Farnesoid X Receptor Activation Impairs Liver Progenitor Cell–Mediated Liver Regeneration via the PTEN‐PI3K‐AKT‐mTOR Axis in Zebrafish

Jung, Kyounghwa; Kim, Minwook; So, Juhoon; Lee, Seung‐Hoon; Ko, Sungjin; Shin, Donghun

doi:10.1002/hep.31679

Cited by 57 publications

(38 citation statements)

References 51 publications

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“…NR0B2 gene expression had no significant correlation with PIK3CB and AKT genes (Figure 4D). These data are in agreement with a recent report showing a negative correlation between FXR/NR0B2 action and PI3K pathway in liver regeneration (38).…”

Section: Nr0b2 Expression Is Negatively Associated With Tumor-infiltrating Lymphocytes and Pi3k Genes In Liver Cancerssupporting

confidence: 94%

The Orphan Nuclear Receptor Gene NR0B2 Is a Favorite Prognosis Factor Modulated by Multiple Cellular Signal Pathways in Human Liver Cancers

Zhu

Chang

et al. 2021

Front. Oncol.

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BackgroundLiver cancer is a leading cause of cancer death worldwide, and novel prognostic factor is needed for early detection and therapeutic responsiveness monitoring. The orphan nuclear receptor NR0B2 was reported to suppress liver cancer development in a mouse model, and its expression levels were reduced in liver cancer tissues and cell lines due to hypermethylation within its promoter region. However, it is not clear if NR0B2 expression is associated with cancer survival or disease progression and how NR0B2 gene expression is regulated at the molecular level.MethodsMultiple cancer databases were utilized to explore NR0B2 gene expression profiles crossing a variety of human cancers, including liver cancers, on several publicly assessable bioinformatics platforms. NR0B2 gene expression with or without kinase inhibitor treatment was analyzed using the qPCR technique, and NR0B2 protein expression was assessed in western blot assays. Two human hepatocellular carcinoma cell lines HepG2 and Huh7, were used in these experiments. NR0B2 gene activation was evaluated using NR0B2 promoter-driven luciferase reporter assays.ResultsNR0B2 gene is predominantly expressed in liver tissue crossing human major organs or tissues, but it is significantly downregulated in liver cancers. NR0B2 expression is mostly downregulated in most common cancers but also upregulated in a few intestinal cancers. NR0B2 gene expression significantly correlated with patient overall survival status in multiple human malignancies, including lung, kidney, breast, urinary bladder, thyroid, colon, and head-neck cancers, as well as liposarcoma and B-cell lymphoma. In liver cancer patients, higher NR0B2 expression is associated with favorite relapse-free and progression-free survival, especially in Asian male patients with viral infection history. In addition, NR0B2 expression negatively correlated with immune infiltration and PIK3CA and PIK3CG gene expression in liver cancer tissues. In HepG2 and Huh7 cells, NR0B2 expression at the transcription level was drastically reduced after MAPK inhibition but was significantly enhanced after PI3K inhibition.ConclusionNR0B2 gene expression is altered mainly in most human malignancies and significantly reduced in liver cancers. NR0B2 is a prognosis factor for patient survival in liver cancers. MAPK and PI3K oppositely modulate NR0B2 expression, and NR0B2 gene upregulation might serve as a therapeutic responsiveness factor in anti-PI3K therapy for liver cancer.

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Section: Nr0b2 Expression Is Negatively Associated With Tumor-infiltrating Lymphocytes and Pi3k Genes In Liver Cancerssupporting

confidence: 94%

The Orphan Nuclear Receptor Gene NR0B2 Is a Favorite Prognosis Factor Modulated by Multiple Cellular Signal Pathways in Human Liver Cancers

Zhu

Chang

et al. 2021

Front. Oncol.

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“…Farnesoid X receptor (FXR), encoded by NR1H4 gene and expressing highly in the liver and intestine, belongs to the nuclear receptor family and takes part in regulating BA homeostasis, glucose and lipid metabolism, liver regeneration, cholestasis and hepatic fibrosis. 5–7 Chronic hepatic injury due to the excessive accumulation of BAs is considered a major culprit for the pathogenesis of HCC. 8 Previously, it was reported that mice would develop liver tumors spontaneously in the absence of FXR, 9 and whole-body loss of NR1H4 gene led to Myc and cyclin-dependent kinase 4 ( Cdk4 ) inductions and BA elevation, eventually resulting in age-dependent hepatic tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

miRNA-382-5p Suppresses the Expression of Farnesoid X Receptor to Promote Progression of Liver Cancer

