RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer

Abstract

Receptor-interacting protein kinase 1 (RIPK1) represents an essential signaling node in cell death and inflammation. Ablation of Ripk1 in liver parenchymal cells (LPC) did not cause a spontaneous phenotype, but led to tumor necrosis factor (TNF)-dependent hepatocyte apoptosis and liver injury without affecting inducible nuclear factor κB (NF-κB) activation. Loss of Ripk1 induced the TNF-dependent proteasomal degradation of the E3-ligase, TNF receptor-associated factor 2 (TRAF2), in a kinase-independent manner, thereby activating caspase-8. Moreover, loss of both Ripk1 and Traf2 in LPC not only resulted in caspase-8 hyperactivation but also impaired NF-κB activation, promoting the spontaneous development of hepatocellular carcinoma. In line, low RIPK1 and TRAF2 expression in human HCCs was associated with an unfavorable prognosis, suggesting that RIPK1 collaborates with TRAF2 to inhibit murine and human hepatocarcinogenesis.

RIPK1-TRAF2 interplay on the TNF/NF-κB signaling, cell death, and cancer development in the liver

“…The clinical relevance of RIPK1 and TRAF2 to human HCC progression is also demonstrated in this paper (7). Low expression of RIPK1 and/or TRAF2 has strong correlation with worse prognosis in patients with HCC; however, detailed analyses of apoptosis and NF-κB activity in tumors warrant further investigation.…”

“…Their findings also suggest another scaffold function of RIPK1 in which RIPK1 stabilizes TRAF2 in hepatocytes, thereby inhibiting caspase-8-mediated apoptosis and liver damage (7). Intriguingly, deubiquitinated RIPK1, in turn, forms a complex IIa with FADD and caspase-8 to induce apoptosis or a complex IIb with RIPK3 to induce necroptosis (14-16) (Figure 1).…”

“…In the recent issue of Cancer Cell , Schneider et al (7) address the in vivo physiological functions of RIPK1 and TRAF2 using liver parenchymal cell (LPC)-specific knockout mice for RIPK1 ( RIPK1 LPC-KO ), as well as TRAF2 ( TRAF2 LPC-KO ), since mice deficient for RIPK1 and TRAF2 die soon after birth due to systemic inflammation (12,13). RIPK1 LPC-KO mice have normal liver function without spontaneous HCC development; however, upon LPS administration, RIPK1 LPC-KO mice show dramatic induction of apoptosis and liver damage with normal response to NF-κB, as compared with wild-type mice (Table 1).…”

“…Previously, Kondylis et al (15) show that deletion of RIPK3 fails to suppress spontaneous liver damage and HCC development observed in NEMO LPC-KO mice. To further examine whether necroptosis is involved in liver damage in the RIPK1 -null background, Schneider et al (7) administer LPS into RIPK1 LPC-KO or RIPK1 LPC-KO /RIPK3 –/– mice. However, RIPK1 LPC-KO / RIPK3 –/– mice show similar apoptosis and liver damage phenotypes to those in RIPK1 LPC-KO mice, although RIPK1 LPC-KO / RIPK3 –/– mice have delayed activation of caspase-8 and caspase-3 than RIPK1 LPC-KO mice.…”

“…To further understand functional association between RIPK1 and TRAF2 and the involvement of NF-κB signaling in spontaneous HCC genesis, Schneider et al (7) investigate liver damage and HCC development in RIPK1 LPC-KO / TRAF2 LPC-KO and TRAF2 LPC-KO / IKKβ LPC-KO mice, in comparison with those in TRAF2 LPC-KO mice. Both RIPK1 LPC-KO / TRAF2 LPC-KO and TRAF2 LPC-KO / IKKβ LPC-KO mice spontaneously develop liver damage and HCC with impaired NF-κB activity; whereas, TRAF2 LPC-KO mice, which show functional NF-κB activity and slightly increased apoptosis/damage in the liver, fail to develop HCC.…”