRNA translation. In addition, we found that inhibiting AFP enhanced the cytotoxicity of therapeutics to AFP-positive HCC cells by activating HuR-mediated Fas/FADD apoptotic signaling. Conclusion: Our study defined the pro-oncogenic role of AFP in HCC progression and uncovered a novel antiapoptotic mechanism connecting AFP to HuR-mediated Fas translation. Our findings suggest that AFP is involved in the pathogenesis and chemosensitivity of HCC and that blockade of AFP may be a promising strategy to treat advanced HCC.

No abstract

MicroRNA-126 (miR-126) has been found to promote angiogenesis, but the underlying mechanisms are still unclear. So, we conducted this study to explore the effect of miR-126 expression on angiogenesis in hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). The expression levels of miR-126 and sprouty-related, EVH1 domain containing protein (Spred)1 in surgically resected HCC tissue, HCC tissue with TACE + operation, and tumor-adjacent tissues were determined by quantitative real-time polymerase chain reaction. The expression levels of miR-126, Spred1, and vascular endothelial growth factor were found by quantitative real-time polymerase chain reaction and Western blot. The microvessel density (MVD) of tumor tissues was determined by immunohistochemical staining. The miR-126 and Spred1 expressions in HCC tissue with TACE + operation were elevated and decreased, respectively, as compared to those in surgically resected HCC tissues and tumor-adjacent tissues (all P<0.001), which indicated that the expression of Spred1 was negatively correlated with miR-126 (P<0.001, r=−0.6224). Based on the bioinformatics analysis and luciferase reporter gene activity detection, Spred1 was found to target miR-126 (P<0.001). Inhibition of miR-126 expression reduces the degree of weight loss and tumor size in TACE model rats. The MVD in TACE + operation group was increased compared to that in the control group; inhibition of miR-126 expression had a reversal effect, to a certain extent, on MVD increase after TACE (all P<0.05). Inhibition of miR-126 expression increased Spred1 expression and decreased vascular endothelial growth factor expression (P<0.01). In summary, this study unveiled the potential mechanism by which miR-126 regulates angiogenesis in HCC tissues through embolization treatment by targeting Spred1, and also showed that the feasibility of TACE with the miR-126 inhibitor has a certain value in the medical treatment of HCC.

This study evaluated if iodine-125 brachytherapy prophylaxis after radiofrequency ablation (RFA) prolongs time to recurrence (TTR) and overall survival (OS) of patients in high risk of locoregional hepatocellular carcinoma (HCC) recurrence. 116 patients with total tumor necrosis after RFA were divided into iodine-125 brachytherapy prophylaxis treatment group and control group. The primary endpoint was TTR, and secondary endpoints were OS and treatment-related adverse events. There were no significant differences among the baseline characteristics of two subgroups patients. The mean iodine-125 particles were 29.8 (26.59 ± 12.51 mCi) per patient. The mean follow-up was 25 months, and mean TTR of treatment and control groups were 21.7 and 15.9 months (P = 0.733); mean OS of two subgroups were 41.7 and 40.9 months (P = 0.316). There were no significant differences of 1-, 2-, 3-, 4-and 5-years TTR and OS and patients’ immunity pre- and 1 month post-treatment. Extrahepatic metastasis was found to have a statistically significant influence on TTR, and AFP, extrahepatic metastasis were found to have a statistically significant influence on OS by multivariate analysis. There was no major complications and procedure related death. Iodine-125 brachytherapy prophylaxis after RFA can’t improve TTR and OS of HCC patients who were in high risk of locoregional tumor recurrence.