肝细胞癌相关胆汁酸代谢失衡及调控机制的研究进展
DOI: 10.3969/j.issn.1001-5256.2021.03.038
利益冲突声明:所有作者均声明不存在利益冲突。
作者贡献声明:刘哲睿负责资料分析,撰写论文;贾晓东负责提出具体修改意见并进行修改;陆荫英负责拟定撰写思路,指导文章写作并最终定稿。
Research advances in hepatocellular carcinoma-related imbalance of bile acid metabolism and related regulatory mechanism
-
摘要: 胆汁酸代谢、肠道菌群及胆汁酸受体调控通路均参与了肝细胞癌(HCC)发生发展的全过程。HCC小鼠模型的肝脏组织、HCC患者的血浆和粪便中某些胆汁酸如甘氨胆酸、牛磺胆酸、牛磺鹅去氧胆酸等水平均显著升高;肠道产胆盐水解酶细菌及梭状芽胞杆菌丰度失衡导致的胆汁酸代谢及机体免疫微环境的改变等也会促进HCC发生;此外,胆汁酸受体如法尼醇X受体、G蛋白偶联受体1、孕烷X受体、本构雄烷受体及鞘氨醇-1-磷酸受体2等多种受体亦被证实可以通过多种途径参与调控HCC的发生发展。胆汁酸代谢的各个环节在HCC的进程中发挥着不同的作用,系统诠释它们之间的相互作用有助于加深对HCC发病机制的认识,开发早期诊断、预后预测及精准治疗的生物靶标。Abstract: Bile acid metabolism, gut microbiota, and bile acid receptors are involved in the development and progression of hepatocellular carcinoma (HCC). There are substantial increases in the levels of some bile acids, such as glycocholic acid, taurocholic acid, and taurochenodeoxycholic acid, in the liver tissue of HCC mice and the serum and feces of HCC patients. Bile acid metabolism due to the imbalance of the abundance of bacteria producing bile salt hydrolases and Clostridium in the intestine and the change in immune microenvironment may also promote the development of HCC. Moreover, some bile acid receptors, such as farnesoid X receptor, G protein-coupled bile acid receptor 1, pregnane X receptor, constitutive androstane receptor, and sphingosine-1-phosphate receptor 2, have been shown to participate in the development and progression of HCC through various pathways. Each link of bile acid metabolism plays a different role in the progression of HCC, and a systematic elaboration of the interaction between these links may help to deepen the understanding of the pathogenesis of HCC and develop the biological targets for early diagnosis, prognosis prediction, and precise treatment.
-
[1] YANG JD, HAINAUT P, GORES GJ, et al. A global view of hepatocellular carcinoma: Trends, risk, prevention and management[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(10): 589-604. DOI: 10.1038/s41575-019-0186-y [2] CRAIG AJ, von FELDEN J, GARCIA-LEZANA T, et al. Tumour evolution in hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(3): 139-152. DOI: 10.1038/s41575-019-0229-4 [3] YANG F, HUANG X, YI T, et al. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor[J]. Cancer Res, 2007, 67(3): 863-867. DOI: 10.1158/0008-5472.CAN-06-1078 [4] JIA W, XIE G, JIA W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(2): 111-128. DOI: 10.1038/nrgastro.2017.119 [5] DAPITO DH, MENCIN A, GWAK GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4[J]. Cancer Cell, 2012, 21(4): 504-516. DOI: 10.1016/j.ccr.2012.02.007 [6] GAO L, LV G, LI R, et al. Glycochenodeoxycholate promotes hepatocellular carcinoma invasion and migration by AMPK/mTOR dependent autophagy activation[J]. Cancer Lett, 2019, 454: 215-223. DOI: 10.1016/j.canlet.2019.04.009 [7] XIE G, WANG X, HUANG F, et al. Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis[J]. Int J Cancer, 2016, 139(8): 1764-1775. DOI: 10.1002/ijc.30219 [8] ALLEN K, JAESCHKE H, COPPLE BL. Bile acids induce inflammatory genes in hepatocytes: A novel mechanism of inflammation during obstructive cholestasis[J]. Am J Pathol, 2011, 178(1): 175-186. DOI: 10.1016/j.ajpath.2010.11.026 [9] FANG Y, HAN SI, MITCHELL C, et al. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes[J]. Hepatology, 2004, 40(4): 961-971. DOI: 10.1002/hep.1840400427 [10] BEUERS U, BILZER M, CHITTATTU A, et al. Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver[J]. Hepatology, 2001, 33(5): 1206-1216. DOI: 10.1053/jhep.2001.24034 [11] HAN J, QIN WX, LI ZL, et al. Tissue and serum metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma[J]. Clin Chim Acta, 2019, 488: 68-75. DOI: 10.1016/j.cca.2018.10.039 [12] LUO P, YIN P, HUA R, et al. A Large-scale, multicenter serum metabolite biomarker identification study for the early detection of hepatocellular carcinoma[J]. Hepatology, 2018, 67(2): 662-675. DOI: 10.1002/hep.29561 [13] XIAO JF, VARGHESE RS, ZHOU B, et al. LC-MS based serum metabolomics for identification of hepatocellular carcinoma biomarkers in Egyptian cohort[J]. J Proteome Res, 2012, 11(12): 5914-5923. DOI: 10.1021/pr300673x [14] CHEN T, XIE G, WANG X, et al. Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma[J]. Mol Cell Proteomics, 2011, 10(7): M110.004945. DOI: 10.1074/mcp.M110.004945 [15] FOLEY MH, O'FLAHERTY S, BARRANGOU R, et al. Bile salt hydrolases: Gatekeepers of bile acid metabolism and host-microbiome crosstalk in the gastrointestinal tract[J]. PLoS Pathog, 2019, 15(3): e1007581. DOI: 10.1371/journal.ppat.1007581 [16] SYDOR S, BEST J, MESSERSCHMIDT I, et al. Altered microbiota diversity and bile acid signaling in cirrhotic and noncirrhotic NASH-HCC[J]. Clin Transl Gastroenterol, 2020, 11(3): e00131. DOI: 10.14309/ctg.0000000000000131 [17] PONZIANI FR, BHOORI S, CASTELLI C, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease[J]. Hepatology, 2019, 69(1): 107-120. DOI: 10.1002/hep.30036 [18] PEREZ MJ, BRIZ O. Bile-acid-induced cell injury and protection[J]. World J Gastroenterol, 2009, 15(14): 1677-1689. DOI: 10.3748/wjg.15.1677 [19] RIDLON JM, KANG DJ, HYLEMON PB. Bile salt biotransformations by human intestinal bacteria[J]. J Lipid Res, 2006, 47(2): 241-259. DOI: 10.1194/jlr.R500013-JLR200 [20] YAMADA S, TAKASHINA Y, WATANABE M, et al. Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice[J]. Oncotarget, 2018, 9(11): 9925-9939. DOI: 10.18632/oncotarget.24066 [21] YOSHIMOTO S, LOO TM, ATARASHI K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome[J]. Nature, 2013, 499(7456): 97-101. DOI: 10.1038/nature12347 [22] MA C, HAN M, HEINRICH B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells[J]. Science, 2018, 360(6391): eaan5931. DOI: 10.1126/science.aan5931 [23] CHIANG J, FERRELL JM. Bile acids as metabolic regulators and nutrient sensors[J]. Annu Rev Nutr, 2019, 39: 175-200. DOI: 10.1146/annurev-nutr-082018-124344 [24] KUIPERS F, BLOKS VW, GROEN AK. Beyond intestinal soap—bile acids in metabolic control[J]. Nat Rev Endocrinol, 2014, 10(8): 488-498. DOI: 10.1038/nrendo.2014.60 [25] WANG X, FU X, van NESS C, et al. Bile acid receptors and liver cancer[J]. Curr Pathobiol Rep, 2013, 1(1): 29-35. DOI: 10.1007/s40139-012-0003-6 [26] SCHAAP FG, TRAUNER M, JANSEN PL. Bile acid receptors as targets for drug development[J]. Nat Rev Gastroenterol Hepatol, 2014, 11(1): 55-67. DOI: 10.1038/nrgastro.2013.151 [27] KIM I, AHN SH, INAGAKI T, et al. