2. Academic Validation
  3. TWEAK Signaling-Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis

TWEAK Signaling-Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis

  • Adv Sci (Weinh). 2023 Apr 21;e2300350. doi: 10.1002/advs.202300350.
Wenting Liu 1 2,  Lu Gao 1 2,  Xiaojuan Hou 1 2,  Shiyao Feng 3,  Haixin Yan 3,  Hongyu Pan 4,  Shichao Zhang 4,  Xue Yang 1 2,  Jinghua Jiang 1 2,  Fei Ye 1 2,  Qiudong Zhao 1 2,  Lixin Wei 1 2,  Zhipeng Han 1 2
Affiliations

Affiliations

  • 1 Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, P. R. China.
  • 2 Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, P. R. China.
  • 3 Department of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, P. R. China.
  • 4 Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, P. R. China.
PMID: 37085918 DOI: 10.1002/advs.202300350
Abstract

The malignant transformation of hepatic progenitor cells (HPCs) in the inflammatory microenvironment is the root cause of hepatocarcinogenesis. However, the potential molecular mechanisms are still elusive. The HPCs subgroup is identified by single-cell RNA (scRNA) Sequencing and the phenotype of HPCs is investigated in the primary HCC model. Bulk RNA Sequencing (RNA-seq) and proteomic analyses are also performed on HPC-derived organoids. It is found that tumors are formed from HPCs in peritumor tissue at the 16th week in a HCC model. Furthermore, it is confirmed that the macrophage-derived TWEAK/Fn14 promoted the expression of inhibitor of differentiation-1 (ID1) in HPCs via NF-κB signaling and a high level of ID1 induced aberrant differentiation of HPCs. Mechanistically, ID1 suppressed differentiation and promoted proliferation in HPCs through the inhibition of HNF4α and Rap1GAP transcriptions. Finally, scRNA Sequencing of HCC patients and investigation of clinical specimens also verified that the expression of ID1 is correlated with aberrant differentiation of HPCs into Cancer Stem Cells, patients with high levels of ID1 in HPCs showed a poorer prognosis. This study provides important intervention targets and a theoretical basis for the clinical diagnosis and treatment of HCC.

Keywords

hepatic progenitor cells; inflammatory microenvironment; inhibitor of differentiation-1; single-cell RNA sequencing; tumor necrosis factor-like weak inducer of apoptosis (TWEAK).

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