Stem Cell Research & Therapy
·
2024
·Vol. 15
·期 1
·1-15
·
IF 7.1
Wang Ping,Wang Min,Liu Lin,Li Hongyi,Liu Helin,Ren Jiangbo,Liu Tianhui,Cong Min,Zhu Zhijun,Zhao Xinyan,Sun Liying,Jia Jidong
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.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 7
·1-22
·
IF 8.1
Tan Diaoyi,Miao Daojia,Zhao Chuanyi,Shi Jian,Lv Qingyang,Lu Feiyi,Ruan Hailong,Xiong Zhiyong,Zhang Xiaoping
Aldehyde dehydrogenases superfamily (ALDHs), which are ubiquitously present in various organisms with diverse subcellular localizations, play a crucial role in regulating malignant tumor progression; Nevertheless, their involvement in clear cell renal cell carcinoma (ccRCC) has not been elucidated. In this study, we performed comprehensive bioinformatics analyses on the 19 ALDHs genes, and identified ALDH9A1 as a key contributor in ccRCC. Expression patterns and clinical relevance of ALDH9A1 were determined using bioinformatics analyses, real-time PCR, western blotting, and immunohistochemistry. To explore the underlying mechanism behind the tumor suppressor role of ALDH9A1, RNA sequencing, methylated RNA immunoprecipitation, luciferase reporter assay, mass spectroscopy, immunoprecipitation, mutational studies and immunofluorescence were employed. The impact of ALDH9A1 in ccRCC progression and metabolic programming was assessed through both in vitro and in vivo. Here, this study revealed ALDH9A1 as a tumor suppressor gene in ccRCC. The fat mass and obesity associated protein (FTO) was identified as a demethylase for ALDH9A1 mRNA, resulting in its reduced stability and expression levels in ccRCC. Functional experiments demonstrated that the deficiency of ALDH9A1 in ccRCC promoted tumor proliferation, invasion, migration and lipid accumulation. Mechanistic insights illustrated that the diminished levels of ALDH9A1 resulted in the failure to sequester nucleophosmin 1 (NPM1) within cytoplasm, thereby suppressing the transcription of IQ motif containing the GTPase-activating protein 2 (IQGAP2), subsequently activating the AKT-mTOR signaling, ultimately fostering tumor progression and lipid accumulation. In conclusion, the present study highlights the robust prognostic significance of ALDH9A1 and delivers a comprehensive understanding of ALDH9A1-NPM1-IQGAP2-AKT axis in ccRCC. These findings established a solid research foundation for novel therapeutic strategies for ccRCC patients.
研究领域:
癌症生物学
·
分子生物学
·
生物信息学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Yijing Zhang,Han Gao,Aiwen Tang,Haiwen Lyu,Zongmin Fan,Jiahui Guo,Yuzhi Wang,Hairong Yi,Qihao Pan,Haidan Luo,Baifu Qin,Boyu Zhang,Xiangqi Meng,Qingxin Liu,Mong-Hong Lee
Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer with poor prognosis. COP9 signalosome subunit 6 (CSN6), a key regulator of different E3 ubiquitin ligases, plays oncogenic roles in various cancers. However, its function in PDAC remains elusive. Here, this demonstrates that human PDAC tumors expressing high levels of CSN6 present with poor prognosis and gemcitabine resistance. Conditional knockout (KO) of CSN6 hinders tumor formation in a KPP spontaneous PDAC mouse model. Proteomic analysis indicates that CSN6 promotes ribosome biogenesis by activating rDNA transcription and protein synthesis. Mechanistically, CSN6 antagonizes DDB1-CUL4 associated factor 1 (DCAF1)-mediated ubiquitination of Nucleophosmin (NPM1), thereby promoting NPM1-orchestrated ribosome biogenesis. In line with CSN6-mediated gemcitabine resistance, CSN6-NPM1 axis enhances ribosome biogenesis, thereby promoting translation of gemcitabine resistance genes, including Cytidine deaminase (CDA), Ribonucleotide reductase subunit M1/2 (RRM1/2). Significantly, combining gemcitabine with NPM1 inhibitor NSC348884 synergistically suppresses CSN6-high pancreatic cancer xenografts. Clinically, CSN6 expression positively correlates with NPM1 in PDAC tissues, and their concurrent high expression is significantly associated with poor clinical outcomes. This study characterizes CSN6 as an oncogenic protein that promotes NPM1 stabilization by interacting with DCAF1, thereby enhancing ribosome biogenesis and cellular resistance to gemcitabine in PDAC. NPM1 may serve as a therapeutic target for CSN6 high PDAC that exhibits gemcitabine drug resistance.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）