Research progress of farnesoid X receptor in regulation of hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LI Xinglong ^1,2 , LI Zhongsheng ^1,2 ,  LI Guodong ^1,2

1. Department of General Surgery, The Fourth Hospital of Harbin Medical University, Harbin 150001, P. R. China;
2. Bio-Bank of Department of General Surgery, The Fourth Hospital of Harbin Medical University, Harbin 150001, P. R. China;

Corresponding author：

LI Guodong, Email: jonathanlgd@163.com

Keywords：

farnesoid X receptor; hepatocellular carcinoma; tumor suppressor gene

DOI：

10.7507/1007-9424.201811003

Video：

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Objective To summarize research progress of farnesoid X receptor (FXR) in regulation of hepatocellular carcinoma (HCC) and explore its potential clinical application value.Method The relevant literatures at home and abroad on the mechanism of FXR regulating occurrence and development of HCC were reviewed.Results In the occurrence and development of HCC, the FXR expression could be down-regulated through the inflammation-related pathways and epigenetic silencing. The FXR mightbe play an important role in the regulatory mechanisms of down-regulation in the HCC, therapeutic targets, drug resistance, and so on.Conclusion FXR plays an important regulatory role in occurrence and development of HCC, which makes FXR might become a potential target in treatment of HCC.

Citation： LI Xinglong, LI Zhongsheng, LI Guodong. Research progress of farnesoid X receptor in regulation of hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(4): 493-497. doi: 10.7507/1007-9424.201811003 Copy

