title: Overexpression of interleukin-35 associates with hepatocellular carcinoma aggressiveness and recurrence after curative resection.
abstract: BACKGROUND
  Aberrant expression of interleukin-35 (IL-35) has been implicated in dampening antitumour immunity. The aim of this study was to explore the prognostic significance of IL-35 expression in patients with hepatocellular carcinoma (HCC) following curative resection. Furthermore, we aimed to formulate an effective prognostic nomogram for HCC after hepatectomy.
  
  
  METHODS
  Immunohistochemistry was applied to explore IL-35 expression as well as CD39(+)Foxp3(+) and Foxp3(+) regulatory T cell (Treg) infiltration in tissue microarrays in primary cohort comprising 210 randomly selected HCC patients who underwent curative resection. The results were further verified in an independent validation cohort of 138 HCC patients.
  
  
  RESULTS
  Patients with higher expression of IL-35 are more likely to suffer postoperative recurrence. Interleukin-35 was also identified as an independent prognostic factor for recurrence free survival in multivariate analysis. No correlation was detected between IL-35 expression and Foxp3(+) Treg infiltration, whereas significant positive correlation was found between IL-35 expression and CD39(+)Foxp3(+) Treg infiltration. In addition, CD39(+)Foxp3(+) Treg infiltration was also an independent predictor for postoperative recurrence. The nomogram comprising tumour size, tumour vascular invasion, IL-35 and CD39(+)Foxp3(+) Tregs had better predictive accuracy when compared with BCLC stage for RFS. These results were further validated in the validation cohort.
  
  
  CONCLUSIONS
  Our data suggest for the first time that IL-35 expression correlates with HCC aggressiveness and emerged as a novel independent prognostic factor for recurrence, thus conferring the rationale to develop a novel therapy of targeting IL-35. Furthermore, IL-35 should be incorporated into nomogram to generate a more accurate predictive model.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.
authors.forename: Yi-Peng
authors.initials: YP
authors.lastname: Fu
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yi
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Cai
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Ni
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: He
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.
authors.forename: Jia-Xing
authors.initials: JX
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.
authors.forename: Zhu-Feng
authors.initials: ZF
authors.lastname: Lu
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Huang
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai 200032, People's Republic of China.|Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China.
authors.forename: Shuang-Jian
authors.initials: SJ
authors.lastname: Qiu
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006498:Hepatectomy / Q000401:mortality*; D006801:Humans; D007124:Immunoenzyme Techniques; D007378:Interleukins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D009367:Neoplasm Staging; D049451:Nomograms; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007378:Interleukins; C532417:interleukin-35, human