Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

Yang, Sheau-Fang; Chang, Chien-Wei; Wei, Ren‐Jie; Shiue, Yow‐Ling; Wang, Shen‐Nien; Yeh, Yao‐Tsung

doi:10.1155/2014/153867

Cited by 81 publications

(86 citation statements)

References 237 publications

(220 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…DEN generates ROS and causes DNA damage, which contributes to the development of HCC. 9,24 As Casp2 −/− mice are more susceptible to oxidative stress-induced damage to lipids, DNA and protein, 24,25 these parameters were measured in liver (Figures 2a, b and d). While no difference in lipid peroxidation (MDA) was observed between WT and Casp2 −/− DEN-injected mice (Figure 2a Liver damage and inflammation is often accompanied by increases in hepatic cell death and proliferation.…”

Section: Resultsmentioning

confidence: 99%

“…P53 is frequently inactivated (mutated) in HCC, impairing the DNA damage response. 24 Therefore, we investigated p53 and p21 levels by immunoblotting. Total p53 protein levels were somewhat increased in DEN-treated WT Increased cellular damage in the absence of cell death is responsible for proliferative advantage in Casp2 −/− mice.…”

Section: Resultsmentioning

confidence: 99%

“…5,21,23 DEN-induced tumour formation involves the generation of DNA adducts, 10 and human HCC is commonly associated with genomic instability. 24 These observations, combined with the known tumour suppressor role in lymphoma and MMTV-driven mammary carcinoma, suggest a possible role of caspase-2 in HCC. Thus, we sought to explore whether caspase-2 deficiency would promote chemically induced hepatic carcinogenesis in liver.…”

mentioning

confidence: 94%

See 2 more Smart Citations

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

et al. 2016

View full text Add to dashboard Cite

Aberrant cell death/survival has a critical role in the development of hepatocellular carcinoma (HCC). Caspase-2, a cell death protease, limits oxidative stress and chromosomal instability. To study its role in reactive oxygen species (ROS) and DNA damageinduced liver cancer, we assessed diethylnitrosamine (DEN)-mediated tumour development in caspase-2-deficient (Casp2 −/− ) mice. Following DEN injection in young animals, tumour development was monitored for 10 months. We found that DEN-treated Casp2 −/− mice have dramatically elevated tumour burden and accelerated tumour progression with increased incidence of HCC, accompanied by higher oxidative damage and inflammation. Furthermore, following acute DEN injection, liver injury, DNA damage, inflammatory cytokine release and hepatocyte proliferation were enhanced in mice lacking caspase-2. Our study demonstrates for the first time that caspase-2 limits the progression of tumourigenesis induced by an ROS producing and DNA damaging reagent. Our findings suggest that after initial DEN-induced DNA damage, caspase-2 may remove aberrant cells to limit liver damage and disease progression. We propose that Casp2 −/− mice, which are more susceptible to genomic instability, are limited in their ability to respond to DNA damage and thus carry more damaged cells resulting in accelerated tumourigenesis. The initiator caspase, caspase-2, has recently emerged as a tumour suppressor with loss of this protein being associated with increased lymphomagenesis in ATM-deficient mice and Eμ-Myc transgenic mice, and MMTV/c-neu-driven mammary carcinoma. 1-4 Caspase-2 has been shown to protect cells from oxidative stress, DNA damage and genomic instability, and caspase-2 deficiency is linked to chromosomal instability and aneuploidy. 1,5,6 However, currently little is known about the possible role of caspase-2 in carcinogenesis induced by ROS and DNA damage.Hepatocellular carcinoma (HCC) is among the most common cancers and is the second leading cause of cancer-related deaths worldwide. 7 Development of HCC is multifaceted progressing from DNA damage to dysplasia, adenoma development and malignant transformation of hepatocytes. 7,8 The major risk factors of HCC include viral hepatitis, excessive alcohol consumption, carcinogens and metabolic diseases. 7,8 Despite this, the molecular causes of the disease are relatively less understood. Diethylnitrosamine (DEN) is a DNA alkylating and ROS inducing carcinogen that is widely used as a model to study the progression of HCC in rodents. 9,10 DEN treatment mimics the human disease by inducing DNA damage in proliferating hepatocytes of infant mice. 9 Increases in the generation of ROS and accumulation of DNA damage can stimulate an inflammatory response and hyperproliferation that helps drive tumour progression. 7-10 It has increasingly been recognised that apoptosis and compensatory proliferation are crucial for progression of certain cancers including HCC. 11-13 While loss of apoptosis would indirectly favour proliferation, this is not universa...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 94%

