Autophagy in the “inflammation-carcinogenesis” pathway of liver and HCC immunotherapy

Yu, Sizhe; Wang, Yu; Li, Jing; Claret, François X.; Li, Qing; Tian, Tao; Liu, Xuan; Ruan, Zhiping; Jiang, Lili; Yao, Yu; Kang, Nan; Lv, Yi; Guo, Hui

doi:10.1016/j.canlet.2017.09.049

Cited by 59 publications

(52 citation statements)

References 109 publications

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“…Some biological processes including apoptosis, autophagy, and DNA damage play critical roles in regulating HCC (Faridah, Ataollahi, & Asmah, ; Gong & Li, ; Liu et al, ; Yu et al, ). Excessive accumulation of intracellular ROS can trigger a series of mitochondria‐associated events, and regulating apoptosis, autophagy, and DNA damage can be considered as one important target for the development of anticancer drugs (Lv et al, ).…”

Section: Introductionmentioning

confidence: 99%

Potent effects of dioscin against hepatocellular carcinoma through regulating TP53‐induced glycolysis and apoptosis regulator (TIGAR)‐mediated apoptosis, autophagy, and DNA damage

Zhang

Han

Chen

et al. 2019

British J Pharmacology

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Background and purpose: Dioscin shows potent effects against cancers. We aimed to elucidate its pharmacological effects and mechanisms of action on hepatocellular carcinoma (HCC) in vivo and in vitro.Experimental approach: Effects of dioscin were investigated in SMMC7721 and HepG2 cells, diethylnitrosamine-induced primary liver cancer in rats, and cell xenografts in nude mice. Isobaric tags for relative and absolution quantitation (iTRAQ)based proteomics was used to find dioscin's targets and investigate its mechanism.Key results: In SMMC7721 and HepG2 cells dioscin markedly inhibited cell proliferation and migration, induced apoptosis, autophagy, and DNA damage. It inhibited DEN-induced primary liver cancer in rats, markedly changed body weights and restored levels of α fetoprotein, alanine transaminase, aspartate transaminase, γ-glutamyltransferase, alkaline phosphatase, and Ki67. It also inhibited growth of xenografts in mice. In SMMC7721 cells, 191 differentially expressed proteins were found after dioscin, based on iTRAQ-based assay. TP53-inducible glycolysis and apoptosis regulator (TIGAR) was identified as being significantly down-regulated by dioscin. Dioscin induced cell apoptosis, autophagy, and DNA damage via increasing expression levels of p53, cleaved PARP, Bax, cleaved caspase-3/9, Beclin-1, and LC3 and suppressing those of Bcl-2, p-Akt, p-mammalian target of rapamycin (mTOR), CDK5, p-ataxia telangiectasia-mutated gene (ATM). The transfection of TIGAR siRNA into SMMC7721 cells and xenografts in nude mice further confirmed that the potent activity of dioscin against HCC is evoked by adjusting TIGAR-mediated inhibition of p53, Akt/mTOR, and CDK5/ATM pathways. Conclusions and implications:The data suggest that dioscin has potential as a therapeutic, and TIGAR as a drug target for treating HCC.

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Section: Introductionmentioning

confidence: 99%

Potent effects of dioscin against hepatocellular carcinoma through regulating TP53‐induced glycolysis and apoptosis regulator (TIGAR)‐mediated apoptosis, autophagy, and DNA damage

Zhang

Han

Chen

et al. 2019

British J Pharmacology

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“…The multifactorial natures of HCC are fully recognized, but genetic factors are considered strong determinants of these diseases, which has encouraged scientists to search for the genes responsible. 20 Many studies have confirmed a critical role of T cell response in the antitumour effect, and therefore, genes encoding molecules involved in T cell response may potentially affect the carcinogenesis of cancers. The present study aims to assess the associations of CTLA-4, TNF and IL 10 polymorphisms with susceptibility to HCC.…”

Section: Discussionmentioning

confidence: 99%

Association of CTLA‐4, TNF alpha and IL 10 polymorphisms with susceptibility to hepatocellular carcinoma

