Caspase-2 deficiency accelerates chemically induced liver cancer in mice

Abstract

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...

The PIDDosome activates p53 in response to supernumerary centrosomes

“…We expect that these events will signal to p53 independently of the PIDDosome, thereby providing a possible explanation for why mouse mutants lacking the PIDDosome are largely normal and not overtly cancer-prone unless further challenged . However, despite the PIDDosome function being more restricted than that displayed by p53, Caspase-2 deficiency was shown recently to be sufficient to predispose mice to chemically induced liver cancer (Shalini et al 2016). Whether the observed Caspase-2 tumor suppressor function in this context requires the PIDDosome and how this relates to the increased hepatocyte ploidy described here need to be addressed experimentally.…”

Caspase 2 in mitotic catastrophe: The terminator of aneuploid and tetraploid cells

“…25,26 Of note, mice deficient for Casp2 also exhibited a reduced lifespan, 23,24 further supporting the role of this caspase for normal tissue homeostasis.…”

“…Importantly, increased rate of aneuploidization and CIN has been detected (1) in Casp2 ¡/¡ mice subjected to chemical carcinogens or oncogenic stress, in which non-diploidy was accompanied by accelerated tumor development and progression, 23,24 and (2) in Casp2 ¡/¡ mouse embryonic fibroblasts (MEFs), in which non-diploidy was associated with escape from senescence, decreased telomere length and increased resistance to antimicrotubular compounds. 25,26 Of note, mice deficient for Casp2 also exhibited a reduced lifespan, 23,24 further supporting the role of this caspase for normal tissue homeostasis.…”

Impaired haematopoietic stem cell differentiation and enhanced skewing towards myeloid progenitors in aged caspase-2-deficient mice

“…For example, caspase-2 deficiency enhances lymphomagenesis in Eμ-Myc transgenic mice that develop B-cell lymphoma 9, 10 and in ataxia telangiectasia mutated (Atm)- deficient mice that spontaneusly develop thymic lymphoma. 11 Furthermore, MMTV/c-neu -driven mammary carcinoma, 12 K-Ras-driven lung carcinoma 13 and diethylnitrosamine-mediated hepatocellular carcinoma 14 also show more rapid develoment of tumours in caspase-2 -deficient ( Casp2 −/− ) mice. In addition, in vitro studies demonstrate that mouse embryonic flibroblasts (MEFs) derived from Casp2 −/− mice become immortalized more readily and show enhanced sensitivity to transformation by oncogenes, including Ras and cMyc.…”

“…9, 15 Interestingly though, not all types of tumours are affected by the loss of caspase-2, 10, 16 suggesting that the nature of cell types involved (such as their proliferative capacity) may determine the participation of caspase-2 as a tumour suppressor. One commonly observed feature of caspase-2 -deficient tumours and MEFs is enhanced aneuploidy, 4, 11, 12, 14, 15, 17 likely because of reduced or inefficient apoptotic removal of aberrant cells in the absence of caspase-2.…”