Abstract

Normal cells become cancer cells after a malignant transformation, but whether cancer cells can be reversed to normal status remains elusive. Here, we report that the combination of hepatocyte nuclear factor 1A (HNF1A), HNF4A and forkhead box protein A3 (FOXA3) synergistically reprograms hepatocellular carcinoma (HCC) cells to hepatocyte-like cells (reprogrammed hepatocytes, rHeps). Our results show that rHeps lose the malignant phenotypes of cancer cells and retrieve hepatocyte-specific characteristics including hepatocyte-like morphology; global expression pattern of genes and specific biomarkers of hepatocytes; and the unique hepatic functions of albumin (ALB) secretion, glycogen synthesis, low-density lipoprotein (LDL) uptake, urea production, cytochrome P450 enzymes induction and drug metabolism. Intratumoral injection of these three factors efficiently shrank patient-derived tumor xenografts and reprogrammed HCC cells in vivo. Most importantly, transplantation of rHeps in the liver of fumarylacetoacetate hydrolase-deficient (Fah−/−) mice led to the reconstruction of hepatic lobules and the restoration of hepatic function. Mechanistically, exogenous expression of HNF1A, HNF4A and FOXA3 in HCC cells initiated the endogenous expression of numerous hepatocyte nuclear factors, which promoted the conversion of HCC cells to hepatocyte-like cells. Collectively, our results indicate the successful conversion of hepatoma cells to hepatocyte-like cells, not only extending our current knowledge of cell reprogramming but also providing a route towards a novel therapeutic strategy for cancer.

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Acknowledgements

The authors would like to thank Dr. Lijian Hui (Laboratory of Molecular Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy for Sciences) for technical assistance and his suggestions in manuscript preparation. This work was supported by grants from the State Key Project of China (2017YFA0504503); the National Natural Science Foundation of China (81772582, 81572897 and 81471948); the Shanghai Pujiang Program (17PJD045); and Key Project of Shanghai Science and Technology Committee (17431906600).

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Author notes

  1. These authors contributed equally: Zhuo Cheng, Zhiying He, Yongchao Cai, Cheng Zhang.

Affiliations

  1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, the Second Military Medical University, Shanghai, China

    • Zhuo Cheng
    • , Cheng Zhang
    • , Gongbo Fu
    • , Hengyu Li
    • , Wen Sun
    • , Xiuliang Cui
    • , Daimin Xiang
    • , Tengfei Zhou
    • , Xiaofeng Li
    • , Hongyang Wang
    •  & Jin Ding
  2. Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China

    • Zhiying He
    • , Yongchao Cai
    •  & Changcheng Liu
  3. Department of Gastroenterology, Changzheng Hospital, the Second Military Medical University, Shanghai, China

    • Beifang Ning
    •  & Weifen Xie
  4. National Center for Liver Cancer, Shanghai, China

    • Hongyang Wang
    •  & Jin Ding

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Contributions

J.D. and H.W. conceived the study. Z.C. and J.D. wrote the manuscript. Z.C., Z.H., Y.C. and C.Z. performed the majority of the experiments. Z.C., C.Z. and H.L. performed the in vitro experiments. Z.C. and X.L. performed the in vivo characterization. B.N., D.X. and T.Z. assisted with rHeps generation and characterization. Z.H., Y.C. and C.L. performed the transplantation into Fah-deficient mice and analyzed the results of the experiment. W.S., X.C. and W.X. provided technical support. Z.H. and Y.C. were involved in manuscript preparation.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Hongyang Wang or Jin Ding.

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DOI

https://doi.org/10.1038/s41422-018-0111-x