Tumor cells express vascular endothelial growth factor (VEGF) that can activate VEGF receptors (VEGFRs) on or within tumor cells to promote growth in an angiogenesis‐independent fashion; however, this autocrine VEGF pathway has not been reported in hepatocellular carcinoma (HCC). Sorafenib, an angiogenic inhibitor, is the only drug approved for use in advanced HCC patients. Yet the treatment efficacy is diverse and the mechanism behind it remains undetermined. Our aims were to study the molecular mechanisms underlying autocrine VEGF signaling in HCC cells and evaluate the critical role of autocrine VEGF signaling on sorafenib treatment efficacy. By immunohistochemistry, we found robust nuclear and cytoplasmic staining for active, phosphorylated VEGF receptor 1 (pVEGFR1) and phosphorylated VEGF receptor 2 (pVEGFR2), and by western blotting we found that membrane VEGFR1 and VEGFR2 increased in HCC tissues. We showed that autocrine VEGF promoted phosphorylation of VEGFR1 and VEGFR2 and internalization of pVEGFR2 in HCC cells, which was both pro‐proliferative through a protein lipase C‐extracellular kinase pathway and self‐sustaining through increasing VEGF, VEGFR1, and VEGFR2 mRNA expressions. In high VEGFR1/2‐expressing HepG2 cells, sorafenib treatment inhibited cell proliferation, reduced VEGFR2 mRNA expression in vitro, and delayed xenograft tumor growth in vivo. These results were not found in low VEGFR1/2‐expressing Hep3B cells. In an advanced HCC population on sorafenib treatment for postoperative recurrence, we found that the absence of VEGFR1 or VEGFR2 expression in resected tumor tissues before sorafenib treatment was associated with poorer overall survival. Conclusion: Autocrine VEGF signaling directly promotes HCC cell proliferation and affects the sorafenib treatment outcome in vitro and in vivo, which may enable better stratification for clinical treatment decisions. (Hepatology 2014;60:1264–1277)
Because the primary surgical treatment options for hepatocellular carcinoma (HCC)-including hepatic resection and liver transplantation-often fail due to recurrence and metastasis, identifying early prognostic biomarkers and therapeutic targets for HCC is of great importance. This study shows that transducin b-like protein 1-related protein (TBLR1) is a key HCC oncogene that plays important roles in HCC proliferation, antiapoptosis, and angiogenesis by regulating the Wnt/ b-catenin pathway. The folate-targeted theranostic small interfering RNA (siRNA) nanomedicine Fa-PEG-g-PEI-SPION/psiRNA-TBLR1 effectively silences the TBLR1 gene in different human HCC cell lines in vitro and in human HCC samples in vivo, resulting in the simultaneous suppression of HCC cell proliferation, antiapoptosis, and angiogenesis. Because of its multi-anticancer functions against HCC, intravenous injection of the folate-targeted siRNA nanomedicine into nude mice bearing intrahepatic or subcutaneous xenografts of human HCC has a significant therapeutic effect. Tumor growth in those animals was almost completely inhibited by treatment with Fa-PEG-g-PEI-SPION/ psiRNA-TBLR1. Moreover, the SPION-encapsulated polyplexes possess high magnetic resonance imaging (MRI) detection sensitivity, which makes tumor-targeted siRNA delivery easily trackable using the clinical MRI technique. Conclusion: The theranostic siRNA nanomedicine examined here possesses great potential for combined gene therapy and MRI diagnosis of HCC. (HEPATOLOGY 2016;63:1240-1255 H epatocellular carcinoma (HCC) is one of the most frequently diagnosed and aggressive malignancies, and more efficient therapeutic interventions are necessary for HCC.(1) Approximately 630,000 new cases of HCC are reported throughout the world every year, and approximately 55% of these cases occur in China. Despite the discovery of the molecular mechanisms of hepatocarcinogenesis and multimodal treatments involving extensive surgical resection, liver transplantation, radiotherapy, chemotherapy, and immunotherapy, the 5-year relative survival rates of patients with HCC are generally less than Abbreviations: ALT, alanine transaminase; HCC, hepatocellular carcinoma; IHC, immunohistochemical; MRI, magnetic resonance imaging; NIRF, near infrared fluorescence imaging; PEG, polyethylene glycol; PEI, polyethylenimine; RNAi, RNA interference; siRNA, small interfering RNA; SPION, superparamagnetic iron oxide nanoparticles; TBIL, total bilirubin; TBLR1, transducin b-like protein 1-related protein; TUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling; VEGF, vascular endothelial growth factor.
