Bortezomib induces tumor-specific cell death and growth inhibition in hepatocellular carcinoma and improves liver fibrosis

2012 ◽  
Vol 48 (6) ◽  
pp. 738-750 ◽  
Author(s):  
Issei Saeki ◽  
Shuji Terai ◽  
Koichi Fujisawa ◽  
Taro Takami ◽  
Naoki Yamamoto ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Liver Fibrosis ◽  
Growth Inhibition ◽  
Specific Cell

scholarly journals Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma

2020 ◽  
Vol 117 (25) ◽  
pp. 14231-14242 ◽  
Author(s):  
Shuixia Tan ◽  
Jing Zhao ◽  
Ziyu Sun ◽  
Shuangyi Cao ◽  
Kongyan Niu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Liver Fibrosis ◽  
Therapeutic Strategy ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Genetic Inactivation ◽  
Downstream Effectors ◽  
Compensatory Proliferation ◽  
Specific Deletion

Transforming growth factor β-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 inTak1ΔHEPmice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using a kinase dead knockin D138N mutation inTak1ΔHEPmice inhibits the expression of liver tumor biomarkers, liver fibrosis, and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single-cell RNA sequencing, we discovered that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.

scholarly journals A Positive Relationship between Betel Nut Chewing and Significant Liver Fibrosis in NAFLD Subjects, but Not in Non-NAFLD Ones

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 914
Author(s):  
Yu-Tsung Chou ◽  
Chung-Hao Li ◽  
Zih-Jie Sun ◽  
Wei-Chen Shen ◽  
Yi-Ching Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cardiovascular Disease ◽  
Liver Fibrosis ◽  
Odds Ratio ◽  
Fatty Liver Disease ◽  
Positive Relationship ◽  
Betel Nut ◽  
Nonalcoholic Fatty Liver ◽  
Betel Nut Chewing ◽  
Significant Liver Fibrosis

Background: Betel nut chewing is associated with oral cancer, cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma (HCC). The aim of this study was to explore the association of betel nut chewing with liver fibrosis in subjects with and without nonalcoholic fatty liver disease (NAFLD). Method: A total of 5967 subjects were enrolled. NAFLD was diagnosed with ultrasonography. Betel nut chewing was classified into non-chewing, ex-chewing, and current chewing, and cumulative dosages were calculated. The aspartate aminotransferase (AST)/platelet ratio index and NAFLD fibrosis scores (NFS) were calculated for evaluation of liver fibrosis. Results: NAFLD increased the associated risk of liver fibrosis in those with (odds ratio (OR): 5.51, 95% confidence interval (CI): 3.09–9.80) and without betel nut chewing (OR: 2.33, 95% CI: 1.64–3.29). In subjects without NAFLD, betel nut chewing was not associated with liver fibrosis (OR: 1.12, 95% CI: 0.44–2.86). In subjects with NAFLD, cumulative betel nut chewing and ex- and current chewing were positively associated with NFS and significant liver fibrosis. Conclusions: In subjects with NAFLD, betel nut chewing, even ex-chewing, was associated with a higher risk of liver fibrosis, where higher cumulative levels were found to increase the risk of significant liver fibrosis. However, the associated risk of liver fibrosis due to betel nut chewing was insignificant in subjects without NAFLD.

scholarly journals Genetic variants of programmed cell death 1 are associated with HBV infection and liver disease progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nghiem Xuan Hoan ◽  
Pham Thi Minh Huyen ◽  
Mai Thanh Binh ◽  
Ngo Tat Trung ◽  
Dao Phuong Giang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Liver Disease ◽  
Programmed Cell Death ◽  
Disease Progression ◽  
Infection Risk ◽  
Hbv Infection ◽  
Liver Disease Progression ◽  
Increased Risk ◽  
Programmed Cell Death 1

AbstractThe inhibitory effects of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) modulates T-cell depletion. T-cell depletion is one of the key mechanisms of hepatitis B virus (HBV) persistence, in particular liver disease progression and the development of hepatocellular carcinoma (HCC). This case–control study aimed to understand the significance of PD-1 polymorphisms (PD-1.5 and PD-1.9) association with HBV infection risk and HBV-induced liver disease progression. Genotyping of PD-1.5 and PD-1.9 variants was performed by direct Sanger sequencing in 682 HBV-infected patients including chronic hepatitis (CHB, n = 193), liver cirrhosis (LC, n = 183), hepatocellular carcinoma (HCC, n = 306) and 283 healthy controls (HC). To analyze the association of PD-1 variants with liver disease progression, a binary logistic regression, adjusted for age and gender, was performed using different genetic models. The PD-1.9 T allele and PD-1.9 TT genotype are significantly associated with increased risk of LC, HCC, and LC + HCC. The frequencies of PD-1.5 TT genotype and PD-1.5 T allele are significantly higher in HCC compared to LC patients. The haplotype CT (PD-1.5 C and PD-1.9 T) was significantly associated with increased risk of LC, HCC, and LC + HCC. In addition, the TC (PD-1.5 T and PD-1.9 C) haplotype was associated with the risk of HCC compared to non-HCC. The PD-1.5 CC, PD-1.9 TT, genotype, and the CC (PD-1.5 C and PD-1.9) haplotype are associated with unfavorable laboratory parameters in chronic hepatitis B patients. PD-1.5 and PD1.9 are useful prognostic predictors for HBV infection risk and liver disease progression.

