Knockout of ASPP2 promotes DEN-induced hepatocarcinogenesis via the NF-κB pathway in mice

Abstract

Apoptosis-stimulating protein p53 2 (ASPP2) is a member of the p53-binding protein family, which is closely related to tumor development. However, the precise mechanism of ASPP2 in liver inflammation and tumorigenesis remains largely unclear. We aimed to characterize the mechanistic significance and clinical implication of ASPP2 in hepatitis and hepatocellular carcinoma (HCC). In this study, ASPP2 knockout (APKO) mice were generated to confirm the role of ASPP2 in the development of hepatitis and HCC. Liver tissues from mice were analyzed by immunohistochemistry, Western blotting, proteomic analysis, ChIP-Seq, and qRT-PCR to evaluate the role of ASPP2 in DEN-induced hepatitis and HCC. We found that APKO promoted the formation of hepatitis/hepatocarcinoma and the increased expression of proinflammatory factors. The proteomics and Western blotting results showed that APKO activated the NF-κB signaling pathway. Further, ChIP-Seq results revealed that NF-κB target genes were dramatically increased in APKO mice. In contrast, blockade of the NF-κB pathway by QNZ reduced the expression of proinflammatory factors and the susceptibility of APKO mice to DEN-induced hepatocarcinogenesis. These results suggested that the absence of ASPP2 activates the NF-κB pathway to promote the occurrence of DEN-induced hepatocarcinogenesis, indicating that ASPP2 may be a potential target for the treatment of hepatocarcinoma.

TP53BP2: Roles in suppressing tumorigenesis and therapeutic opportunities

“… 71 , 72 The binding pattern of NF-κB to TP53BP2 is similar to that of its natural inhibitor I-κB, suggesting that TP53BP2 may also be an inhibitor of NF-κB. 25 Wang et al 51 investigated the effects of TP53BP2 on the NF-κB pathway and hepatocellular carcinoma, suggesting that TP53BP2 knockdown can promote hepatic inflammation and hyperplasia by activating the NF-κB pathway, and overexpression of TP53BP2 can inhibit NF-κB pathway and prevent HCC. In TP53BP2 deficient squamous cell carcinoma (SCC) mice, TP53BP2 binds to I-κB and mediates p63 inhibition by inhibiting ΔNp63 (a component of the NF-κB transcription complex) via Rel/A P65, and regulates SCC through inflammatory signaling pathway.…”

“… 50 Preclinical studies also showed that diethylnitrosamine (DEN) could activate NF-κB pathway in TP53BP2 deficient mice and promote the formation of mouse liver cancer model. 51 Regarding chemotherapy, TP53BP2 can enhance the chemosensitivity of HCC by inhibiting the expression of X-linked inhibitors of apoptosis protein (XIAP). 52 The deletion of TP53BP2 disrupts stem-like properties and chemotherapeutic resistance to HCC via Src/FAK/Snail axis.…”

ASPP2 Is Phosphorylated by CDK1 during Mitosis and Required for Pancreatic Cancer Cell Proliferation

“…ASPP2 is defined as a haploinsufficient tumor suppressor due to the fact that ASPP2 haplodeficiency in mice develops spontaneous tumors [22,23]. The ASPP2 heterozygous knockout mice also exhibit an increased rate of tumor formation upon radiation or carcinogen insults [23,24]. Studies have shown that downregulation of ASPP2 promotes cancer cell proliferation, motility, and chemo-resistance in some types of carcinomas [25][26][27][28].…”