Key Takeaways & Executive Findings
- •• NPM1 is highly expressed in hepatic progenitor cells and cHCC-CCA tissues, and its expression is upregulated by IL6, a key cytokine in malignant transformation. • Knockdown of NPM1 suppresses proliferation and induces apoptosis in hepatic progenitor cells via inhibition of the mTOR signalling pathway and activation of apoptosis pathways. • The small-molecule inhibitor NSC348884, which disrupts NPM1 dimerization, effectively induces apoptosis in BEL-7402 cells and inhibits tumour growth in a xenograft model, suggesting a novel therapeutic strategy for cHCC-CCA. • Targeting NPM1 may offer a promising approach to prevent recurrence and improve outcomes in patients with cHCC-CCA.
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.
1. Introduction
“Mixed” or “combined” hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver malignancy that has more frequent vascular invasion and lymph node metastasis than hepatocellular carcinoma (HCC), thus resulting in a worse prognosis and poor outcomes [1]. Liver resection is the first-line treatment for cHCC-CCA, yet the 5-year overall survival is still lower than 30% [2, 3]. Furthermore, there is no significant anti-tumour efficacy of sorafenib, a first-line treatment for advanced HCC, or gemcitabine and cisplatin, the standard therapy for intrahepatic cholangiocarcinoma, on unresectable cHCC-CCA [4]. Therefore, there is an urgent need to develop new therapeutic strategies for this disease.
cHCC-CCA is defined as a liver tumour with both hepatocytic and cholangiocytic characteristics and is thought to be derived from hepatic progenitor cells [5, 6]. Recent findings confirm that hepatic progenitor cells serve as the origin of cHCC-CCA in the presence of chronic inflammation dependent on IL6 signalling [7]. Even after cHCC-CCA resection, remaining hepatic progenitor cells are involved in malignancy recurrence [8]. Therefore, targeting hepatic progenitor cells may be a therapeutic strategy for cHCC-CCA.
Nucleophosmin 1 (NPM1) is a molecule that is located primarily in the nucleus of cells and is involved in a variety of cellular processes, including ribosome assembly [9, 10], DNA repair [11, 12], the regulation of cell growth and proliferation [13, 14], and the development and progression of certain types of cancer [15–17]. Clinically, NPM1 is among the genes associated with the survival time of HCC patients [18], and upregulation of NPM1 is correlated with the ...
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Ping Wang, Min Wang, Lin Liu, Hongyi Li, Helin Liu, Jiangbo Ren, Tianhui Liu, Min Cong, Zhijun Zhu, Xinyan Zhao, Liying Sun, Jidong Jia (2026). Targeting NPM1 inhibits proliferation and promotes apoptosis of hepatic progenitor cells via suppression of mTOR signalling pathway. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-024-03898-8
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Frequently Asked Questions
What is the role of NPM1 in hepatic progenitor cells?
NPM1 is highly expressed in hepatic progenitor cells and is involved in their proliferation. Targeting NPM1 inhibits proliferation and promotes apoptosis, suggesting a potential therapeutic target for cHCC-CCA.
How does NPM1 affect the mTOR signalling pathway?
Knockdown of NPM1 suppresses the mTOR signalling pathway, leading to reduced proliferation and increased apoptosis in hepatic progenitor cells.
What is NSC348884 and how does it work?
NSC348884 is a small-molecule inhibitor that disrupts NPM1 dimer formation. It induces apoptosis in BEL-7402 cells and inhibits tumour growth in a xenograft model, potentially by downregulating IL-6R and mTOR signalling.
What is the significance of this study for cHCC-CCA treatment?
The study suggests that targeting NPM1 could be a novel therapeutic strategy for cHCC-CCA, as it inhibits proliferation and induces apoptosis in hepatic progenitor cells and BEL-7402 cells, potentially reducing recurrence and improving patient outcomes.
What are the key findings regarding IL6 and NPM1 expression?
IL6, a cytokine involved in malignant transformation, dose-dependently increases NPM1 and PCNA expression in hepatic progenitor cells, indicating a link between inflammation and NPM1 upregulation.
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