4‐phenylbutyric acid promotes hepatocellular carcinoma via initiating cancer stem cells through activation of PPAR‐α

Autor: Wang Hongyang, Yushan Miao, Wen Wen, Ya-Ping Dong, Satdarshan P.S. Monga, Can Chen, Le-Xing Yu, Junyan Tao, Yan Ling, Xiao-Fei Chen, Qiqi Cao, Shuzhen Chen, Jiao-Jiao Tang, Zhe-Cai Fan, Han Yu, Yu-Ting Song
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
Medicine (General)
Liver tumor
Carcinoma
Hepatocellular
Carcinogenesis
Medicine (miscellaneous)
Peroxisome proliferator-activated receptor
4‐phenylbutyric acid (4‐PBA)
Mice
Nude
cancer stem cell (CSC)
03 medical and health sciences
hepatocellular carcinoma (HCC)
Mice
R5-920
0302 clinical medicine
Downregulation and upregulation
Cancer stem cell
parasitic diseases
medicine
Animals
PPAR alpha
Wnt Signaling Pathway
Research Articles
chemistry.chemical_classification
Liver Neoplasms
medicine.disease
Phenylbutyrates
peroxisome proliferator‐activated receptor‐α (PPAR‐α)
Mice
Inbred C57BL
030104 developmental biology
chemistry
030220 oncology & carcinogenesis
Cancer research
Unfolded protein response
Neoplastic Stem Cells
Molecular Medicine
Stem cell
Signal transduction
Liver cancer
Research Article
Zdroj: Clinical and Translational Medicine
Clinical and Translational Medicine, Vol 11, Iss 4, Pp n/a-n/a (2021)
ISSN: 2001-1326
Popis: Background and aims 4‐phenylbutyric acid (4‐PBA) is a low molecular weight fatty acid that is used in clinical practice to treat inherited urea cycle disorders. In previous reports, it acted as a chemical chaperone inhibiting endoplasmic reticulum (ER) stress and unfolded protein response signaling. A few studies have suggested its function against hepatic fibrosis in mice models. However, its role in hepatocarcinogenesis remained unknown. Methods 4‐PBA was administered alone or in combination with diethylnitrosamine to investigate its long‐term effect on liver tumorigenesis. The role of 4‐PBA in oncogene‐induced hepatocellular carcinoma (HCC) mice model using sleeping beauty system co‐expressed with hMet and β‐catenin point mutation (S45Y) was also observed. RNA‐seq and PCR array were used to screen the pathways and genes involved. In vitro and in vivo studies were conducted to explore the effect of 4‐PBA on liver and validate the underlying mechanism. Results 4‐PBA alone didn't cause liver tumor in long term. However, it promoted liver tumorigenesis in HCC mice models via initiation of liver cancer stem cells (LCSCs) through Wnt5b‐Fzd5 mediating β‐catenin signaling. Peroxisome proliferator‐activated receptors (PPAR)‐α induced by 4‐PBA was responsible for the activation of β‐catenin signaling. Thus, intervention of PPAR‐α reversed 4‐PBA‐induced initiation of LCSCs and HCC development in vivo. Further study revealed that 4‐PBA could not only upregulate the expression of PPAR‐α transcriptionally but also enhance its stabilization via protecting it from proteolysis. Moreover, high PPAR‐α expression predicted poor prognosis in HCC patients. Conclusions 4‐PBA could upregulate PPAR‐α to initiate LCSCs by activating β‐catenin signaling pathway, promoting HCC at early stage. Therefore, more discretion should be taken to monitor the potential tumor‐promoting effect of 4‐PBA under HCC‐inducing environment.
4‐PBA could promote HCC at early stage of tumor development in vivo.4‐PBA initiated CSCs via activating Wnt5b‐Fzd5‐β‐catenin signaling pathway dependent of PPAR‐α activation.4‐PBA could not only regulate the expression of PPAR‐α transcriptionally, but also stabilize it via direct binding.
Databáze: OpenAIRE
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