scholarly journals Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation

Metallomics ◽  
2020 ◽  
Author(s):  
Caroline I. Davis ◽  
Xingxing Gu ◽  
Ryan M. Kiefer ◽  
Martina Ralle ◽  
Terence P. Gade ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Genetic Manipulation ◽  
Copper Homeostasis ◽  
Glycolytic Metabolism ◽  
Copper Chelation ◽  
Oncogenic Pathways ◽  
Pharmacologic Inhibition

Bioavailable Cu fuels oncogenic pathways that drive tumorigenesis. Intriguingly, genetic manipulation or pharmacologic inhibition of intracellular Cu diminishes hypoxia-induced glycolytic metabolism and attenuates HCC tumorigenic properties.

scholarly journals Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 743
Author(s):  
Mohammad Alkhatib ◽  
Velia Di Maio ◽  
Valentina De Murtas ◽  
Ennio Polilli ◽  
Martina Milana ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multivariable Analysis ◽  
Viral Fitness ◽  
Cellular Proteins ◽  
Genetic Determinants ◽  
Hcv Genotype ◽  
Genotype 1B ◽  
Oncogenic Pathways ◽  
Cirrhotic Patients ◽  
Cycle Regulation

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p < 0.001). Focusing on HCC-group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell-cycle regulation (p53, p85-PIK3, and β-catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV-mediated oncogenesis. The role of theseNS5A domain-1 mutations in triggering pro-oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation.

scholarly journals Anti-neoplastic Effect of Ginkgolide C through Modulating c-Met Phosphorylation in Hepatocellular Carcinoma Cells

2020 ◽  
Vol 21 (21) ◽  
pp. 8303
Author(s):  
Min Hee Yang ◽  
Seung Ho Baek ◽  
Jae-Young Um ◽  
Kwang Seok Ahn
Keyword(s):  
Hepatocellular Carcinoma ◽  
Invasion And Migration ◽  
Oncogenic Pathways ◽  
Tumor Growth And Metastasis ◽  
And Migration ◽  
Induced Apoptosis ◽  
Interfering Rna ◽  
Hepatocyte Growth ◽  
Hcc Cells ◽  
Met Phosphorylation

Ginkgolide C (GGC) derived from Ginkgo biloba, has been reported to exhibit various biological functions. However, the anti-neoplastic effect of GGC and its mechanisms in liver cancer have not been studied previously. Hepatocyte growth factor (HGF)/c-mesenchymal–epithelial transition receptor (c-Met) pathway can regulate tumor growth and metastasis in hepatocellular carcinoma (HCC) cells. This study aimed to evaluate the anti-neoplastic effect of GGC against HCC cells and we observed that GGC inhibited HGF-induced c-Met and c-Met downstream oncogenic pathways, such as PI3K/Akt/mTOR and MEK/ERK. In addition, GGC also suppressed the proliferation of expression of diverse tumorigenic proteins (Bcl-2, Bcl-xL, Survivin, IAP-1, IAP-2, Cyclin D1, and COX-2) and induced apoptosis. Interestingly, the silencing of c-Met by small interfering RNA (siRNA) mitigated c-Met expression and enhanced GGC-induced apoptosis. Moreover, it was noted that GGC also significantly reduced the invasion and migration of HCC cells. Overall, the data clearly demonstrate that GGC exerts its anti-neoplastic activity through modulating c-Met phosphorylation and may be used as an effective therapy against HCC.

scholarly journals Prebiotics: A Novel Approach to Treat Hepatocellular Carcinoma

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Naz Fatima ◽  
Tasleem Akhtar ◽  
Nadeem Sheikh
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Antitumor Effect ◽  
Gut Permeability ◽  
Gut Flora ◽  
Effective Barrier ◽  
The Third ◽  
Oncogenic Pathways ◽  
Novel Approach ◽  
Genetic Modifications

Hepatocellular carcinoma is one of the fatal malignancies and is considered as the third leading cause of death. Mutations, genetic modifications, dietary aflatoxins, or impairments in the regulation of oncogenic pathways may bring about liver cancer. An effective barrier against hepatotoxins is offered by gut-liver axis as a change in gut permeability and expanded translocation of lipopolysaccharides triggers the activation of Toll-like receptors which stimulate the process of hepatocarcinogenesis. Prebiotics, nondigestible oligosaccharides, have a pivotal role to play when it comes to inducing an antitumor effect. A healthy gut flora balance is imperative to downregulation of inflammatory cytokines and reducing lipopolysaccharides induced endotoxemia, thus inducing the antitumor effect.

scholarly journals Combined Chibby and β-Catenin Predicts Clinical Outcomes in Patients with Hepatocellular Carcinoma

2020 ◽  
Vol 21 (6) ◽  
pp. 2060
Author(s):  
Ming-Chao Tsai ◽  
Chao-Cheng Huang ◽  
Yu-Ching Wei ◽  
Ting-Ting Liu ◽  
Ming-Tsung Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Genetic Manipulation ◽  
Expression Patterns ◽  
D1 Protein ◽  
Disease Free Survival ◽  
Clinicopathological Parameters ◽  
Advanced Tumor ◽  
Low Expression

