Data from Farnesoid X Receptor Constructs an Immunosuppressive Microenvironment and Sensitizes FXR<sup>high</sup>PD-L1<sup>low</sup> NSCLC to Anti–PD-1 Immunotherapy
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<div>Abstract<p>The farnesoid X receptor (FXR) regulates inflammation and immune responses in a subset of immune-mediated diseases. We previously reported that FXR expression promotes tumor cell proliferation in non–small cell lung cancer (NSCLC). Here we study the relevance of FXR to the immune microenvironment of NSCLC. We found an inverse correlation between FXR and PD-L1 expression in a cohort of 408 NSCLC specimens; from this, we identified a subgroup of FXR<sup>high</sup>PD-L1<sup>low</sup> patients. We showed that FXR downregulates PD-L1 via transrepression and other mechanisms in NSCLC. Cocultured with FXR<sup>high</sup>PD-L1<sup>low</sup> NSCLC cell lines, effector function and proliferation of CD8<sup>+</sup> T cell <i>in vitro</i> are repressed. We also detected downregulation of PD-L1 in FXR-overexpressing Lewis lung carcinoma (LLC) mouse syngeneic models, indicating an FXR<sup>high</sup>PD-L1<sup>low</sup> subtype in which FXR suppresses tumor-infiltrating immune cells. Anti–PD-1 therapy was effective against FXR<sup>high</sup>PD-L1<sup>low</sup> mouse LLC tumors. Altogether, our findings demonstrate an immunosuppressive role for FXR in the FXR<sup>high</sup>PD-L1<sup>low</sup> NSCLC subtype and provide translational insights into therapeutic response in PD-L1<sup>low</sup> NSCLC patients treated with anti–PD-1. We recommend FXR<sup>high</sup>PD-L1<sup>low</sup> as a biomarker to predict responsiveness to anti–PD-1 immunotherapy.</p></div>Keywords:
Farnesoid X receptor
The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids (BAs). In response to ligand‐binding, FXR regulates many genes involved in BA, lipid, and lipoprotein metabolism. To identify new FXR target genes, microarray technology was used to profile total RNA extracted from HepG2 cells treated with the natural FXR agonist chenodeoxycholic acid (CDCA). Interestingly, a significant increase of transcript level of the very low density lipoprotein receptor (VLDLR) was observed. Our data, resulting from selective FXR activation, FXR RNA silencing and FXR‐deficient mice, clearly demonstrate that BAs up‐regulate VLDLR transcript levels via a FXR‐dependent mechanism in vitro in human and in vivo in mouse liver cells.
Farnesoid X receptor
Small heterodimer partner
Chenodeoxycholic acid
Liver X receptor
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Background: Long noncoding RNA SNHG10 has been reported to promote the development of liver cancer. While by analyzing The Cancer Genome Atlas (TCGA) dataset we observed the downregulation of SNHG10 in non-small cell lung cancer (NSCLC). This study aimed to investigate the roles of SNHG10 in NSCLC. Materials and Methods: This study included 60 pairs of NSCLC and nontumor tissue samples collected from 60 NSCLC patients (males and females, 39–66 years, 50.9 ± 5.5 years). Gene expression was detected by quantitative polymerase chain reaction and western blot. Overexpression experiments were used to analyze gene interactions. Effects of cell transfections on cell proliferation were analyzed by performing CCK-8 cell proliferation assays. Results: We confirmed the downregulation of SNHG10 in NSCLC. In addition, low expression level of SNHG10 predicted the poor survival of NSCLC patients. SNHG10 can directly interact with miR-543, while overexpression of miR-543 failed to downregulate SNHG10. However, SNHG10 overexpression led to upregulation of sirtuin 1 (SIRT1), a downstream target of miR-543. Cell proliferation assay showed that SNHG10 and SIRT1 overexpression led to the decreased proliferation rate of NSCLC cells. In contrast, miR-543 over-expression played an opposite role and reduced the effects of SNHG10 and SIRT1 overexpression. Conclusions: In conclusion, SNHG10 sponges miR-543 to upregulate tumor suppressive SIRT1 in NSCLC to suppress cell proliferation.
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The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids (BAs). In response to ligand-binding, FXR regulates many genes involved in BA, lipid, and lipoprotein metabolism. To identify new FXR target genes, microarray technology was used to profile total RNA extracted from HepG2 cells treated with the natural FXR agonist chenodeoxycholic acid (CDCA). Interestingly, a significant increase of transcript level of the very low density lipoprotein receptor (VLDLR) was observed. Our data, resulting from selective FXR activation, FXR RNA silencing and FXR-deficient mice, clearly demonstrate that BAs up-regulate VLDLR transcript levels via a FXR-dependent mechanism in vitro in human and in vivo in mouse liver cells.
Farnesoid X receptor
Small heterodimer partner
Chenodeoxycholic acid
Liver X receptor
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Objective: To investigate the modulating effect of β-glycyrrhetic acid(β-GA) on the activity of farnesoid X receptor(FXR).Methods: FXR was transiently transfected into HepG2 cells,and the effect of β-GA on FXR activity was determined.The effect of β-GA on HepG2 cell viability was detected by Celltiter-Glo.The effect of β-GA on FXR target genes was determined by real-time q-PCR.Results: β-GA specifically and does-dependently decreased the activity of FXR induced by CDCA,and selectively down-regulated the expressions of FXR target genes.Conclusion: β-GA can selectively modulate the activity of FXR.
