Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Chen SZ

PROVIDER: S-EPMC8087947 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Chen Shu-Zhen SZ Ling Yan Y Yu Le-Xing LX Song Yu-Ting YT Chen Xiao-Fei XF Cao Qi-Qi QQ Yu Han H Chen Can C Tang Jiao-Jiao JJ Fan Zhe-Cai ZC Miao Yu-Shan YS Dong Ya-Ping YP Tao Jun-Yan JY Monga Satdarshan P S SPS Wen Wen W Wang Hong-Yang HY

Clinical and translational medicine 20210401 4

<h4>Background and aims</h4>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.<h4>Methods</h4>4-PBA was administered alone or i ...[more]

PMID: 33931972

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Dataset Information

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

Background and aims

Methods

Results

Conclusions

Publications

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

Similar Datasets

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