scholarly journals Hepatoblastoma: glutamine depletion hinders cell viability in the embryonal subtype but high GLUL expression is associated with better overall survival

2021 ◽  
Author(s):  
Andreas Schmidt ◽  
Angela Armento ◽  
Ovidio Bussolati ◽  
Martina Chiu ◽  
Verena Ellerkamp ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Growth Inhibition ◽  
Cell Viability ◽  
Cell Lines ◽  
Prognostic Significance ◽  
Asparagine Synthetase ◽  
Inhibition Of Proliferation ◽  
Its Gene ◽  
Glutamine Synthesis

Abstract Purpose Glutamine plays an important role in cell viability and growth of various tumors. For the fetal subtype of hepatoblastoma, growth inhibition through glutamine depletion was shown. We studied glutamine depletion in embryonal cell lines of hepatoblastoma carrying different mutations. Since asparagine synthetase was identified as a prognostic factor and potential therapeutic target in adult hepatocellular carcinoma, we investigated the expression of its gene ASNS and of the gene GLUL, encoding for glutamine synthetase, in hepatoblastoma specimens and cell lines and investigated the correlation with overall survival. Methods We correlated GLUL and ASNS expression with overall survival using publicly available microarray and clinical data. We examined GLUL and ASNS expression by RT-qPCR and by Western blot analysis in the embryonal cell lines Huh-6 and HepT1, and in five hepatoblastoma specimens. In the same cell lines, we investigated the effects of glutamine depletion. Hepatoblastoma biopsies were examined for histology and CTNNB1 mutations. Results High GLUL expression was associated with a higher median survival time. Independent of mutations and histology, hepatoblastoma samples showed strong GLUL expression and glutamine synthesis. Glutamine depletion resulted in the inhibition of proliferation and of cell viability in both embryonal hepatoblastoma cell lines. ASNS expression did not correlate with overall survival. Conclusion Growth inhibition resulting from glutamine depletion, as described for the hepatoblastoma fetal subtype, is also detected in established embryonal hepatoblastoma cell lines carrying different mutations. At variance with adult hepatocellular carcinoma, in hepatoblastoma asparagine synthetase has no prognostic significance.

scholarly journals A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis

Med ◽  
2021 ◽  
Author(s):  
Naoto Fujiwara ◽  
Masahiro Kobayashi ◽  
Austin J. Fobar ◽  
Ayaka Hoshida ◽  
Cesia A. Marquez ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Fibrosis ◽  
Advanced Liver Fibrosis ◽  
Carcinoma Risk

scholarly journals Selective Anti-Cancer Effects of Plasma-Activated Medium and Its High Efficacy with Cisplatin on Hepatocellular Carcinoma with Cancer Stem Cell Characteristics

2021 ◽  
Vol 22 (8) ◽  
pp. 3956
Author(s):  
Yan Li ◽  
Tianyu Tang ◽  
Hae June Lee ◽  
Kiwon Song
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Cell Lines ◽  
Primary Liver Cancer ◽  
Atmospheric Pressure Plasma ◽  
Normal Liver ◽  
Normal Liver Cell ◽  
Ample Evidence ◽  
Huh7 Cells ◽  
Anti Cancer

Hepatocellular carcinoma (HCC) is a major histological subtype of primary liver cancer. Ample evidence suggests that the pathological properties of HCC originate from hepatic cancer stem cells (CSCs), which are responsible for carcinogenesis, recurrence, and drug resistance. Cold atmospheric-pressure plasma (CAP) and plasma-activated medium (PAM) induce apoptosis in cancer cells and represent novel and powerful anti-cancer agents. This study aimed to determine the anti-cancer effect of CAP and PAM in HCC cell lines with CSC characteristics. We showed that the air-based CAP and PAM selectively induced cell death in Hep3B and Huh7 cells with CSC characteristics, but not in the normal liver cell line, MIHA. We observed both caspase-dependent and -independent cell death in the PAM-treated HCC cell lines. Moreover, we determined whether combinatorial PAM therapy with various anti-cancer agents have an additive effect on cell death in Huh7. We found that PAM highly increased the efficacy of the chemotherapeutic agent, cisplatin, while enhanced the anti-cancer effect of doxorubicin and the targeted-therapy drugs, trametinib and sorafenib to a lesser extent. These findings support the application of CAP and PAM as anti-cancer agents to induce selective cell death in cancers containing CSCs, suggesting that the combinatorial use of PAM and some specific anti-cancer agents is complemented mechanistically.

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