NRF2/SHH Signaling Cascade Promotes Tumor-Initiating Cell Lineage and Drug Resistance in Hepatocellular Carcinoma

Hoi Wing Leung, Eunice Yuen Ting Lau, Oi Ning Leung, Mang Leng Lei, Ho Kit Mok, Victor Wan San Ma, William C.S. Cho, Irene Ng, Jing Ping Yun, Shao Hang Cai , Hua Jian Yu , Stephanie Ma, Kin Wah Lee

Research output: Journal article publicationJournal articleAcademic researchpeer-review

36 Citations (Scopus)


Solid evidence shows that tumor-initiating cells (T-ICs) are the root of tumor relapse and drug resistance, which lead to a poor prognosis in patients with hepatocellular carcinoma (HCC). Through an in vitro liver T-IC enrichment approach, we identified nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a transcription regulator that is significantly activated in enriched liver T-IC populations. In human HCCs, NRF2 was found to be overexpressed, which was associated with poor patient survival. Through a lentiviral based knockdown approach, NRF2 was found to be critical for regulating liver T-IC properties, including self-renewal, tumorigenicity, drug resistance and expression of liver T-IC markers. Furthermore, we found that ROS-induced NRF2 activation regulates sorafenib resistance in HCC cells. Mechanistically, NRF2 was found to physically bind to the promoter of sonic hedgehog homolog (SHH), which triggers activation of the sonic hedgehog pathway. The effect of NRF2 knockdown was eliminated upon administration of recombinant SHH, demonstrating that NRF2 mediated T-IC function via upregulation of SHH expression. Our study suggests a novel regulatory mechanism for the canonical sonic hedgehog pathway that may function through the NRF2/SHH/GLI signaling axis, thus mediating T-IC phenotypes.

Original languageEnglish
Pages (from-to)48-56
Number of pages9
JournalCancer Letters
Publication statusPublished - 28 Apr 2020


  • Drug resistance
  • Hepatocellular carcinoma
  • Sonic hedgehog
  • Sorafenib
  • Tumor initiating cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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