Fructose-1,6-bisphosphatase (FBP1), one of the rate-limiting gluconeogenic enzymes, plays critical roles in several cancers and is treated as a tumour suppressor. However, its role in hepatocellular carcinoma (HCC) is unclear. Here, we demonstrated that FBP1 was significantly inhibited during Snail-induced epithelial to mesenchymal transition (EMT) and tissues in HCC. Restoration of FBP1 expression in HCC cancer cells suppressed EMT phenotype, tumour migration and tumour growth induced by Snail overexpression in SMMC-7721 cells. Gene set enrichment analyses revealed significantly enriched terms, including WNT, Notch, ESC, CSR and PDGF, in the group with high Snail and low FBP1 compared with those with low Snail and high FBP1. Low FBP1 expression was significantly correlated with higher AFP level, satellite nodules, portal vein tumour thrombus, and advanced tumour stage. Survival analyses showed that FBP1 was an independent prognostic factor for overall survival and recurrence-free survival. In conclusion, our study revealed a vital role for FBP1 in Snail-induced EMT and prognostic prediction in HCC.
BackgroundPeripheral blood monocyte count is an easily assessable parameter of systemic inflammatory response. The aim of this study was to determine whether monocyte count was prognostic in hepatocellular carcinoma (HCC) following hepatic resection.MethodsWe retrospectively reviewed 351 patients with HCC treated with hepatic resection from 2006 to 2009. Preoperative absolute peripheral monocyte count, demographics, and clinical and pathological data were analyzed.ResultsOn univariate and multivariate analysis, elevated monocyte counts (≥545/mm3), tumor size ≥5 cm, non-capsulation, and multiple tumors were associated with poor disease-free survival (DFS) and overall survival (OS). The 1-, 3- and 5-year DFS rates were 58%, 41% and 35%, respectively, for patients with monocyte counts <545/mm3, and 36%, 23% and 21% for patients with monocyte counts ≥545/mm3. Correspondingly, the 1-, 3- and 5-year OS rates were 79%, 53% and 46% for monocyte counts <545/mm3, and 64%, 36% and 29% for monocyte counts ≥545/mm3. Subgroup analysis indicated that DFS after hepatic resection in hepatitis B virus (HBV)-infected patients was significantly better in those with a peripheral blood monocyte counts <545/mm3, but it did not differ between patients without HBV infection. In addition, DFS was significantly better for patients with a peripheral blood monocyte count <545/mm3, whether or not cirrhosis was present. Patients with elevated monocyte counts tended to have larger tumors.ConclusionsElevated preoperative monocyte count is an independent predictor of worse prognosis for patients with HCC after hepatic resection, especially for those with HBV infection. Postoperative adjuvant treatment might be considered for patients with elevated preoperative monocyte counts.
The objective of this study is to improve the overall prognosis of patients with hepatocellular carcinoma (HCC); therefore, new therapeutic methods that can be used in vivo are urgently needed. In this study, the relationship between the quantities of microRNA (miR)‐125b‐5p in clinical specimens and clinicopathological parameters is analyzed. A folate‐conjugated nanocarrier is used to transfect miR‐125b‐5p in vivo and to observe the therapeutic effect on HCC. The inhibitory effect and mechanism of miR‐125b‐5p on hepatoma cells are also studied. Data from clinical specimens and in vitro experiments confirm that the miR‐125b‐5p quantity is negatively correlated with progression, and the target protein that regulates the epithelial–mesenchymal transition (EMT)/cancer stem cells (CSC) potential in HCC is STAT3. The miR‐125b‐5p/STAT3 axis inhibits the invasion, migration, and growth of HCC via inactivation of the wnt/β‐Catenin pathway. miR‐125b‐5p‐loaded nanomedicine effectively inhibits the EMT/CSC potential of hepatoma cells in vivo together with their magnetic resonance imaging (MRI) visualization characteristics. An HCC‐therapeutic and MRI‐visible nanomedicine platform that achieves noninvasive treatment effect monitoring and timely individualized treatment course adjustment is developed.
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