Role of IL-33 expression in oncogenesis and development of human hepatocellular carcinoma

Abstract

Interleukin-33 (IL-33), a newly-discovered cytokine belonging to the IL-1 family, serves an important role in inflammation. However, it is not clear whether IL-33 is of clinical significance in hepatocarcinogenesis. The present study was designed to investigate the role of IL-33 during oncogenesis and development of hepatocellular carcinoma (HCC). IL-33 protein expression was detected in 76 HCC (including 36 para-carcinoma), 33 cirrhosis, 30 hepatitis, and 20 normal liver tissues using immunohistochemistry. IL-33 mRNA expression in carcinoma and para-carcinoma tissues was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). The possible correlation between IL-33 and clinicopathological parameters of HCC was also analyzed. Significant differences in IL-33 expression were not observed among normal, hepatic, and cirrhotic tissues (P>0.05), whereas the level of protein positive rate was markedly reduced in HCC tissues (P<0.01). Positive staining of IL-33 in non-cancerous liver (NCL) tissues (i.e. normal, hepatitis, and liver cirrhosis) was located predominantly in the nucleus and occasionally in the cytoplasm of hepatocytes; however, the expression in HCC tissues was mostly restricted to the cytoplasm. A significant alteration in protein localization was observed in HCC tissues as compared with NCL tissues (P<0.01). In comparison with HCC tissues, cytoplasmic staining of IL-33 was increased in para-carcinoma tissues. RT-PCR assay further confirmed relatively high mRNA expression levels of IL-33 in para-carcinoma tissues. IL-33 expression was significantly negatively associated with tumor histological grade (r=−0.279, P=0.015), but not with year, gender, tumor size, clinical stage, HCC with hepatitis and cirrhosis background, lymph node metastasis or intrahepatic vascular embolism (P>0.05). Therefore, the aberrant expression of IL-33 is associated with oncogenesis and progression of HCC and the cytoplasmic accumulation of the protein may serve a role in hepatocarcinogenesis.

The DNA methylation profile of liver tumors in C3H mice and identification of differentially methylated regions involved in the regulation of tumorigenic genes

“…7d ). IL33 activates NF-kB and ERK signaling pathways and is implicated in HCC [ 37 ]. The present study newly demonstrates the possibility that IL33 is a down-stream target of Mst1r and is involved in the liver tumors of C3H mice and in human HCC.…”

The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment

“…IL-33 expression was negatively associated with HCC histological grade, but not with other parameters including lymph node metastasis. Together, this suggests that cytoplasmic/non-nuclear IL-33 might play a role in HCC development (60). …”

IL-33 Released in the Liver Inhibits Tumor Growth via Promotion of CD4+ and CD8+ T Cell Responses in Hepatocellular Carcinoma

“…In contrast, IL-33 was involved in tumoral oncogenesis in myeloproliferative neoplasms and colorectal cancer (40,41). Although IL-33 can be expressed in both cytoplasm and nucleus, HCC tissues only showed cytoplasmic IL-33 staining, which suggests that cytoplasmic or released IL-33 might play a role in HCC development (42). Moreover, tumor-infiltrating, IL-33-producing effector memory CD8 + T cells have been shown to be associated with prolonged survival of HCC patients (43), suggesting IL-33 produced in the tumor microenvironment could be an important mediator of antitumor immune response.…”