1.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin, 2017, 67(1): 7-30.
2.	Shalapour S, Lin XJ, Bastian IN, et al. Author correction: Inflammation-induced IgA⁺ cells dismantle anti-liver cancer immunity. Nature, 2018, 561(7721): E1.
3.	Singh V, Yeoh BS, Chassaing B, et al. Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell, 2018, 175(3): 679-694.
4.	Pathak P, Xie C, Nichols RG, et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology, 2018, 68(4): 1574-1588.
5.	Liu X, Guo GL, Kong B, et al. Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice. Hepatology, 2018, 68(1): 304-316.
6.	Boesjes M, Bloks VW, Hageman J, et al. Hepatic farnesoid X-receptor isoforms α2 and α4 differentially modulate bile salt and lipoprotein metabolism in mice. PLoS One, 2014, 9(12): e115028.
7.	Wolfe A, Thomas A, Edwards G, et al. Increased activation of the Wnt/β-catenin pathway in spontaneous hepatocellular carcinoma observed in farnesoid X receptor knockout mice. J Pharmacol Exp Ther, 2011, 338(1): 12-21.
8.	Li J, Zhang Y, Kuruba R, et al. Roles of microRNA-29a in the antifibrotic effect of farnesoid X receptor in hepatic stellate cells. Mol Pharmacol, 2011, 80(1): 191-200.
9.	de Aguiar Vallim TQ, Tarling EJ, Kim T, et al. MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma high-density lipoprotein after activation of the nuclear receptor farnesoid X receptor. Circ Res, 2013, 112(12): 1602-1612.
10.	Kumagai A, Fukushima J, Takikawa H, et al. Enhanced expression of farnesoid X receptor in human hepatocellular carcinoma. Hepatol Res, 2013, 43(9): 959-969.
11.	Liu N, Meng Z, Lou G, et al. Hepatocarcinogenesis in FXR^-/- mice mimics human HCC progression that operates through HNF1α regulation of FXR expression. Mol Endocrinol, 2012, 26(5): 775-785.
12.	Chen Y, Song X, Valanejad L, et al. Bile salt export pump is dysregulated with altered farnesoid X receptor isoform expression in patients with hepatocellular carcinoma. Hepatology, 2013, 57(4): 1530-1541.
13.	Zhang Y, Gong W, Dai S, et al. Downregulation of human farnesoid X receptor by miR-421 promotes proliferation and migration of hepatocellular carcinoma cells. Mol Cancer Res, 2012, 10(4): 516-522.
14.	Blokker BA, Maijo M, Echeandia M, et al. Fine-tuning of SIRT1 expression is essential to protect the liver from cholestatic liver disease. Hepatology, 2018 Sep 19. doi: 10.1002/hep.30275.
15.	Qiu J, Peng B, Tang Y, et al. CpG methylation signature predicts recurrence in early-stage hepatocellular carcinoma: results from a multicenter study. J Clin Oncol, 2017, 35(7): 734-742.
16.	Bailey AM, Zhan L, Maru D, et al. FXR silencing in human colon cancer by DNA methylation and KRAS signaling. Am J Physiol Gastrointest Liver Physiol, 2014, 306(1): G48-G58.
17.	Kim KH, Choi S, Zhou Y, et al. Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice. Hepatology, 2017, 66(2): 498-509.
18.	Li G, Kong B, Zhu Y, et al. Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice. Toxicol Appl Pharmacol, 2013, 272(2): 299-305.
19.	Telbisz Á, Homolya L. Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function. Expert Opin Ther Targets, 2016, 20(4): 501-514.
20.	Meng Z, Wang X, Gan Y, et al. Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice. J Hepatol, 2012, 57(5): 1004-1012.
21.	Guo F, Xu Z, Zhang Y, et al. FXR induces SOCS3 and suppresses hepatocellular carcinoma. Oncotarget, 2015, 6(33): 34606-34616.
22.	赵英安, 李福军. microRNA 在肝癌复发转移中的研究进展. 中国普外基础与临床杂志, 2018, 25(11): 1403-1407.
23.	He J, Zhao K, Zheng L, et al. Upregulation of microRNA-122 by farnesoid X receptor suppresses the growth of hepatocellular carcinoma cells. Mol Cancer, 2015, 14: 163.
24.	Yang F, Hu Y, Liu HX, et al. MiR-22-silenced cyclin A expression in colon and liver cancer cells is regulated by bile acid receptor. J Biol Chem, 2015, 290(10): 6507-6515.
25.	Yang F, Gong J, Wang G, et al. Waltonitone inhibits proliferation of hepatoma cells and tumorigenesis via FXR-miR-22-CCNA2 signaling pathway. Oncotarget, 2016, 7(46): 75165-75175.
26.	Lee J, Padhye A, Sharma A, et al. A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition. J Biol Chem, 2010, 285(17): 12604-12611.
27.	Lee CG, Kim YW, Kim EH, et al. Farnesoid X receptor protects hepatocytes from injury by repressing miR-199a-3p, which increases levels of LKB1. Gastroenterology, 2012, 142(5): 1206-1217.
28.	Liu X, Zhang X, Ji L, et al. Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma. Oncotarget, 2015, 6(6): 4226-4238.
29.	Jiang Y, Iakova P, Jin J, et al. Farnesoid X receptor inhibits gankyrin in mouse livers and prevents development of liver cancer. Hepatology, 2013, 57(3): 1098-1106.
30.	Deuschle U, Schüler J, Schulz A, et al. FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model. PLoS One, 2012, 7(10): e43044.
31.	Wang YD, Chen WD, Li C, et al. Farnesoid X receptor antagonizes JNK signaling pathway in liver carcinogenesis by activating SOD3. Mol Endocrinol, 2015, 29(2): 322-331.
32.	Zhang Q, Feng Y, Kennedy D. Multidrug-resistant cancer cells and cancer stem cells hijack cellular systems to circumvent systemic therapies, can natural products reverse this? Cell Mol Life Sci, 2017, 74(5): 777-801.
33.	邓大炜, 吴斌, 严舒, 等. 肝细胞肝癌 SMMC-7721 细胞中 FOXQ1 基因沉默对奥沙利铂的化疗增敏作用. 中国普外基础与临床杂志, 2018, 25(3): 289-295.
34.	Martinez-Becerra P, Vaquero J, Romero MR, et al. No correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors. Mol Pharm, 2012, 9(6): 1693-1704.
35.	Vaquero J, Briz O, Herraez E, et al. Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds. Biochim Biophys Acta, 2013, 1833(10): 2212-2219.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin, 2017, 67(1): 7-30.