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine[J]. J Lipid Res, 2007, 48(12): 2664-2672. DOI: 10.1194/jlr.M700330-JLR200 [28] KIM I, MORIMURA K, SHAH Y, et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice[J]. Carcinogenesis, 2007, 28(5): 940-946. DOI: 10.1093/carcin/bgl249 [29] WANG YD, CHEN WD, WANG M, et al. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response[J]. Hepatology, 2008, 48(5): 1632-1643. DOI: 10.1002/hep.22519 [30] GUO F, XU Z, ZHANG Y, et al. FXR induces SOCS3 and suppresses hepatocellular carcinoma[J]. Oncotarget, 2015, 6(33): 34606-34616. DOI: 10.18632/oncotarget.5314 [31] PRASAD S, GUPTA SC, TYAGI AK. Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals[J]. Cancer Lett, 2017, 387: 95-105. DOI: 10.1016/j.canlet.2016.03.042 [32] NOMOTO M, MIYATA M, YIN S, et al. Bile acid-induced elevated oxidative stress in the absence of farnesoid X receptor[J]. Biol Pharm Bull, 2009, 32(2): 172-178. DOI: 10.1248/bpb.32.172 [33] MENG Z, WANG Y, WANG L, et al. FXR regulates liver repair after CCl4-induced toxic injury[J]. Mol Endocrinol, 2010, 24(5): 886-897. DOI: 10.1210/me.2009-0286 [34] DEUSCHLE U, SCHVLER 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[J]. PLoS One, 2012, 7(10): e43044. DOI: 10.1371/journal.pone.0043044 [35] MARUYAMA T, MIYAMOTO Y, NAKAMURA T, et al. Identification of membrane-type receptor for bile acids (M-BAR)[J]. Biochem Biophys Res Commun, 2002, 298(5): 714-719. DOI: 10.1016/S0006-291X(02)02550-0 [36] KEITEL V, HÄUSSINGER D. Perspective: TGR5 (Gpbar-1) in liver physiology and disease[J]. Clin Res Hepatol Gastroenterol, 2012, 36(5): 412-419. DOI: 10.1016/j.clinre.2012.03.008 [37] POLS TW, NOMURA M, HARACH T, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading[J]. Cell Metab, 2011, 14(6): 747-757. DOI: 10.1016/j.cmet.2011.11.006 [38] CHEN WD, YU D, FORMAN BM, et al. Deficiency of G-protein-coupled bile acid receptor Gpbar1 (TGR5) enhances chemically induced liver carcinogenesis[J]. Hepatology, 2013, 57(2): 656-666. DOI: 10.1002/hep.26019 [39] PÉAN N, DOIGNON I, GARCIN I, et al. The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice[J]. Hepatology, 2013, 58(4): 1451-1460. DOI: 10.1002/hep.26463 [40] SHIN DJ, WANG L. Bile acid-activated receptors: A review on FXR and other nuclear receptors[J]. Handb Exp Pharmacol, 2019, 256: 51-72. [41] DONG B, LEE JS, PARK YY, et al. Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis[J]. Nat Commun, 2015, 6: 5944. DOI: 10.1038/ncomms6944 [42] WEBSTER CR, ANWER MS. Hydrophobic bile acid apoptosis is regulated by sphingosine-1-phosphate receptor 2 in rat hepatocytes and human hepatocellular carcinoma cells[J]. Am J Physiol Gastrointest Liver Physiol, 2016, 310(10): g865-g873. DOI: 10.1152/ajpgi.00253.2015 [43] LIU R, ZHAO R, ZHOU X, et al. Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2[J]. Hepatology, 2014, 60(3): 908-918. DOI: 10.1002/hep.27085 [44] WU M, ZHAI S, GAO J, et al. Diagnosis of hepatocellular carcinoma using a novel anti-glycocholic acid monoclonal antibody-based method[J]. Oncol Lett, 2019, 17(3): 3103-3112.
本文二维码
计量
- 文章访问数: 667
- HTML全文浏览量: 145
- PDF下载量: 74
- 被引次数: 0