Hepatic inflammation-fibrosis-cancer axis in the rat hepatocellular carcinoma induced by diethylnitrosamine

  • Yong-fang Ding
  • Zhen-hui Wu
  • Ying-jie Wei
  • Luan Shu
  • Yun-ru Peng
Original Article – Cancer Research



Hepatocellular carcinoma (HCC) cases are closely associated with chronic inflammation and fibrosis which is known as hepatic inflammation-fibrosis-cancer (IFC) axis. The aim of this study is to elucidate the development characteristics of the rat HCC model based on IFC axis.


The diethylnitrosamine (DEN)-induced rat HCC, which presents a stepwise histopathological progression that is similar to human HCC, was used to analyze the features of the different stages (inflammation, fibrosis, cancer). Rats were injected DEN at a dose of 30 mg/kg body weight twice a week for 11 weeks and the animals were observed until week 20. Time series sera and organ samples from the DEN animal model were collected to evaluate the dynamic changes.


It was found that serum biochemical indicators (AST, ALT, ALP, TP, T-BIL, IL-6, TNF-α) from DEN-treated group were higher than that from control group. Fibrosis-related index in serum and live tissue were increased, respectively, from week 4 after DEN treatment. The expression of TGF-β1 and α-SMA in DEN-treated group was higher than that in control group. JAK2/STAT3 signaling was significantly up-regulated in DEN-treated group compared to that in control group. The histological examination confirmed that the hepatocarcinogenesis model was successfully established, and 100% of the animals in the DEN-exposed group developed liver tumors at 20 weeks. According to the pathological changes, the model characterized resulted in three stages: the inflammation stage (week 2–6), the fibrosis stage (week 8–12), and the HCC stage (week 14–20).


The results suggested that the HCC development was associated with IFC axis. The serial progression of hepatocarcinogenesis was according to the sequence of hepatic inflammation, fibrosis and then hepatic tumor.


Hepatocellular carcinoma Liver inflammation Liver fibrosis Inflammation-fibrosis-cancer (IFC) axis 


Compliance with ethical standards

Conflict of interest

The author(s) declare(s) that they have no conflicts of interest to disclose.


This study was supported by a Grant from the National Natural Science Foundation of China (Nos. 81373888, 81102884).

Ethical approval

This study was approved by the Animal Experimental Ethical Committee of Jiangsu Province Academy of Traditional Chinese Medicine.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Yong-fang Ding
    • 1
    • 2
  • Zhen-hui Wu
    • 3
  • Ying-jie Wei
    • 1
    • 2
  • Luan Shu
    • 1
    • 2
  • Yun-ru Peng
    • 1
    • 2
  1. 1.Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingPeople’s Republic of China
  2. 2.Jiangsu Province Academy of Traditional Chinese MedicineNanjingPeople’s Republic of China
  3. 3.Nanjing University of Chinese MedicineNanjingPeople’s Republic of China

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