We read the discussion about interleukin (IL)-22 as a negative prognostic indicator in viral hepatitis-related hepatocellular carcinoma (HCC). It is clear that IL-22 is a hepatoprotective cytokine. A phase I clinical trial of IL-22 has been carried out (http://www.businesswire.com/news/home/20120906005611/en/Generon-Initiates-Phase-Clinical-Study-F-652-Australia). On the other hand, Radaeva et al. reported that IL-22 also promoted human HCC growth by activating signal transducer and activator of transcription 3 (STAT3) and subsequently up-regulating STAT3 target genes, which was confirmed by others. Recently, our group reported that IL-22 transgenic (Tg) mice developed more and larger liver tumor after diethylnitrosamine injection. Interestingly, IL-22 Tg mice did not spontaneously develop liver tumors. These findings suggest that IL-22 alone does not initiate liver tumors, but can promote hepatic carcinogenesis together with other risk factors.
We recently demonstrated that IL-22 can also promote the growth of liver progenitor cells (LPCs), which partially explains the expansion of LPCs in chronic viral hepatitis patients resulting from higher IL-22 levels in these patients. LPCs are considered as an important source of liver cancer stem cells. To test whether IL-22-induced LPC expansion contributes to carcinogenesis, we fed wild type (WT) and IL-22 Tg mice with a 3,5-diethoxycarbonyl-1,4-dihydro-collidin diet for 7 months. Only 1 of 4 IL-22 Tg mice developed liver tumor, compared to 0 of 4 in WT mice. Although our study is preliminary, it suggests that additional factors are necessary for the transformation from LPCs to liver cancer stem cells (LCSCs). The hypothesis was supported by a study that found that increased tumorigenicity was discovered in LPCs with hepatitis B virus x protein expression.
Taken together, elevated IL-22 can promote the growth of LPCs and HCC. However, in addition to IL-22, other factors, such as viral infection, are necessary for the transformation of LPCs to LCSCs and subsequent HCC initialization.
Dechun Feng, Ph.D.
Laboratory of Liver Diseases
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health