scholarly journals Treatment with low-dose sorafenib in combination with a novel benzimidazole derivative bearing a pyrolidine side chain provides synergistic anti-proliferative effects against human liver cancer

RSC Advances ◽  
2017 ◽  
Vol 7 (26) ◽  
pp. 16253-16263 ◽  
Author(s):  
Ming-Hua Hsu ◽  
Shih-Ming Hsu ◽  
Yu-Cheng Kuo ◽  
Chih-Yu Liu ◽  
Cheng-Ying Hsieh ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Human Liver ◽  
Low Dose ◽  
Benzimidazole Derivative ◽  
Side Chain ◽  
The World ◽  
Human Liver Cancer

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and deadliest cancers in the world.

scholarly journals ImmunoPET as Stoichiometric Sensor for Glypican-3 in Models of Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Olivia J. Kelada ◽  
Nicholas T. Gutsche ◽  
Meghan Bell ◽  
Rose M. Berman ◽  
Kwamena E. Baidoo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Flow Cytometry ◽  
Liver Cancer ◽  
Cell Lines ◽  
Human Liver ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Human Liver Cancer ◽  
Gpc3 Expression

BackgroundHepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. While conventional imaging approaches like ultrasound, CT, and MRI play critical roles in the diagnosis and surveillance of HCC, improved methods for detection and assessment of treatment response are needed. One promising approach is the use of radiolabeled antibodies for positron emission tomography (immunoPET) imaging. Glypican-3 (GPC3) is a proteoglycan that is highly expressed in the majority of HCC tumors. GPC3-specific antibodies are used to diagnose HCC histopathologically, and have been proposed as a treatment of HCC. Here, we design, synthesize and demonstrate that our humanized immunoPET agent, [89Zr]Zr-DFO-TAB-H14, can stoichiometrically bind to models of human liver cancer with varied GPC3 expression. Methods: The GPC3-specific monoclonal humanized IgG1, TAB-H14, was used as a scaffold for engineering our immunoPET agent. Fluorescent and deferroxamine (DFO) chelate conjugates of TAB-H14 were characterized using mass spectrometry. Binding affinity of TAB-H14 and conjugates for GPC3 was determined in cell-free biolayer interferometry, and cell-based radioimmunoassays. GPC3-expression was assessed by flow cytometry and immunofluorescence using commercially available anti-GPC3 antibodies and TAB-H14 in GPC3−(A431) and GPC3+ cell lines including an engineered line (A431-GPC3+, G1) and liver cancer lines (HepG2, Hep3B, and Huh7). DFO-TAB-H14, was radiolabeled with Zr-89. Mice were subcutaneously engrafted with the aforementioned cell lines and in vivo target engagement of the immunoPET agent [89Zr]Zr-DFO-TAB-H14 was determined using PET/CT, quantitative biodistribution, and autoradiography. Results: TAB-H14 demonstrated subnanomolar to nanomolar affinity for human GPC3. Fluorescently tagged TAB-H14 was able to bind to GPC3 on cell membranes of GPC3-expressing lines by flow cytometry. These results were confirmed by immunofluorescence staining of A431, G1 HepG2, Hep3B, and Huh7 tumor sections. ImmunoPET imaging with [89Zr]Zr-DFO-TAB-H14 showed stoichiometric tumor uptake corresponding to the cell surface expression levels. Autoradiography and immunostaining confirmed in vivo findings. Conclusion: We systematically demonstrate that the humanized immnoPET agent [89Zr]Zr-DFO-TAB-H14 specifically and stoichiometrically binds to GPC3 in several models of human liver cancer, serving as a promising in vivo GPC3 sensor. This agent may provide utility in HCC diagnosis and surveillance, and the selection of candidates for GPC3-directed therapies.

scholarly journals Fermentable fiber-induced hepatocellular carcinoma in mice recapitulates gene signatures found in human liver cancer

PLoS ONE ◽  
2020 ◽  
Vol 15 (6) ◽  
pp. e0234726 ◽  
Author(s):  
Darshan Shimoga Chandrashekar ◽  
Rachel M. Golonka ◽  
Beng San Yeoh ◽  
David J. Gonzalez ◽  
Mathias Heikenwälder ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Human Liver ◽  
Gene Signatures ◽  
Human Liver Cancer

scholarly journals EZH2-mediated epigenetic silencing of ZIC4 in hepatocellular carcinoma

2020 ◽  
Author(s):  
Jinghui Wang ◽  
Zhu Yang ◽  
Fengxi Long ◽  
Li Luo ◽  
Gao Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Human Liver ◽  
Antitumor Effect ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Silencing ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Human Liver Cancer

Abstract Background: The present study aimed to explore the role of ZIC4 in human liver cancer.Methods: Illumina450 genome-wide methylation data was downloaded from The Cancer Genome Atlas for 50 available liver tumor/surrounding pairs. Wound healing test, colony formation and flow cytometry assay were utilized to analyze cell migration, survival and apoptosis. The effects of EZH2 and ZIC4 on tumor growth were also investigated through in vivo xenograft and orthotopic implantation experiments. Results: ZIC4 was hypermethylated in liver cancer tissues and cell lines. EZH2 knockdown and DZNep mediated H3K27me3 contributes to ZIC4 expression. The antitumor effect of EZH2 knockdown on hepatocellular carcinoma growth, metastasis and epithelial-mesenchymal transition progression in vitro were rescued by sh-ZIC4. Downregulation of ZIC4 also rescued the antitumor effect of DZNep in vivo.Conclusions: Epigenetic silencing of ZIC4 by EZH2 mediated H3K27me3 is an important mechanism in human liver cancer and provide a new therapeutic target for the treatment of hepatocellular carcinoma disease.

scholarly journals Pathogenetic and Prognostic Significance of Inactivation of RASSF Proteins in Human Hepatocellular Carcinoma

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Diego F. Calvisi ◽  
Matthias Evert ◽  
Frank Dombrowski
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Human Liver ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Prognostic Significance ◽  
Dismal Prognosis ◽  
Human Liver Cancer ◽  
Cellular Inhibitors

Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide, with limited treatment options and a dismal prognosis. Thus, there is a strong need to expand the basic and translational research on this deadly disease in order to improve the prognosis of HCC patients. Although the etiologic factors responsible for HCC development have been identified, the molecular pathogenesis of liver cancer remains poorly understood. Recent evidence has shown the frequent downregulation of Ras association domain family (RASSF) proteins both in the early and late stages of hepatocarcinogenesis. Here, we summarize the data available on the pathogenetic role of inactivation of RASSF proteins in liver cancer, the molecular mechanisms responsible for suppression of RASSF proteins in HCC, and the possible clinical implications arising from these discoveries. Altogether, the data indicate that inactivation of the RASSF1A tumor suppressor is ubiquitous in human liver cancer, while downregulation of RASSF2 and RASSF5 proteins is limited to specific HCC subsets. Also, the present findings speak in favour of therapeutic strategies aimed at reexpressing RASSF1A, RASSF2, and RASSF5 genes and/or inactivating the RASSF cellular inhibitors for the treatment of human liver cancer.

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