Research Papers:

Differentiation-inducing therapeutic effect of Notch inhibition in reversing malignant transformation of liver normal stem cells via MET

Hao Luo, Wei-Hui Liu, Hong-Yin Liang, Hong-Tao Yan, Ning Lin, Dong-Yu Li, Tao Wang and Li-Jun Tang _

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Oncotarget. 2018; 9:18885-18895. https://doi.org/10.18632/oncotarget.24421

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Hao Luo1,2,*, Wei-Hui Liu2,*, Hong-Yin Liang2,*, Hong-Tao Yan2,*, Ning Lin3, Dong-Yu Li2, Tao Wang2,* and Li-Jun Tang1,2

1Third Military Medical University, Chongqing 400038, China

2General Surgery Center, Chengdu Military General Hospital, Chengdu 610083, China

3Department of Clinical Nutrition, Chengdu Military General Hospital, Chengdu 610083, China

*These authors contributed equally to this work

Correspondence to:

Li-Jun Tang, email: [email protected]

Tao Wang, email: [email protected]

Keywords: liver cancer stem cells; liver normal stem cells; malignant transformation; Notch inhibition; differentiation inducing therapy

Received: August 23, 2017     Accepted: January 01, 2018     Epub: February 05, 2018     Published: April 10, 2018


Background: Liver cancer stem cells (LCSCs) are the key factors for cancer metastasis, recurrent, and drug resistance. LCSCs are originated from either hepatocytes dedifferentiation or differentiation arresting of liver normal stem cells (LNSCs). Differentiation-inducing therapy is a novel strategy in solid tumors. Furthermore, Notch signaling pathway has been proved to play important role in the process of hepatocytes differentiation. In previous study, a malignant transformation cellular model of LNSCs has been built up, and in this study we are trying to illustrate whether inhibition of Notch can reverse this malignant tendency and drive these malignant cells back to differentiate into mature hepatocytes.

Results: Inhibition of Notch signaling pathway can down-regulate the stemness-related cancer markers, lower the proliferative status, alleviate the invasive characteristic, or attenuate the metastasis tendency. What is more, it can help the malignantly transformed cells to regain the mature hepatic function of glucagon synthesis, urea metabolism, albumin production, and indocyanine-green (ICG) clearance.

Materials and Methods: HOX transcript antisense RNA (HOTAIR) expression was enhanced in LNSCs via lentivirus transduction to set up the malignant transformation cellular model. Then, a Notch inhibitor was applied to induce malignantly transformed cells differentiate into mature hepatocytes, and malignant abilities of proliferation, invasiveness, tumorigenesis as well as mature hepatocyte function were observed and compared.

Conclusions: The data demonstrate that the anti-tumor effects of Notch inhibition may lie not only on killing the cancer cells or LCSCs directly, it can also induce the LCSCs differentiation into mature hepatocytes via mesenchymal-epithelial transition (MET) progress or downgrade the malignancy.

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