MicroRNAs and Benign Biliary Tract Diseases

Abstract

Cholangiocytes, the epithelial cells lining the biliary tree, represent only a small portion of the total liver cell population (3–5%), but they are responsible for the secretion of up to 40% of total daily bile volume. In addition, cholangiocytes are the target of a diverse group of liver diseases affecting the biliary tract, the cholangiopathies; for most of these conditions, the pathological mechanisms are unclear. MicroRNAs (miRNAs) are small, noncoding RNAs that posttranscriptionally regulate gene expression. Thus, it is not surprising that altered miRNA profiles underlie the dysregulation of several proteins involved in the pathobiology of the cholangiopathies, as well as showing promise as diagnostic and prognostic tools. Here the authors review recent work relevant to the role of miRNAs in the etiopathogenesis of several of the cholangiopathies (i.e., fibroinflammatory cholangiopathies and polycystic liver diseases), discuss their value as prognostic and diagnostic tools, and provide suggestions for further research.

Keywords

cholangiocytes - microRNAs - cholangiopathies - cholangiocarcinoma - polycystic liver disease - primary biliary cirrhosis - primary sclerosing cholangitis - biliary atresia

• References

• 1 Lazaridis KN, Strazzabosco M, Larusso NF. The cholangiopathies: disorders of biliary epithelia. Gastroenterology 2004; 127 (5) 1565-1577
• 2 Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136 (2) 215-233
• 3 Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov 2010; 9 (10) 775-789
• 4 Hand NJ, Master ZR, Le Lay J, Friedman JR. Hepatic function is preserved in the absence of mature microRNAs. Hepatology 2009; 49 (2) 618-626
• 5 Sekine S, Ogawa R, Ito R , et al. Disruption of Dicer1 induces dysregulated fetal gene expression and promotes hepatocarcinogenesis. Gastroenterology 2009; 136 (7) 2304-2315.e1 , 4
• 6 Sekine S, Ogawa R, Mcmanus MT, Kanai Y, Hebrok M. Dicer is required for proper liver zonation. J Pathol 2009; 219 (3) 365-372
• 7 Chandok N. Polycystic liver disease: a clinical review. Ann Hepatol 2012; 11 (6) 819-826
• 8 Gevers TJ, Drenth JP. Diagnosis and management of polycystic liver disease. Nat Rev Gastroenterol Hepatol 2013; 10 (2) 101-108
• 9 Masyuk T, Masyuk A, LaRusso N. Cholangiociliopathies: genetics, molecular mechanisms and potential therapies. Curr Opin Gastroenterol 2009; 25 (3) 265-271
• 10 Strazzabosco M, Somlo S. Polycystic liver diseases: congenital disorders of cholangiocyte signaling. Gastroenterology 2011; 140 (7) 1855-1859 , 1859.e1
• 11 Bhatt K, Mi QS, Dong Z. microRNAs in kidneys: biogenesis, regulation, and pathophysiological roles. Am J Physiol Renal Physiol 2011; 300 (3) F602-F610
• 12 Lee SO, Masyuk T, Splinter P , et al. MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease. J Clin Invest 2008; 118 (11) 3714-3724
• 13 Masyuk T, Masyuk A, LaRusso N. MicroRNAs in cholangiociliopathies. Cell Cycle 2009; 8 (9) 1324-1328
• 14 Pandey P, Brors B, Srivastava PK , et al. Microarray-based approach identifies microRNAs and their target functional patterns in polycystic kidney disease. BMC Genomics 2008; 9 (1) 624
• 15 Gresh L, Fischer E, Reimann A , et al. A transcriptional network in polycystic kidney disease. EMBO J 2004; 23 (7) 1657-1668
• 16 Wang E, Hsieh-Li HM, Chiou YY , et al. Progressive renal distortion by multiple cysts in transgenic mice expressing artificial microRNAs against Pkd1. J Pathol 2010; 222 (3) 238-248
• 17 Schena FP, Serino G, Sallustio F. MicroRNAs in kidney diseases: new promising biomarkers for diagnosis and monitoring. Nephrol Dial Transplant 2014; 29 (4) 755-763
• 18 Tan YC, Blumenfeld J, Rennert H. Autosomal dominant polycystic kidney disease: genetics, mutations and microRNAs. Biochim Biophys Acta 2011; 1812 (10) 1202-1212
