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High expression of IL-17 and IL-17RE associate with poor prognosis of hepatocellular carcinoma

Rui Liao12, Jian Sun12, Han Wu12, Yong Yi12, Jia-Xing Wang12, Hong-Wei He12, Xiao-Yan Cai12, Jian Zhou12, Yun-Feng Cheng3, Jia Fan12 and Shuang-Jian Qiu123*

Author Affiliations

1 Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, China

2 Key Laboratory of Carcinogenesis and Cancer Invasion, the Chinese Ministry of Education, Shanghai, China

3 Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China

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Journal of Experimental & Clinical Cancer Research 2013, 32:3  doi:10.1186/1756-9966-32-3

Published: 11 January 2013

Abstract

Background

Hepatocellular carcinoma (HCC) is a typical malignancy in a background of chronic inflammation. Th17 cells (a major source of IL-17) constitute crucial components of infiltrating inflammatory/immune cells in HCC and can amplify inflammatory response via binding to interleukin-17 receptor (IL-17R). Thus, we investigated the expression and clinical significance of IL-17 and IL-17 receptor family cytokines in HCC.

Methods

The expression and prognostic value of IL-17 and IL-17R (A-E) were examined in 300 HCC patients after resection. Six Th17 associated cytokines in serum (n = 111) were quantified using enzyme-linked immunosorbent assays. Phenotypic features of IL-17+ CD4+ T cells were determined by flow cytometry analysis.

Results

High expression of intratumoral IL-17 and IL1-7RE were significantly associated with poorer survival (p = 0.016 and <0.001, respectively) and increased recurrence (both P < 0.001) of HCC patients. Moreover, intratumoral IL-17, individually or synergistically with IL-17RE, could predict HCC early recurrence and late recurrence. Also, peritumoral IL-17RE showed the prognostic ability in HCC (P < 0.001 for OS/TTR). Furthermore, expression levels of Th17 associated cytokines including IL-6, -22, -17R and TNF-α were increased in serum of HCC patients compared to haemangioma patients. Importantly, activated human hepatic stellate cells induced in vitro expansion of IL-17+ CD4+ T cells.

Conclusions

High expression of IL-17 and IL-17RE were promising predictors for poor outcome of HCC patients. The protumor power of IL-17 producing CD4+ T cells was probably involved in the crosstalk with different types of inflammatory/immune cells in HCC.

Keywords:
Interleukin-17; Receptor; Hepatic stellate cell; Prognosis; Hepatocellular carcinoma