Chibby is an antagonist of β-catenin and is considered a potential tumor suppressor protein, but the role of Chibby in hepatocellular carcinoma (HCC) has not been characterized. The expression patterns of Chibby and β-catenin in HCC specimens and paired adjacent noncancerous tissues were measured by Western blotting and immunohistochemistry. The correlations between Chibby expression and clinicopathological parameters were analyzed. Then the biological functions of Chibby were analyzed in vitro. The Chibby protein was significantly downexpressed in human primary HCC tissues compared to that in matched adjacent normal liver tissue and is a risk factor for HCC recurrence and shorter survival. Furthermore, we found that in HCC tissues the high expression of β-catenin with low expression of Chibby in the nuclei was an independent predictor for disease-free survival (DFS) (p = 0.012) and overall survival (OS) (p = 0.005). Subsequent genetic manipulation in vitro studies revealed that Chibby knockdown induced the expression of β-catenin and C-myc, cyclin D1 protein, which promoted cell proliferation and invasiveness. In contrast, overexpression of Chibby decreased β-catenin expression and inhibited the cell proliferation and invasiveness. Our results suggest that low expression of Chibby was associated with advanced tumor-node-metastasis (TNM) stage and poor differentiation. Furthermore, the combination of Chibby and β-catenin can predict poor prognosis in patients with HCC. Chibby inhibited HCC progression by blocking β-catenin signaling in vitro. Chibby is a biomarker and may be a potential therapeutic target for HCC.

scholarly journals Fermentable fibers induce rapid macro- and micronutrient depletion in Toll-like receptor 5-deficient mice

2020 ◽  
Vol 318 (5) ◽  
pp. G955-G965
Author(s):  
Rachel M. Golonka ◽  
Beng San Yeoh ◽  
Yaqi Li ◽  
Piu Saha ◽  
Ahmed A. Abokor ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Genetic Manipulation ◽  
Biliary Disease ◽  
Micronutrient Deficiencies ◽  
Toll Like Receptor ◽  
Chemical Induction ◽  
Novel Approach ◽  
Fiber Diet ◽  
Toll Like Receptor 5 ◽  
Deficient Mice

Feeding a dietary, fermentable fiber diet to a subset of Toll-like receptor 5 deficient (T5KO) mice induces early onset hyperbilirubinemia and cholemia that later manifests to hepatocellular carcinoma (HCC). Our study highlights that fermentable fiber-induced cholestasis is characterized with modest macro- and micronutrient deficiencies that may further contribute to hepatic biliary disease. Compared with chemical induction, immunization, surgery, or genetic manipulation, these findings provide a novel approach to study the cholestatic subtype of HCC.

Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma

2016 ◽  
Vol 12 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Supritha G. Swamy ◽  
Vivek H. Kameshwar ◽  
Priya B. Shubha ◽  
Chung Yeng Looi ◽  
Muthu K. Shanmugam ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Oncogenic Pathways

scholarly journals A 16q22.1 variant confers susceptibility to colorectal cancer as a distal regulator of ZFP90

Oncogene ◽  
2019 ◽  
Vol 39 (6) ◽  
pp. 1347-1360
Author(s):  
Chen-Yang Yu ◽  
Ji-Xuan Han ◽  
Junfang Zhang ◽  
Penglei Jiang ◽  
Chaoqin Shen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Manipulation ◽  
Association Studies ◽  
Transcript Level ◽  
Causal Variant ◽  
Genome Wide Association Studies ◽  
Single Nucleotide ◽  
Enhancer Element ◽  
Oncogenic Pathways ◽  
Genome Wide

Abstract Genome-wide association studies (GWASs) implicate 16q22.1 locus in risk for colorectal cancer (CRC). However, the underlying oncogenic mechanisms remain unknown. Here, through comprehensive filtration, we prioritized rs7198799, a common SNP in the second intron of the CDH1, as the putative causal variant. In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript level of biological plausible candidate gene ZFP90 via expression quantitative trait loci analysis. Mechanistically, causal variant rs7198799 resides in an enhancer element and remotely regulate ZFP90 expression by targeting the transcription factor NFATC2. Remarkably, CRISPR/Cas9-guided single-nucleotide editing demonstrated the direct effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype. Furthermore, ZFP90 affects several oncogenic pathways, including BMP4, and promotes carcinogenesis in patients and in animal models with ZFP90 specific genetic manipulation. Taken together, these findings reveal a risk SNP-mediated long-range regulation on the NFATC2-ZFP90-BMP4 pathway underlying the initiation of CRC.

scholarly journals Pharmacologic Inhibition of the Menin–MLL Interaction Leads to Transcriptional Repression of PEG10 and Blocks Hepatocellular Carcinoma

2017 ◽  
Vol 17 (1) ◽  
pp. 26-38 ◽  
Author(s):  
Katarzyna Kempinska ◽  
Bhavna Malik ◽  
Dmitry Borkin ◽  
Szymon Klossowski ◽  
Shirish Shukla ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcriptional Repression ◽  
Pharmacologic Inhibition

Copper chelation as a new treatment strategy to counteract hepatocellular carcinoma

2021 ◽  
Vol 53 ◽  
pp. S38-S39
Author(s):  
S.J. Santini ◽  
M.R. Braghini ◽  
A. Alisi ◽  
C. Balsano
Keyword(s):  
Hepatocellular Carcinoma ◽  
Treatment Strategy ◽  
Copper Chelation ◽  
New Treatment
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