• 19 Sokol RJ, Shepherd RW, Superina R, Bezerra JA, Robuck P, Hoofnagle JH. Screening and outcomes in biliary atresia: summary of a National Institutes of Health workshop. Hepatology 2007; 46 (2) 566-581
• 20 Padgett KA, Lan RY, Leung PC , et al. Primary biliary cirrhosis is associated with altered hepatic microRNA expression. J Autoimmun 2009; 32 (3–4) 246-253
• 21 Aron JH, Bowlus CL. The immunobiology of primary sclerosing cholangitis. Semin Immunopathol 2009; 31 (3) 383-397
• 22 Wiesner RH, Grambsch PM, Dickson ER , et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 1989; 10 (4) 430-436
• 23 Bergquist A, Ekbom A, Olsson R , et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002; 36 (3) 321-327
• 24 Boberg KM, Bergquist A, Mitchell S , et al. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol 2002; 37 (10) 1205-1211
• 25 Bezerra JA. Potential etiologies of biliary atresia. Pediatr Transplant 2005; 9 (5) 646-651
• 26 Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet 2009; 374 (9702) 1704-1713
• 27 Hand NJ, Horner AM, Master ZR , et al. MicroRNA profiling identifies miR-29 as a regulator of disease-associated pathways in experimental biliary atresia. J Pediatr Gastroenterol Nutr 2012; 54 (2) 186-192
• 28 Bessho K, Shanmukhappa K, Sheridan R , et al. Integrative genomics identifies candidate microRNAs for pathogenesis of experimental biliary atresia. BMC Syst Biol 2013; 7: 104
• 29 Roderburg C, Urban GW, Bettermann K , et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 2011; 53 (1) 209-218
• 30 Yamaura Y, Nakajima M, Takagi S, Fukami T, Tsuneyama K, Yokoi T. Plasma microRNA profiles in rat models of hepatocellular injury, cholestasis, and steatosis. PLoS ONE 2012; 7 (2) e30250
• 31 Glaser S, Meng F, Han Y , et al. Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and microRNA let7a in mice. Gastroenterology 2014; 146 (7) 1795-808.e12
• 32 Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014; 383 (9935) 2168-2179
• 33 Meng F, Henson R, Lang M , et al. Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 2006; 130 (7) 2113-2129
• 34 Kawahigashi Y, Mishima T, Mizuguchi Y , et al. MicroRNA profiling of human intrahepatic cholangiocarcinoma cell lines reveals biliary epithelial cell-specific microRNAs. J Nippon Med Sch 2009; 76 (4) 188-197
• 35 Chen L, Yan HX, Yang W , et al. The role of microRNA expression pattern in human intrahepatic cholangiocarcinoma. J Hepatol 2009; 50 (2) 358-369
• 36 Meng F, Henson R, Wehbe-Janek H, Smith H, Ueno Y, Patel T. The MicroRNA let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes. J Biol Chem 2007; 282 (11) 8256-8264
• 37 Selaru FM, Olaru AV, Kan T , et al. MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3. Hepatology 2009; 49 (5) 1595-1601
• 38 He Q, Cai L, Shuai L , et al. Ars2 is overexpressed in human cholangiocarcinomas and its depletion increases PTEN and PDCD4 by decreasing microRNA-21. Mol Carcinog 2013; 52 (4) 286-296
• 39 Lu L, Byrnes K, Han C, Wang Y, Wu T. miR-21 targets 15-PGDH and promotes cholangiocarcinoma growth. Mol Cancer Res 2014; 12 (6) 890-900
• 40 Chusorn P, Namwat N, Loilome W , et al. Overexpression of microRNA-21 regulating PDCD4 during tumorigenesis of liver fluke-associated cholangiocarcinoma contributes to tumor growth and metastasis. Tumour Biol 2013; 34 (3) 1579-1588
• 41 Razumilava N, Bronk SF, Smoot RL , et al. miR-25 targets TNF-related apoptosis inducing ligand (TRAIL) death receptor-4 and promotes apoptosis resistance in cholangiocarcinoma. Hepatology 2012; 55 (2) 465-475
• 42 Zhang J, Han C, Wu T. MicroRNA-26a promotes cholangiocarcinoma growth by activating β-catenin. Gastroenterology 2012; 143 (1) 246-56.e8
• 43 Mott JL, Kobayashi S, Bronk SF, Gores GJ. mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 2007; 26 (42) 6133-6140
• 44 Okamoto K, Miyoshi K, Murawaki Y. miR-29b, miR-205 and miR-221 enhance chemosensitivity to gemcitabine in HuH28 human cholangiocarcinoma cells. PLoS ONE 2013; 8 (10) e77623
