LRH-1 drives hepatocellular carcinoma partially through induction of c-myc and cyclin E1, and suppression of p21

Xiao, Li; Wang, Yuliang; Liang, Weicheng; Liu, Liping; Pan, Nannan; Deng, Huimin; Li, Luqian; Zou, Chang; Chan, F.H.Y.; Zhou, Yiwen

doi:10.2147/cmar.s162887

Cited by 24 publications

(23 citation statements)

References 37 publications

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“…For example, the role of LRH-1 in the regulation of lipid and glucose metabolism in the liver is subject to experimental targeting during metabolic syndrome and in type 1 and 2 diabetes [2][3][4][5][6]21,29 . Similarly, LRH-1 is overexpressed in many tumors of endodermal tissues, such as hepatocellular carcinoma, pancreatic tumors, and colorectal cancers, where it drives proliferation via the transcriptional control of cell cycle-regulating genes, such as cyclins D1 and E1 7,10,[30][31][32] . Thus, LRH-1 inhibitors may have great potential in the treatment of these tumors 33 .…”

Section: Discussionmentioning

confidence: 99%

Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis

et al. 2020

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Liver receptor homolog-1 (LRH-1, Nr5a2) is an orphan nuclear receptor mainly expressed in tissues of endodermal origin, where its physiological role has been extensively studied. LRH-1 has been implicated in liver cell differentiation and proliferation, as well as glucose, lipid, and bile acid metabolism. In addition, increasing evidence highlights its role in immunoregulatory processes via glucocorticoid synthesis in the intestinal epithelium. Although the direct function of LRH-1 in immune cells is fairly elucidated, a role of LRH-1 in the regulation of macrophage differentiation has been recently reported. In this study, we aimed to investigate the role of LRH-1 in the regulation of pro-inflammatory cytokine production in macrophages. Our data demonstrate that pharmacological inhibition, along with LRH-1 knockdown, significantly reduced the lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines in the macrophage line RAW 264.7 cells, as well as in primary murine macrophages. This inhibitory effect was found to be independent of defects of LRH-1-regulated cell proliferation or toxic effects of the LRH-1 inhibitors. In contrast, LRH-1 inhibition reduced the mitochondrial ATP production and metabolism of macrophages through downregulation of the LRH-1 targets glucokinase and glutminase-2, and thus impairing the LPS-induced macrophage activation. Interestingly, in vivo pharmacological inhibition of LRH-1 also resulted in reduced tumor necrosis factor (TNF) production and associated decreased liver damage in a macrophage-and TNF-dependent mouse model of hepatitis. Noteworthy, despite hepatocytes expressing high levels of LRH-1, pharmacological inhibition of LRH-1 per se did not cause any obvious liver damage. Therefore, this study proposes LRH-1 as an emerging therapeutic target in the treatment of inflammatory disorders, especially where macrophages and cytokines critically decide the extent of inflammation.

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Section: Discussionmentioning

confidence: 99%

Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis

et al. 2020

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“…68 Through an analogous strategy, the reversion of ALCL translocation was achieved in a patient cell line, restoring the integrity of the two involved chromosomes. Recent studies have also shown that TALEN gene editing technology used to knock out genes in cancer cells (including cells from prostate cancer, 76 breast cancer, 77 and hepatocellular carcinoma (HCC) 78 ) is a powerful and broadly applicable platform to explore gene mutations at the molecular level.…”

Section: Cancer Researchmentioning

confidence: 99%

Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects

Li¹,

Yang²,

Hong³

et al. 2020

Sig Transduct Target Ther

1,376

869

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Based on engineered or bacterial nucleases, the development of genome editing technologies has opened up the possibility of directly targeting and modifying genomic sequences in almost all eukaryotic cells. Genome editing has extended our ability to elucidate the contribution of genetics to disease by promoting the creation of more accurate cellular and animal models of pathological processes and has begun to show extraordinary potential in a variety of fields, ranging from basic research to applied biotechnology and biomedical research. Recent progress in developing programmable nucleases, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas-associated nucleases, has greatly expedited the progress of gene editing from concept to clinical practice. Here, we review recent advances of the three major genome editing technologies (ZFNs, TALENs, and CRISPR/Cas9) and discuss the applications of their derivative reagents as gene editing tools in various human diseases and potential future therapies, focusing on eukaryotic cells and animal models. Finally, we provide an overview of the clinical trials applying genome editing platforms for disease treatment and some of the challenges in the implementation of this technology.

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“…To examine the detailed mechanisms underlying M2 macrophages' role in regulating HCC cells invasion and migration, we tested the expression of proteins that have been connected with cancer cell invasion and migration [12][13][14][15][16][17][18] in both culture alone and in co-culture. The exploratory experiments led to the focus on MMP9 as the results showed that MMP9 protein expression was increased after co-culture, both in SK-HEP-1 and HA22T HCC cells ( Fig.…”

Section: Mechanism Dissection Of How M2 Macrophages Increase the Hcc mentioning

confidence: 99%

M2 Macrophages Promote HCC Cells Invasion and Migration via miR-149-5p/MMP9 Signaling

Liu¹,

Yin²,

Ouyang³

et al. 2020

J. Cancer

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The roles of M2 macrophages on promoting tumor progression and chemotherapy resistance have been well studied in many cancers, such as pancreatic cancer, kidney cancer and so on, but its linkage to HCC cells still remains unclear. Here we found that M2 macrophages could alter miR-149-5p to increase MMP9 expression in HCC cells and mechanism dissection revealed that miR-149-5p might directly target the 3'UTR of MMP9-mRNA to suppress its translation. The in vivo orthotopic xenografts mouse model with oemiR-149-5p also validated in vitro data. Together, these findings suggest that M2 macrophages may through altering the miR-149-5p to promote HCC progression and targeting the M2 macrophages/ miR149-5P/MMP9 signaling may help in the development of the novel therapies to better suppress the HCC progression.

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LRH-1 drives hepatocellular carcinoma partially through induction of c-myc and cyclin E1, and suppression of p21

Cited by 24 publications

References 37 publications

Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis

Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis

Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects

M2 Macrophages Promote HCC Cells Invasion and Migration via miR-149-5p/MMP9 Signaling

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