Nie¹,

Liu²,

Wei³

et al. 2021

CMAR

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Background The dysregulation of microRNAs (miRNAs) and hepatotoxicity due to the aberrant accumulation of bile acids (BAs) are notorious causes that predispose an individual to the development of hepatocellular carcinoma (HCC). Farnesoid X receptor (FXR), encoded by NR1H4 gene, has been identified as a crucial BA receptor to maintain the homeostasis of BA pool and its expression is decreased in HCC. miR-382-5p plays an important role in the pathogenesis of many human malignancies and was reported to promote the proliferation and differentiation of normal liver cells and liver regeneration. However, there is still some controversy about its role in HCC microenvironment. This study aims to explore the expression pattern of miR-382-5p in HCC and its role in regulating FXR during the development of HCC. Methods Tissues collected from 30 HCC patients were subjected to extraction of total RNA and quantitative real-time PCR (qRT-PCR) for the analyses of miR-382-5p expression and NR1H4 mRNA levels, and their expressions were verified by analyzing the online HCC-related GSE datasets. The role of miR-382-5p in regulating cellular proliferation and expression of FXR in different HCC cell lines was analyzed by qRT-PCR, Western Blot, real-time cellular analysis (RTCA) and luciferase reporter assays. The role of miR-382-5p in regulating downstream genes of FXR in HCC cells was also analyzed. Results miR-382-5p was upregulated in HCC tissues and inversely associated with the downregulation of NR1H4 mRNA levels. The luciferase reporter assay proved that miR-382-5p directly targeted the 3ʹ-untranslated region (3ʹ-UTR) of human NR1H4 mRNA. Overexpression of miR-382-5p led to a malignant proliferation of HCC cells by suppressing the expression of FXR. In contrast, blocking the endogenous miR-382-5p was sufficient to suppress the cellular proliferation rate of HCC through increasing FXR expression. Additionally, miR-382-5p inhibited the expression of some target genes of FXR, including SHP, FGF19 and SLC51A , and this inhibitory effect was FXR-dependent. Conclusion Therefore, miR-382-5p promotes the progression of HCC in vitro by suppressing FXR and could serve as a valuable therapeutic target for HCC treatment.

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“…Furthermore, farnesoid X receptor (FXR) has been identified as inhibitors of the alternative liver regeneration by enhancing phosphatase and tensin homolog (PTEN) activity. It has been confirmed in zebrafish that FXR activation blocks LPC-to-hepatocyte differentiation, but not BEC-to-LPC dedifferentiation [ 33 ]. Importantly, it is supposed that these pathways might be manipulated to induce LPC differentiation for treatment of patients with ESLD.…”

Section: The Alternative Liver Regenerationmentioning

confidence: 99%

Liver Regeneration and Cell Transplantation for End-Stage Liver Disease

Cai

2021

Biomolecules

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Liver transplantation is the only curative option for end-stage liver disease; however, the limitations of liver transplantation require further research into other alternatives. Considering that liver regeneration is prevalent in liver injury settings, regenerative medicine is suggested as a promising therapeutic strategy for end-stage liver disease. Upon the source of regenerating hepatocytes, liver regeneration could be divided into two categories: hepatocyte-driven liver regeneration (typical regeneration) and liver progenitor cell-driven liver regeneration (alternative regeneration). Due to the massive loss of hepatocytes, the alternative regeneration plays a vital role in end-stage liver disease. Advances in knowledge of liver regeneration and tissue engineering have accelerated the progress of regenerative medicine strategies for end-stage liver disease. In this article, we generally reviewed the recent findings and current knowledge of liver regeneration, mainly regarding aspects of the histological basis of regeneration, histogenesis and mechanisms of hepatocytes’ regeneration. In addition, this review provides an update on the regenerative medicine strategies for end-stage liver disease. We conclude that regenerative medicine is a promising therapeutic strategy for end-stage liver disease. However, further studies are still required.

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Farnesoid X Receptor Activation Impairs Liver Progenitor Cell–Mediated Liver Regeneration via the PTEN‐PI3K‐AKT‐mTOR Axis in Zebrafish

Cited by 57 publications

References 51 publications

The Orphan Nuclear Receptor Gene NR0B2 Is a Favorite Prognosis Factor Modulated by Multiple Cellular Signal Pathways in Human Liver Cancers

The Orphan Nuclear Receptor Gene NR0B2 Is a Favorite Prognosis Factor Modulated by Multiple Cellular Signal Pathways in Human Liver Cancers

miRNA-382-5p Suppresses the Expression of Farnesoid X Receptor to Promote Progression of Liver Cancer

Liver Regeneration and Cell Transplantation for End-Stage Liver Disease

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