• 45 Hu C, Huang F, Deng G, Nie W, Huang W, Zeng X. miR-31 promotes oncogenesis in intrahepatic cholangiocarcinoma cells via the direct suppression of RASA1. Exp Ther Med 2013; 6 (5) 1265-1270
• 46 Yang H, Li TW, Peng J , et al. A mouse model of cholestasis-associated cholangiocarcinoma and transcription factors involved in progression. Gastroenterology 2011; 141 (1) 378-388 , 388.e1–388.e4
• 47 Zeng B, Li Z, Chen R , et al. Epigenetic regulation of miR-124 by hepatitis C virus core protein promotes migration and invasion of intrahepatic cholangiocarcinoma cells by targeting SMYD3. FEBS Lett 2012; 586 (19) 3271-3278
• 48 Wang Q, Tang H, Yin S, Dong C. Downregulation of microRNA-138 enhances the proliferation, migration and invasion of cholangiocarcinoma cells through the upregulation of RhoC/p-ERK/MMP-2/MMP-9. Oncol Rep 2013; 29 (5) 2046-2052
• 49 Braconi C, Huang N, Patel T. MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes. Hepatology 2010; 51 (3) 881-890
• 50 Peng F, Jiang J, Yu Y , et al. Direct targeting of SUZ12/ROCK2 by miR-200b/c inhibits cholangiocarcinoma tumourigenesis and metastasis. Br J Cancer 2013; 109 (12) 3092-3104
• 51 Qiu YH, Wei YP, Shen NJ , et al. miR-204 inhibits epithelial to mesenchymal transition by targeting slug in intrahepatic cholangiocarcinoma cells. Cell Physiol Biochem 2013; 32 (5) 1331-1341
• 52 Li B, Han Q, Zhu Y, Yu Y, Wang J, Jiang X. Down-regulation of miR-214 contributes to intrahepatic cholangiocarcinoma metastasis by targeting Twist. FEBS J 2012; 279 (13) 2393-2398
• 53 Meng F, Wehbe-Janek H, Henson R, Smith H, Patel T. Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes. Oncogene 2008; 27 (3) 378-386
• 54 Chen Y, Luo J, Tian R, Sun H, Zou S. miR-373 negatively regulates methyl-CpG-binding domain protein 2 (MBD2) in hilar cholangiocarcinoma. Dig Dis Sci 2011; 56 (6) 1693-1701
• 55 Iwaki J, Kikuchi K, Mizuguchi Y , et al. MiR-376c down-regulation accelerates EGF-dependent migration by targeting GRB2 in the HuCCT1 human intrahepatic cholangiocarcinoma cell line. PLoS ONE 2013; 8 (7) e69496
• 56 Zhong XY, Yu JH, Zhang WG , et al. MicroRNA-421 functions as an oncogenic miRNA in biliary tract cancer through down-regulating farnesoid X receptor expression. Gene 2012; 493 (1) 44-51
• 57 Olaru AV, Ghiaur G, Yamanaka S , et al. MicroRNA down-regulated in human cholangiocarcinoma control cell cycle through multiple targets involved in the G1/S checkpoint. Hepatology 2011; 54 (6) 2089-2098
• 58 Banales JM, Sáez E, Uriz M , et al. Up-regulation of microRNA 506 leads to decreased Cl-/HCO3- anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis. Hepatology 2012; 56 (2) 687-697
• 59 Chen XM, Splinter PL, O'Hara SP, LaRusso NF. A cellular micro-RNA, let-7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection. J Biol Chem 2007; 282 (39) 28929-28938
• 60 Hu G, Zhou R, Liu J , et al. MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge. J Immunol 2009; 183 (3) 1617-1624
• 61 Hu G, Zhou R, Liu J, Gong AY, Chen XM. MicroRNA-98 and let-7 regulate expression of suppressor of cytokine signaling 4 in biliary epithelial cells in response to Cryptosporidium parvum infection. J Infect Dis 2010; 202 (1) 125-135
• 62 Munoz-Garrido P, García-Fernández de Barrena M, Hijona E , et al. MicroRNAs in biliary diseases. World J Gastroenterol 2012; 18 (43) 6189-6196
• 63 Haga H, Yan I, Takahashi K, Wood J, Patel T. Emerging insights into the role of microRNAs in the pathogenesis of cholangiocarcinoma. Gene Expr 2014; 16 (2) 93-99
• 64 Natarajan MA, Wehrkamp CJ, Mohr AM, Mott JL. MicroRNA function in human diseases. Med Epigenet 2013; 1: 106-115
• 65 Medina JF, , Martínez-Ansó, Vazquez JJ, Prieto J. Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology 1997; 25 (1) 12-17
