CYP2E1 deficit mediates cholic acid-induced malignant growth in hepatocellular carcinoma cells

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Abstract

Background

Increased level of serum cholic acid (CA) is often accompanied with decreased CYP2E1 expression in hepatocellular carcinoma (HCC) patients. However, the roles of CA and CYP2E1 in hepatocarcinogenesis have not been elucidated. This study aimed to investigate the roles and the underlying mechanisms of CYP2E1 and CA in HCC cell growth.

Methods

The proteomic analysis of liver tumors from DEN-induced male SD rats with CA administration was used to reveal the changes of protein expression in the CA treated group. The growth of CA-treated HCC cells was examined by colony formation assays. Autophagic flux was assessed with immunofluorescence and confocal microscopy. Western blot analysis was used to examine the expression of CYP2E1, mTOR, AKT, p62, and LC3II/I. A xenograft tumor model in nude mice was used to examine the role of CYP2E1 in CA-induced hepatocellular carcinogenesis. The samples from HCC patients were used to evaluate the clinical value of CYP2E1 expression.

Results

CA treatment significantly increased the growth of HCC cells and promoted xenograft tumors accompanied by a decrease of CYP2E1 expression. Further studies revealed that both in vitro and in vivo, upregulated CYP2E1 expression inhibited the growth of HCC cells, blocked autophagic flux, decreased AKT phosphorylation, and increased mTOR phosphorylation. CYP2E1 was involved in CA-activated autophagy through the AKT/mTOR signaling. Finally, decreased CYP2E1 expression was observed in the tumor tissues of HCC patients and its expression level in tumors was negatively correlated with the serum level of total bile acids (TBA) and gamma-glutamyltransferase (GGT).

Conclusions

CYP2E1 downregulation contributes to CA-induced HCC development presumably through autophagy regulation. Thus, CYP2E1 may serve as a potential target for HCC drug development.

Supplementary Information

The online version contains supplementary material available at 10.1186/s10020-024-00844-5.

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Most cited references 58

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Xiaohua Li, Shikun He, Binyun Ma (2020)

Autophagy, as a type II programmed cell death, plays crucial roles with autophagy-related (ATG) proteins in cancer. Up to now, the dual role of autophagy both in cancer progression and inhibition remains controversial, in which the numerous ATG proteins and their core complexes including ULK1/2 kinase core complex, autophagy-specific class III PI3K complex, ATG9A trafficking system, ATG12 and LC3 ubiquitin-like conjugation systems, give multiple activities of autophagy pathway and are involved in autophagy initiation, nucleation, elongation, maturation, fusion and degradation. Autophagy plays a dynamic tumor-suppressive or tumor-promoting role in different contexts and stages of cancer development. In the early tumorigenesis, autophagy, as a survival pathway and quality-control mechanism, prevents tumor initiation and suppresses cancer progression. Once the tumors progress to late stage and are established and subjected to the environmental stresses, autophagy, as a dynamic degradation and recycling system, contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis. This indicates that regulation of autophagy can be used as effective interventional strategies for cancer therapy.

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Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis

Xinyang Song, Ximei Sun, Sungwhan F. Oh … (2019)

The metabolic pathways encoded by the human gut microbiome constantly interact with host gene products through numerous bioactive molecules1. Primary bile acids (BAs) are synthesized within hepatocytes and released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins2. Some BAs (approximately 5%) escape into the colon, where gut commensal bacteria convert them into various intestinal BAs2 that are important hormones that regulate host cholesterol metabolism and energy balance via several nuclear receptors and/or G-protein-coupled receptors3,4. These receptors have pivotal roles in shaping host innate immune responses1,5. However, the effect of this host-microorganism biliary network on the adaptive immune system remains poorly characterized. Here we report that both dietary and microbial factors influence the composition of the gut BA pool and modulate an important population of colonic FOXP3+ regulatory T (Treg) cells expressing the transcription factor RORγ. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this Treg cell population. Restoration of the intestinal BA pool increases colonic RORγ+ Treg cell counts and ameliorates host susceptibility to inflammatory colitis via BA nuclear receptors. Thus, a pan-genomic biliary network interaction between hosts and their bacterial symbionts can control host immunological homeostasis via the resulting metabolites.

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Recent insights into the function of autophagy in cancer

Ravi Amaravadi, Alec C Kimmelman, Eileen White (2016)

In this review, Amaravadi et al. discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response. Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumor-promoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.

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Author and article information

Contributors

Shaobo Hu: hsb9999@126.com

Yuchen Liu: yuchen.liu@jhun.edu.cn

Zhengqi Fu:

ORCID: http://orcid.org/0000-0003-0923-7234

lilyfzq@163.com

Journal

Journal ID (nlm-ta): Mol Med

Journal ID (iso-abbrev): Mol Med

Title: Molecular Medicine

Publisher: BioMed Central (London )

ISSN (Print): 1076-1551

ISSN (Electronic): 1528-3658

Publication date (Electronic): 7 June 2024

Publication date PMC-release: 7 June 2024

Publication date Collection: 2024

Volume: 30

Electronic Location Identifier: 79

Affiliations

[1 ]Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, ( https://ror.org/041c9x778) Wuhan, 430056 China

[2 ]Cancer Institute, School of Medicine, Jianghan University, ( https://ror.org/041c9x778) Wuhan, 430056 China

[3 ]Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, ( https://ror.org/041c9x778) Wuhan, 430056 China

[4 ]Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, ( https://ror.org/041c9x778) Wuhan, 430056 China

[5 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Liver transplant center, Union Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; Wuhan, 430022 China

[6 ]Department of Pathology, Renmin Hospital of Huangpi District of Jianghan University, ( https://ror.org/041c9x778) Wuhan, 430399 China

Author information

Zhengqi Fu http://orcid.org/0000-0003-0923-7234

Article

Publisher ID: 844

DOI: 10.1186/s10020-024-00844-5

PMC ID: 11157842

PubMed ID: 38844847

SO-VID: 3d79b741-b9a8-4996-a27d-a53059c7a815

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 11 March 2024

Date accepted : 22 May 2024

Funding

Funded by: The National Natural Science Foundation of China

Award ID: 81872040

Award Recipient : Zhengqi Fu

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Keywords: cholic acid,cyp2e1,hepatocellular cancer,cell growth,autophagy

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Keywords: cholic acid, cyp2e1, hepatocellular cancer, cell growth, autophagy

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CYP2E1 deficit mediates cholic acid-induced malignant growth in hepatocellular carcinoma cells

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Abstract

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Supplementary Information

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Most cited references 58

Autophagy and autophagy-related proteins in cancer

Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis

Recent insights into the function of autophagy in cancer

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