2. Academic Validation
  3. Targeting NPM1 inhibits proliferation and promotes apoptosis of hepatic progenitor cells via suppression of mTOR signalling pathway

Targeting NPM1 inhibits proliferation and promotes apoptosis of hepatic progenitor cells via suppression of mTOR signalling pathway

  • Stem Cell Res Ther. 2024 Sep 11;15(1):292. doi: 10.1186/s13287-024-03898-8.
Ping Wang 1 2 3,  Min Wang 4 5 6,  Lin Liu 4 5 6,  Hongyi Li 4 5 6,  Helin Liu 4 5 6,  Jiangbo Ren 4 5 6,  Tianhui Liu 4 5 6,  Min Cong 4 5 6,  Zhijun Zhu 6 7 8,  Xinyan Zhao 4 5 6,  Liying Sun 9 10 11,  Jidong Jia 12 13 14
Affiliations

Affiliations

  • 1 Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. wangping2009@ccmu.edu.cn.
  • 2 Beijing Key Laboratory On Translational Medicine On Liver Cirrhosis, Beijing, 100050, China. wangping2009@ccmu.edu.cn.
  • 3 National Clinical Research Center for Digestive Disease, Beijing, 100069, China. wangping2009@ccmu.edu.cn.
  • 4 Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
  • 5 Beijing Key Laboratory On Translational Medicine On Liver Cirrhosis, Beijing, 100050, China.
  • 6 National Clinical Research Center for Digestive Disease, Beijing, 100069, China.
  • 7 Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
  • 8 Clinical Center for Paediatric Liver Transplantation, Capital Medical University, Beijing, 100069, China.
  • 9 Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. sunxlx@outlook.com.
  • 10 Beijing Key Laboratory On Translational Medicine On Liver Cirrhosis, Beijing, 100050, China. sunxlx@outlook.com.
  • 11 National Clinical Research Center for Digestive Disease, Beijing, 100069, China. sunxlx@outlook.com.
  • 12 Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. jia_jd@ccmu.edu.cn.
  • 13 Beijing Key Laboratory On Translational Medicine On Liver Cirrhosis, Beijing, 100050, China. jia_jd@ccmu.edu.cn.
  • 14 National Clinical Research Center for Digestive Disease, Beijing, 100069, China. jia_jd@ccmu.edu.cn.
PMID: 39256792 DOI: 10.1186/s13287-024-03898-8
Abstract

Background: Hepatic progenitor cells serve not only as the origin of combined hepatocellular cholangiocarcinoma (cHCC-CCA) but are also responsible for malignancy recurrence after surgical resection. Nucleophosmin 1 (NPM1) has been implicated in Cancer metastasis and poor prognosis. This study aimed to determine the expression of NPM1 by hepatic progenitor cells in cHCC-CCA and the effects of targeting NPM1 on hepatic progenitor cells and BEL-7402 cells with characteristics of both progenitor cells and cHCC-CCA.

Methods: First, NPM1 was detected by RT‒PCR, western blotting, and double-immunofluorescence staining in cHCC-CCA tissues. NPM1 expression was subsequently analysed in rat hepatic progenitor cells cultured in vitro and in interleukin 6 (IL6)-treated cells. The effects and mechanism of NPM1 on hepatic progenitor cells were determined by knocking down NPM1 and performing RNA Sequencing analysis. Finally, NSC348884, a small-molecule inhibitor that disrupts NPM1 dimer formation, was used to confirm the function of NPM1 in BEL-7402 cells.

Results: Both human hepatic progenitor cells in cHCC-CCA tissues and rat in vitro cultured hepatic progenitor cells highly expressed NPM1. IL6, a cytokine involved in the malignant transformation of hepatic progenitor cells, dose-dependently increased NPM1 and PCNA expression. Knocking down NPM1 reduced IL6R transcription (P < 0.0001) and inhibited the proliferation (P = 0.0065) of hepatic progenitor cells by suppressing the mTOR signalling pathway and activating the Apoptosis pathway. Furthermore, knocking down NPM1 in hepatic progenitor cells resulted in more apoptotic cells (7.33 ± 0.09% vs. 3.76 ± 0.13%, P < 0.0001) but fewer apoptotic cells in the presence of NSC348884 (47.57 ± 0.49% vs. 63.40 ± 0.05%, P = 0.0008) than in the control cells, suggesting that low-NPM1-expressing cells are more resistant to NSC348884. In addition, NSC348884 induced the Apoptosis of BEL-7402 cells with an IC50 of 2.77 μmol/L via the downregulation of the IL-6R and mTOR signalling pathways and inhibited the growth of BEL-7402 cells in a subcutaneous xenograft tumour model (P = 0.0457).

Conclusions: Targeting NPM1 inhibits proliferation and induces Apoptosis in hepatic progenitor cells and BEL-7402 cells, thus serving as a potential therapy for cHCC-CCA.

Keywords

Apoptosis; Liver progenitor cells; Nucleophosmin 1; mTOR signalling pathway.

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