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As a member of nuclear receptor superfamily, farnesoid X receptor (FXR) has been shown to regulate numerous metabolic pathways, which include playing an important role in bile acid metabolism, maintaining lipid and glucose homeostasis when FXR is activated. With the prevalence of the glucose and lipids disorder, FXR attracts increasing attention. It may be a potential target for the treatment of type 2 diabetes mellitus and lipid disorders.
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Carbohydrate Metabolism
Metabolic pathway
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microRNAs (miRNAs) dysregulation is widely involved in cancer progression and contributed to sustained cell proliferation by directly targeting multiple targets. Therefore, better understanding the underlying mechanism of miRNA in carcinogenesis may improve diagnostic and therapeutic strategies for malignancy. In our study, we found that mir-765 is upregulated in both hepatocellular carcinoma (HCC) cell lines and tissues, compared to human normal liver cell line and adjacent non-cancerous tissues, respectively. Overexpression of mir-765 increased HCC cells proliferation and tumorigenicity, whereas inhibition of mir-765 reverses this effect. Furthermore, we demonstrated that INPP4B as a direct target of mir-765 and ectopic expression of mir-765 repressed INPP4B expression, resulting in upregulation of p-AKT, Cyclin D1, and downregulation of p-FOXO3a, p21 expression in HCC. Strikingly, we found that silencing the expression of INPP4B is the essential biological function of miR-765 during HCC cell proliferation. Collectively, our findings reveal that miR-765 is a potential onco-miR that participates in carcinogenesis of human HCC by suppressing INPP4B expression, and might represent a potential therapeutic target for HCC patients.
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Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily. It is highly related to the formation of metabolic syndrome and the glucose homeostasis, and therefore represents an important drug target against metabolic diseases and diabetes. In recent years, great progress has been made in the agonists, antagonists, and crystal structures of FXR. The diverse FXR ligands and their structure-activity relationship are reviewed in this article. The advances in the crystal structures of FXR in complex with different ligands are also introduced.
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Journal Article Critical role of farnesoid X receptor for hepatocellular carcinoma cell proliferation Get access Tomofumi Fujino, Tomofumi Fujino * 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan *Tomofumi Fujino, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. Tel: +81 42 676 4513, Fax: +81 42 676 4508, email: tfujino@ps.toyaku.ac.jp Search for other works by this author on: Oxford Academic PubMed Google Scholar Airi Takeuchi, Airi Takeuchi 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Akiko Maruko-Ohtake, Akiko Maruko-Ohtake 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Yosuke Ohtake, Yosuke Ohtake 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Junichi Satoh, Junichi Satoh 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Tomonori Kobayashi, Tomonori Kobayashi 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Toshiaki Tanaka, Toshiaki Tanaka 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Haruka Ito, Haruka Ito 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Ryosuke Sakamaki, Ryosuke Sakamaki 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Ryo Kashimura, Ryo Kashimura 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar ... Show more Ken Ando, Ken Ando 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Tomoko Nishimaki-Mogami, Tomoko Nishimaki-Mogami 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Yasuhito Ohkubo, Yasuhito Ohkubo 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Naomi Kitamura, Naomi Kitamura 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Ryuichiro Sato, Ryuichiro Sato 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Kiyomi Kikugawa, Kiyomi Kikugawa 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Makio Hayakawa Makio Hayakawa 1School of Pharmacy, Tokyo University of Pharmacy and Life Science; 2Department of Radiopharmacy, Tohoku Pharmaceutical University; 3Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology; 4The National Institute of Health Sciences; and 5Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Biochemistry, Volume 152, Issue 6, December 2012, Pages 577–586, https://doi.org/10.1093/jb/mvs101 Published: 10 September 2012 Article history Received: 01 August 2012 Accepted: 20 August 2012 Published: 10 September 2012
Farnesoid X receptor
Hepatic carcinoma
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Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and plays an important role in maintaining bile acid, lipid and glucose homeostasis. Bile acids are endogenous ligands for FXR. However, bile acids may also activate pathways independent of FXR. The development of specific FXR agonists has provided important insights into the role of FXR in metabolism. Recent data have demonstrated that FXR is a therapeutic target for treatment of certain metabolic disorders. This review will focus on recent advances in the role of FXR in metabolic disease.
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Metabolic pathway
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Farnesoid X 受体(FXR， NR1H4 ) 是原子荷尔蒙受体总科的一个成员。当然而，他们变老时，以前，研究证明 FXR/ 老鼠自发地得了肝肿瘤的关联到人的 hepatocellular，癌(HCC ) 不清楚。这研究的目的是观察 FXR 表示是否也是在 HCC 的 downregulated 并且在 HCC 讨论减少的 FXR 表示的机制。FXR 和小 heterodimer 搭挡(SHP ) 的表示被即时 PCR 和 immunohistochemical 技术测量。FXR 和它的倡导者活动的表示上的支持 inflammatory cytokines 的效果在主要 hepatocytes 或 HepG2 和 Huh7 房间线被决定。我们的结果证明在人的 HCC 的 FXR 和它的目标基因 SHP 的那表情是强烈与正常的肝纸巾相比的 downregulated。另外，支持 inflammatory cytokines 对由禁止 FXR 倡导者活动的减少 FXR 表示有能力。在结论，这个工作表明 FXR，建议在人的 HCC 开发的 FXR 的一个潜在的角色表示是强烈，在人的 HCC 的 downregulated，它可以被引起由减少了 FXR 倡导者活动。
Farnesoid X receptor
Small heterodimer partner
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