2. Shalapour S, Lin XJ, Bastian IN, et al. Author correction: Inflammation-induced IgA⁺ cells dismantle anti-liver cancer immunity. Nature, 2018, 561(7721): E1.
3. Singh V, Yeoh BS, Chassaing B, et al. Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell, 2018, 175(3): 679-694.
4. Pathak P, Xie C, Nichols RG, et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology, 2018, 68(4): 1574-1588.
5. Liu X, Guo GL, Kong B, et al. Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice. Hepatology, 2018, 68(1): 304-316.
6. Boesjes M, Bloks VW, Hageman J, et al. Hepatic farnesoid X-receptor isoforms α2 and α4 differentially modulate bile salt and lipoprotein metabolism in mice. PLoS One, 2014, 9(12): e115028.
7. Wolfe A, Thomas A, Edwards G, et al. Increased activation of the Wnt/β-catenin pathway in spontaneous hepatocellular carcinoma observed in farnesoid X receptor knockout mice. J Pharmacol Exp Ther, 2011, 338(1): 12-21.
8. Li J, Zhang Y, Kuruba R, et al. Roles of microRNA-29a in the antifibrotic effect of farnesoid X receptor in hepatic stellate cells. Mol Pharmacol, 2011, 80(1): 191-200.
9. de Aguiar Vallim TQ, Tarling EJ, Kim T, et al. MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma high-density lipoprotein after activation of the nuclear receptor farnesoid X receptor. Circ Res, 2013, 112(12): 1602-1612.
10. Kumagai A, Fukushima J, Takikawa H, et al. Enhanced expression of farnesoid X receptor in human hepatocellular carcinoma. Hepatol Res, 2013, 43(9): 959-969.
11. Liu N, Meng Z, Lou G, et al. Hepatocarcinogenesis in FXR^-/- mice mimics human HCC progression that operates through HNF1α regulation of FXR expression. Mol Endocrinol, 2012, 26(5): 775-785.
12. Chen Y, Song X, Valanejad L, et al. Bile salt export pump is dysregulated with altered farnesoid X receptor isoform expression in patients with hepatocellular carcinoma. Hepatology, 2013, 57(4): 1530-1541.
13. Zhang Y, Gong W, Dai S, et al. Downregulation of human farnesoid X receptor by miR-421 promotes proliferation and migration of hepatocellular carcinoma cells. Mol Cancer Res, 2012, 10(4): 516-522.
14. Blokker BA, Maijo M, Echeandia M, et al. Fine-tuning of SIRT1 expression is essential to protect the liver from cholestatic liver disease. Hepatology, 2018 Sep 19. doi: 10.1002/hep.30275.
15. Qiu J, Peng B, Tang Y, et al. CpG methylation signature predicts recurrence in early-stage hepatocellular carcinoma: results from a multicenter study. J Clin Oncol, 2017, 35(7): 734-742.
16. Bailey AM, Zhan L, Maru D, et al. FXR silencing in human colon cancer by DNA methylation and KRAS signaling. Am J Physiol Gastrointest Liver Physiol, 2014, 306(1): G48-G58.
17. Kim KH, Choi S, Zhou Y, et al. Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice. Hepatology, 2017, 66(2): 498-509.
18. Li G, Kong B, Zhu Y, et al. Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice. Toxicol Appl Pharmacol, 2013, 272(2): 299-305.
19. Telbisz Á, Homolya L. Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function. Expert Opin Ther Targets, 2016, 20(4): 501-514.
20. Meng Z, Wang X, Gan Y, et al. Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice. J Hepatol, 2012, 57(5): 1004-1012.
21. Guo F, Xu Z, Zhang Y, et al. FXR induces SOCS3 and suppresses hepatocellular carcinoma. Oncotarget, 2015, 6(33): 34606-34616.
22. 赵英安, 李福军. microRNA 在肝癌复发转移中的研究进展. 中国普外基础与临床杂志, 2018, 25(11): 1403-1407.
23. He J, Zhao K, Zheng L, et al. Upregulation of microRNA-122 by farnesoid X receptor suppresses the growth of hepatocellular carcinoma cells. Mol Cancer, 2015, 14: 163.
24. Yang F, Hu Y, Liu HX, et al. MiR-22-silenced cyclin A expression in colon and liver cancer cells is regulated by bile acid receptor. J Biol Chem, 2015, 290(10): 6507-6515.
25. Yang F, Gong J, Wang G, et al. Waltonitone inhibits proliferation of hepatoma cells and tumorigenesis via FXR-miR-22-CCNA2 signaling pathway. Oncotarget, 2016, 7(46): 75165-75175.
26. Lee J, Padhye A, Sharma A, et al. A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition. J Biol Chem, 2010, 285(17): 12604-12611.
27. Lee CG, Kim YW, Kim EH, et al. Farnesoid X receptor protects hepatocytes from injury by repressing miR-199a-3p, which increases levels of LKB1. Gastroenterology, 2012, 142(5): 1206-1217.
28. Liu X, Zhang X, Ji L, et al. Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma. Oncotarget, 2015, 6(6): 4226-4238.
29. Jiang Y, Iakova P, Jin J, et al. Farnesoid X receptor inhibits gankyrin in mouse livers and prevents development of liver cancer. Hepatology, 2013, 57(3): 1098-1106.
30. Deuschle U, Schüler J, Schulz A, et al. FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model. PLoS One, 2012, 7(10): e43044.
31. Wang YD, Chen WD, Li C, et al. Farnesoid X receptor antagonizes JNK signaling pathway in liver carcinogenesis by activating SOD3. Mol Endocrinol, 2015, 29(2): 322-331.
32. Zhang Q, Feng Y, Kennedy D. Multidrug-resistant cancer cells and cancer stem cells hijack cellular systems to circumvent systemic therapies, can natural products reverse this? Cell Mol Life Sci, 2017, 74(5): 777-801.
33. 邓大炜, 吴斌, 严舒, 等. 肝细胞肝癌 SMMC-7721 细胞中 FOXQ1 基因沉默对奥沙利铂的化疗增敏作用. 中国普外基础与临床杂志, 2018, 25(3): 289-295.
34. Martinez-Becerra P, Vaquero J, Romero MR, et al. No correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors. Mol Pharm, 2012, 9(6): 1693-1704.
35. Vaquero J, Briz O, Herraez E, et al. Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds. Biochim Biophys Acta, 2013, 1833(10): 2212-2219.

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Research progress of farnesoid X receptor in regulation of hepatocellular carcinoma

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