See 1 more Smart Citation

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

et al. 2016

View full text Add to dashboard Cite

show abstract

“…HCC is one of the most common malignancies, is highly metastatic and is the third-leading cause of cancer-associated mortality worldwide (13,14). The majority of traditional chemotherapeutic agents exhibit an extensive profile of side effects, therefore the development of novel drugs with high efficiency and low toxicity is warranted.…”

Section: Discussionmentioning

confidence: 99%

Bovine lactoferricin P13 triggers ROS-mediated caspase-dependent apoptosis in SMMC7721 cells

Meng

et al. 2016

Oncology Letters

View full text Add to dashboard Cite

Abstract. Bovine lactoferricin P13 (LfcinB-P13) is a peptide derived from LfcinB. In the present study, the effect of LfcinB-P13 on the human liver cancer cell line SMMC7721 was investigated in vitro and in vivo. The results of the present study indicate that LfcinB-P13 significantly decreased SMMC7721 cell viability in vitro (P=0.032 vs. untreated cells), while exhibiting low cytotoxicity in the wild-type liver cell line L02. In addition, the rate of apoptosis in SMMC7721 cells was significantly increased following treatment with 40 and 60 µg/ml LfcinB-P13 (P=0.0053 vs. the control group), which was associated with an increase in the level of reactive oxygen species (ROS) and the activation of caspase-3 and -9. Furthermore, ROS chelation led to the suppression of LfcinB-P13-mediated caspase-3 and -9 activation in SMMC7721 cells. LfcinB-P13 was demonstrated to markedly inhibit tumor growth in an SMMC7721-xenograft nude mouse model. The results of the present study indicate that LfcinB-P13 is a novel candidate therapeutic agent for the treatment of liver cancer.

show abstract

“…Although substantial progress has been achieved in both prevention and treatment of HCC in recent years, effective therapeutic alternatives for advanced HCC are limited [7,8]. An increasing number of evidences demonstrate that the development of HCC is associated with perturbed DNA damage response and repair pathway [9,10]. Therefore, targeting the components of DNA damage response might be a potential effective treatment for HCC.…”

Section: Introductionmentioning

confidence: 99%

A Direct Interaction Between P53-Binding Protein 1 and Minichromosome Maintenance Complex in Hepg2 Cells

Chen

Weng

Zhang

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. DNA damage repair in cancer cells is a promising approach for the treatment of cancers. We aimed to explore the potential interaction between p53-binding protein 1 (53BP1) and minichromosome maintenance (MCMs) proteins during DNA damage in human hepatoma HepG2 cells. Methods: The recombinant vectors of 53BP1 and MCMs with tags were constructed and transfected into HepG2 cells. Immunoprecipitation (IP) and mass spectrometry (MS) were performed to identify the possible interactions between 53BP1 and MCMs, and glutathione S-transferase (GST) pull-down assay was carried out to detect the direct interaction. Moreover, the expressions of MCM2 and MCM6 were suppressed by specific short hairpin RNAs (shRNAs), and then the chromatin fraction and foci formation of 53BP1 were examined under the condition of DNA damage. Results: The results showed that MCM2/3/5/6 was immunoprecipitated against the hemaglutinin (HA)-tagged 53BP1 in HepG2 cell nuclei. GST results revealed that there was a direct interaction between 53BP1 and MCMs complex. Moreover, the non-chromatin level of 53BP1 was significantly increased by down-regulation of MCM2 or MCM6, but was statistically decreased the chromatin level. Furthermore, we observed that knockdown of MCM2 or MCM6 could statistically inhibit the foci formation of 53BP1 in HepG2 cell nuclei upon bleomycin-induced DNA damage (P < 0.01). Conclusion: Our results suggest that there is a direct interaction between 53BP1 and MCMs, which is essential for 53BP1 chromatin fraction and foci formation in hepatoma HepG2 cells.

show abstract

Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

Cited by 81 publications

References 237 publications

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

Bovine lactoferricin P13 triggers ROS-mediated caspase-dependent apoptosis in SMMC7721 cells

A Direct Interaction Between P53-Binding Protein 1 and Minichromosome Maintenance Complex in Hepg2 Cells

Contact Info

Product

Resources

About