Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

Abstract

Etiologic risk factors for hepatocellular carcinoma can be involved in the transformation process by directly targeting intracellular signaling pathways or by indirectly stimulating chronic cycles of hepatocyte destruction and regeneration. However, the contribution of these two routes to hepatocarcinogenesis has not been determined, partly because of the difficulty in distinguishing damaged and regenerated hepatocytes. Here we report that induced deletion of the damaged DNA binding protein 1 (DDB1) abrogates the self-renewing capacity of hepatocytes, resulting in compensatory proliferation of DDB1-expressing hepatocytes. Constitutive stimulation of this regeneration process leads to development of hepatocellular carcinoma, which surprisingly contains no disruption of the DDB1 gene, indicating a cell-nonautonomous role of DDB1 inactivation in tumor initiation. Our results suggest that viruses and hepatoxins may cause liver tumors by simply driving hepatocyte turnover without directly targeting cancer cells. of all primary liver cancers, is the fifth most common cancer and the third leading cause of cancer death worldwide (1). HCC development follows a multistep progression from hepatic dysplasia to neoplasia, with accumulation of somatic mutations and chromosomal alterations (2). Conventionally, these genetic alterations are identified in human liver tumor samples by gene expression profiling, genomic and proteomic analysis, and direct sequencing. Candidate genes are subsequently validated in cell cultures and animals. This methodology has led to the identification of oncogenes and tumor suppressor genes important for liver tumor development, such as those regulating Wnt/β-catenin, p53, EGFR receptor tyrosine kinases, and MET/HGF pathways (3).Alternatively, interactions between host factors and HCC-associated pathogens such as hepatitis B virus (HBV) and hepatitis C virus (HCV) can be investigated to understand early molecular and cellular alterations leading to HCC initiation. HBV encodes a nonstructural regulatory protein, HBx, that is required for HBV replication and implicated in HBV-associated HCC (4). How HBx contributes to hepatocarcinogenesis is unclear, but is believed to involve its myriad target host proteins, one of which is the damaged DNA binding protein 1 (DDB1) (5). DDB1 is the linker protein for the Cullin 4 (Cul4) E3 ubiquitin ligase (6), which regulates ubiquitination and proteasomal degradation of proteins essential for nucleotide excision repair [DDB2 (7) and CSB (8)], cell cycle progression [p21 (9, 10), p27 (11), and Myc (12)], DNA replication [Cdt1 (13) and POLH-1 (14)], and cell growth [c-Jun (15) and TSC2 (16)]. Other substrates of the E3 ligase, including XPC (7), histones H3 and H4 (17), and histone H2A (18), are modified without degradation to facilitate DNA damage repair. Several viral regulatory proteins such as the HIV Vpr protein (19) and the simian virus 5 V protein (20) can hijack the E3 ligase to target undesired host factors and benefit the respective viral life cycle.In this...

Sorafenib-resistant hepatocellular carcinoma stratified by phosphorylated ERK activates PD-1 immune checkpoint

“…DEN, a chemical carcinogen, can induce hepatoma in mice after injected to 14-day old pups [19], and the tumors found in mice aged over 8 months were all pERK + , determined by Western blot of tumor lysates (Figure 2A) and immunohistochemical staining of tumor sections (Figure 2B). By contrast, tumors dissected from a genetic mouse model DDB1 F/F ;Alb-Cre +/− , in which tumorigenesis is driven by continuous hepatocyte turnover and progenitor cell activation [20, 21], express no pERK (Figure 2A and 2B). After tumors were visually confirmed and photographed after median laparotomy (Supplementary Figure 2A and 2B), both groups of mice were treated with sorafenib or PBS daily for three weeks after complete recovery from surgery.…”

Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR ‐ SET 7‐deficient livers

“…Notwithstanding, liver regeneration after most forms of acute injury or 2/3 rd partial hepatectomy does not rely on progenitor cell activation, but instead involves the proliferation of existing previously quiescent hepatocytes (Malato et al , 2011; Español-Suñer et al , 2012; Schaub et al , 2014; Yanger et al , 2014). Progenitor-dependent regeneration is probably restricted to chronic injury conditions coupled with impaired hepatocyte replication potential (Yamaji et al , 2010; Friedman & Kaestner, 2011; Wang et al , 2011; Miyajima et al , 2014). …”

A core component of the CUL4 ubiquitin ligase complexes, DDB1, regulates spermatogenesis in the Chinese mitten crab, Eriocheir sinensis

“…DDB1 plays an important role in controlling levels of cell cycle regulators and maintaining genomic stability (Cang et al, 2007), and deletion of DDB1 abolished the self-renewing capacity of hepatocytes, thereby inducing liver tumorigenesis (Yamaji et al, 2010). Therefore, we speculated that DDB1 might play a role in spermatogenesis of E. sinensis.…”