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Developmental Stage-Specific Embryonic Induction of HepG2 Cell Differentiation

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Abstract

Background

Although hepatocellular carcinoma cells can sometimes undergo differentiation in an embryonic microenvironment, the mechanism is poorly understood.

Aim

The developmental stage-specific embryonic induction of tumor cell differentiation was investigated.

Methods

Both chick and mouse liver extracts and hepatoblast-enriched cells at different developmental stages were used to treat human hepatoma HepG2 cells, and the effects on the induction of differentiation were evaluated. The nuclear factors controlling differentiation, hepatocyte nuclear factor (HNF)-4α, HNF-1α, HNF-6 and upstream stimulatory factor-1 (USF-1), and the oncogene Myc and alpha-fetoprotein (AFP) were measured. HNF-4α RNA interference was used to verify the role of HNF-4α. Embryonic induction effects were further tested in vivo by injecting HepG2 tumor cells into immunodeficient nude mice.

Results

The 9–11-days chick liver extracts and 13.5–14.5-days mouse hepatoblast-enriched cells could inhibit proliferation and induce differentiation of HepG2 cells, leading to either death or maturation to hepatocytes. The maturation of surviving HepG2 cells was confirmed by increases in the expressions of HNF-4α, HNF-1α, HNF-6, and USF-1, and decreases in Myc and AFP. The embryonic induction of HepG2 cell maturation could be attenuated by HNF-4α RNA interference. Furthermore, the 13.5-days mouse hepatoblast culture completely eliminated HepG2 tumors with inhibited Myc and induced HNF-4α, confirming this embryonic induction effect in vivo.

Conclusions

This study demonstrated that developmental stage-specific embryonic induction of HepG2 cell differentiation might help in understanding embryonic differentiation and oncogenesis.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81470595) and the Hebei Natural Science Foundation (H2015206101).

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Author notes

    Authors and Affiliations

    1. Department of Biochemistry, Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China

      Yanhong Zong, Zhigang Xiao, Mengxuan Zhu, Hui Xiao, Jinsheng Qi & Kun Liu

    2. Department of Molecular Biology, Hebei Key Lab of Laboratory Animal, Hebei Medical University, Shijiazhuang, 050017, Hebei, China

      Yanning Li

    3. Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China

      Hui Wang

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    1. Yanning Li
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    Correspondence to Jinsheng Qi.

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    Additional information

    Yanning Li and Yanhong Zong contributed equally to this work.

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    10620_2015_3966_MOESM1_ESM.tif

    Supplemental Fig. 1 Mouse primary hepatoblasts. Albumin was found in nearly all cells, indicating that they were hepatoblast-enriched cells. Scale bar = 30 μm (TIF 957 kb)

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    Li, Y., Zong, Y., Xiao, Z. et al. Developmental Stage-Specific Embryonic Induction of HepG2 Cell Differentiation. Dig Dis Sci 61, 1098–1106 (2016). https://doi.org/10.1007/s10620-015-3966-4

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    • DOI: https://doi.org/10.1007/s10620-015-3966-4

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