Hepatic inflammation-fibrosis-cancer axis in the rat hepatocellular carcinoma induced by diethylnitrosamine
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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.
KeywordsHepatocellular 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).
This study was approved by the Animal Experimental Ethical Committee of Jiangsu Province Academy of Traditional Chinese Medicine.
- Di Virgilio F (2014) Purinergic receptors in cancer and inflammation: from Rudolph Virchow to Geoff Burnstock. Purinergic signallling, vol 10. Springer, Netherlands, pp 657–658Google Scholar
- Kishida N, Matsuda S, Itano O (2016) Development of a novel mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis using a high-fat, choline-deficient diet and intraperitoneal injection of diethylnitrosamine. BMC Gastroenterol 16:61. doi: 10.1186/s12876-016-0477-5 CrossRefPubMedPubMedCentralGoogle Scholar
- Li C, Bi X, Huang Y et al (2014) Variants identified by hepatocellular carcinoma and chronic hepatitis B virus infection susceptibility GWAS associated with survival in HBV-related hepatocellular carcinoma. PloS One 9(7):e101586. doi: 10.1371/journal.pone.0101586 CrossRefPubMedPubMedCentralGoogle Scholar
- Uehara T, Pogribny I P, Rusyn I (2014) The DEN and CCl4-induced mouse model of fibrosis and inflammation-associated hepatocellular carcinoma. Curr Protoc Pharmacol 66:14.30.1–14.30.10Google Scholar