Wang

Tai-chang

2019

Scand J Immunol

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Our aim was to evaluate the association of genetic polymorphisms of immunoregulatory molecules with susceptibility to hepatocellular carcinoma (HCC). The polymorphisms in CTLA‐4 (−318 T/C, CT60 G/A), TNF (−238 G/A, −308 G/A) and IL10 (−592 C/A, −819 C/T) were genotyped by PCR and DNA sequencing. The functional relevance of the polymorphisms was examined by ELISAs, in vitro lymphocyte proliferation assay and cytotoxic assay. The CTLA‐4 −318 TC/TT, CTLA‐4 CT60 GG, IL10 −592 CA and −819 CT/TT variants, CTLA‐4 −318 T and IL 10 −819 T alleles were positively associated with HCC risk (P < .05). While TNF −238 AA variant, TNF −238 A allele were associated with decreased risk of HCC (P < .05). Furthermore, combinations of CTLA‐4 −318 TC/TT and TNF −238 GG/GA; CTLA‐4 −318 TC/TT and IL 10 −819 CC; CTLA‐4 −318 CC and IL 10 −819 CT/TT in patients with HCC were statistically significant (P < .05). Peripheral blood mononuclear cells (PBMCs) carrying −318 TC/TT genotypes exhibited significantly lower proliferation rates, decreased IL‐2, IL‐4 levels, fewer cytolytic activities and elevated TGF‐β levels. For IL 10 −819 C/T, the CC genotype was significantly associated with higher proliferation rate, decreased TGF‐β, IL‐10 levels and higher cytolytic activities (P < .05). For TNF −238 G/A, the AA genotype only had association with serum IL‐2, IL‐4 (P < .05). In addition, we also found that CTLA‐4 −318 T/C, IL‐10 −819 T/C variants, combinations of CTLA‐4 −318 CC with IL 10 −819 CT or TT, CTLA‐4 −318 TC or TT with IL 10 −819 CT or TT were associated with the severity of HCC. These findings suggest that CTLA‐4 −318 TC/TT and IL 10 −819 CT/TT could promote the pathogenesis of HCC, which might be related with down‐regulation of Th1/Th2‐type cytokines and/or up‐regulation of Th3‐type cytokines.

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“…Concerning hepatic carcinogenesis, increased levels of proinflammatory cytokines and gene polymorphisms in the IL1‐β gene have been shown to be associated with HCC in patients with viral hepatitis . As autophagy can limit excessive inflammation, autophagy has been proposed as a protective mechanism in the inflammation‐related HCC development . The development and growth of HCC are associated with proinflammatory mediators in the tumour microenvironment, stage and aetiology of liver disease as well as on the genetic background of the patient.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy is a central mechanism for maintaining homeostasis, metabolism and survival, thereby stabilizing the cell against metabolic stress and apoptosis . In carcinogenesis, autophagy plays a dual role: although maintaining autophagy is important for the survival of already established tumours, autophagy can also suppress the initiation and development of malignant tumours and decrease the susceptibility to carcinogens, especially under inflammatory conditions . In addition there is a role for autophagy in limiting immune activation and inflammation .…”

Section: Introductionmentioning

confidence: 99%

The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis

Reuken

Lutz

Casper

et al. 2019

Liver International

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Background and aims: Protein and organelle turnover by autophagy is a key component to maintain cellular homeostasis. Loss of the autophagy protein ATG16L1 is associated with reduced bacterial killing and aberrant interleukin-1β production, perpetuating inflammation and carcinogenesis. Here we hypothesized that the functional p.T300A gene variant in ATG16L1 is associated with an increased risk for hepatocellular carcinoma (HCC) in cirrhosis. Methods:A case-control study was performed using a prospective derivation cohort (107 patients with HCC and 101 controls) and an independent validation cohort (124 patients with HCC and 108 controls) of patients with cirrhosis of any aetiology. ATG16L1 p.T300A (rs2241880) and PNPLA3 p.I148M (rs738409) variants were determined by real-time PCR.Results: The G allele of the ATG16L1 p.T300A variant was more frequent in patients with HCC compared to controls without HCC in the derivation cohort (0.62 vs. 0.51, P = .022) and in the validation cohort (0.59 vs. 0.50, P = .045). In combined analysis, the odds ratios (OR) were 1.76 (95% CI: 1.07-2.88) for G allele positivity and 2.43 (95% CI: 1.37-4.31) for p.T300A G allele homozygosity. This association was independent from the presence of a PNPLA3 variant, which was also associated with HCC (OR 2.10; 95% CI: 1.20-3.66), and it remained significant after adjustment for male sex, age and aetiology in multivariate analysis. Conclusion:The common germ-line ATG16L1 gene variant is a risk factor for HCC in patients with cirrhosis. Personalized strategies employing the genetic risk conferred by ATG16L1 and PNPLA3 may be used for risk-based surveillance in cirrhosis. K E Y W O R D S ATG16L1, autophagy, cirrhosis, genetic polymorphisms, hepatocellular carcinoma | 2361 REUKEN Et al.

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Autophagy in the “inflammation-carcinogenesis” pathway of liver and HCC immunotherapy

Cited by 59 publications

References 109 publications

Potent effects of dioscin against hepatocellular carcinoma through regulating TP53‐induced glycolysis and apoptosis regulator (TIGAR)‐mediated apoptosis, autophagy, and DNA damage

Potent effects of dioscin against hepatocellular carcinoma through regulating TP53‐induced glycolysis and apoptosis regulator (TIGAR)‐mediated apoptosis, autophagy, and DNA damage

Association of CTLA‐4, TNF alpha and IL 10 polymorphisms with susceptibility to hepatocellular carcinoma

The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis

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