Interleukin‐1β/Iinterleukin‐1 receptor‐associated kinase 1 inflammatory signaling contributes to persistent Gankyrin activation during hepatocarcinogenesis

Abstract

Hepatocellular carcinoma (HCC) is a prototype of inflammation‐associated cancer. Oncoprotein Gankyrin, which mostly increases in HCC, plays a critical role in HCC development and metastasis. However, the exact mechanism of Gankyrin up‐regulation in HCC remains unclear. A Gankyrin luciferase reporter was developed to screen a potential regulator for Gankyrin from a list of proinflammatory cytokines, and interleukin (IL)‐1β was found as one of its activators. In clinical premalignant and malignant liver disease samples, enhanced IL‐1β/interleukin‐1 receptor‐associated kinase 1 (IRAK‐1) signaling accompanied by increased Gankyrin was observed. Lower expression of Gankyrin and phospho‐IRAK‐1 are favorable prognostic markers for HCC. A similar correlation was observed in the diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. The results from Gankyrin reporter activity, real‐time polymerase chain reaction, or immunoblotting further confirmed the up‐regulation of Gankyrin by IL‐1β/IRAK‐1 inflammatory signaling. Moreover, a series of Gankyrin's truncated reporters were constructed, and electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) were performed to analyze the properties of Gankyrin promoter. Mechanistically, the core promoter of Gankyrin contains the binding site of nuclear factor Y (NF‐Y) family members, which can recruit histone acetyltransferase coactivator E1A‐binding protein p300 (p300) or CREB‐binding protein (CBP) to promote Gankyrin transcription. Conversely, knockdown of NF‐Y, p300, or CBP inhibits Gankyrin expression. IL‐1β stimulation causes sequential phosphorylation of IRAK‐1, c‐Jun N‐terminal kinase (JNK), and p300 and enhances recruitment of the p300/CBP/NF‐Y complex to Gankyrin promoter. Inhibition of phospho‐JNK impairs IL‐1β/IRAK‐1 signaling‐mediated up‐regulation of Gankyrin. Conclusion: The finding of IL‐1β/IRAK‐1 signaling promoting Gankyrin expression through JNK and NF‐Y/p300/CBP complex provides a fresh view on inflammation‐enhanced hepatocarcinogenesis. (Hepatology 2015;61:585‐597)

Association Between Functional PSMD10 Rs111638916 Variant Regulated by MiR-505 and Gastric Cancer Risk in a Chinese Population

“…Given their important functions in cancer initiation and progression, methylation changes are currently being investigated as potential biomarkers for early cancer detection, and prediction of cancer progression and chemotherapeutic sensitivity. A recent study found that significant methylation changes in PSMD10, which encodes gankyrin, were more frequent in gastric carcinoma and GC with metastasis compared with normal samples, suggesting that PSMD10 may act as a tumor suppressor gene, as well as an oncogene, as previously reported [15,16]. Gankyrin was initially purified and characterized by Tanaka and coworkers as the p28 component of the regulatory subunit of the 26S proteasome, which is an ATP-dependent protease responsible for the degradation of proteins [17].…”

Identification of the anti-tumor activity and mechanisms of nuciferine through a network pharmacology approach

“…Recent data have demonstrated that aberrant activation of the PI3K/AKT pathway is also frequently implicated in the development of neuroblastoma and correlates with poor prognosis [31] . IL-1β is a pleiotropic pro-inflammatory cytokine, and its levels are increased in many cancers, including colon cancers [32] and hepatocarcinomas [33] . Interestingly, PI3K and IL1B are located within a hub region in the connected subnetwork that is targeted by nucif- Our results also suggested that nuciferine can directly target the neuroblastoma-or colorectal cancer-associated proteins.…”

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

“…115 ( Figure 2) summarizes current knowledge about activation of Gankyrin in liver cancer and Gankyrin-dependent activities which contribute to development of liver cancer. The activation of Gankyrin in rodent models of carcinogenesis is mediated perhaps by two important events: de-repression of the Gankyrin promoter by reducing FXR signaling and subsequent activation by interleukin-1α/IRAK-1signaling.…”