• 66 Melero S, Spirlì C, Zsembery A , et al. Defective regulation of cholangiocyte Cl-/HCO3(-) and Na+/H+ exchanger activities in primary biliary cirrhosis. Hepatology 2002; 35 (6) 1513-1521
• 67 Banales JM, Arenas F, Rodríguez-Ortigosa CM , et al. Bicarbonate-rich choleresis induced by secretin in normal rat is taurocholate-dependent and involves AE2 anion exchanger. Hepatology 2006; 43 (2) 266-275
• 68 Banales JM, Prieto J, Medina JF. Cholangiocyte anion exchange and biliary bicarbonate excretion. World J Gastroenterol 2006; 12 (22) 3496-3511
• 69 Raynaud P, Carpentier R, Antoniou A, Lemaigre FP. Biliary differentiation and bile duct morphogenesis in development and disease. Int J Biochem Cell Biol 2011; 43 (2) 245-256
• 70 Wills ES, Roepman R, Drenth JP. Polycystic liver disease: ductal plate malformation and the primary cilium. Trends Mol Med 2014; 20 (5) 261-270
• 71 Temmerman F, Missiaen L, Bammens B , et al. Systematic review: the pathophysiology and management of polycystic liver disease. Aliment Pharmacol Ther 2011; 34 (7) 702-713
• 72 Gunay-Aygun M. Liver and kidney disease in ciliopathies. Am J Med Genet C Semin Med Genet 2009; 151C (4) 296-306
• 73 Desmet VJ. Ludwig symposium on biliary disorders—part I. Pathogenesis of ductal plate abnormalities. Mayo Clin Proc 1998; 73 (1) 80-89
• 74 Tzur G, Israel A, Levy A , et al. Comprehensive gene and microRNA expression profiling reveals a role for microRNAs in human liver development. PLoS ONE 2009; 4 (10) e7511
• 75 Hand NJ, Master ZR, Eauclaire SF, Weinblatt DE, Matthews RP, Friedman JR. The microRNA-30 family is required for vertebrate hepatobiliary development. Gastroenterology 2009; 136 (3) 1081-1090
• 76 Mott JL, Kurita S, Cazanave SC, Bronk SF, Werneburg NW, Fernandez-Zapico ME. Transcriptional suppression of mir-29b-1/mir-29a promoter by c-Myc, hedgehog, and NF-kappaB. J Cell Biochem 2010; 110 (5) 1155-1164
• 77 Chen XM, O'Hara SP, LaRusso NF. The immunobiology of cholangiocytes. Immunol Cell Biol 2008; 86 (6) 497-505
• 78 Harada K, Shimoda S, Sato Y, Isse K, Ikeda H, Nakanuma Y. Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis. Clin Exp Immunol 2009; 157 (2) 261-270
• 79 Jafri M, Donnelly B, Bondoc A, Allen S, Tiao G. Cholangiocyte secretion of chemokines in experimental biliary atresia. J Pediatr Surg 2009; 44 (3) 500-507
• 80 Karrar A, Broomé U, Södergren T , et al. Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis. Gastroenterology 2007; 132 (4) 1504-1514
• 81 Mimura Y, Sakisaka S, Harada M, Sata M, Tanikawa K. Role of hepatocytes in direct clearance of lipopolysaccharide in rats. Gastroenterology 1995; 109 (6) 1969-1976
• 82 Sasatomi K, Noguchi K, Sakisaka S, Sata M, Tanikawa K. Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 1998; 29 (3) 409-416
• 83 Harada K, Nakanuma Y. Cholangiopathy with respect to biliary innate immunity. Int J Hepatol 2012; 2012: 793569
• 84 Chen XM, O'Hara SP, Nelson JB , et al. Multiple TLRs are expressed in human cholangiocytes and mediate host epithelial defense responses to Cryptosporidium parvum via activation of NF-kappaB. J Immunol 2005; 175 (11) 7447-7456
• 85 Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 2006; 103 (33) 12481-12486
• 86 Zhou R, Hu G, Gong AY, Chen XM. Binding of NF-kappaB p65 subunit to the promoter elements is involved in LPS-induced transactivation of miRNA genes in human biliary epithelial cells. Nucleic Acids Res 2010; 38 (10) 3222-3232
• 87 O'Hara SP, Splinter PL, Gajdos GB , et al. NFkappaB p50-CCAAT/enhancer-binding protein beta (C/EBPbeta)-mediated transcriptional repression of microRNA let-7i following microbial infection. J Biol Chem 2010; 285 (1) 216-225
• 88 Huang Q, Liu L, Liu CH , et al. MicroRNA-21 regulates the invasion and metastasis in cholangiocarcinoma and may be a potential biomarker for cancer prognosis. Asian Pac J Cancer Prev 2013; 14 (2) 829-834
• 89 Karakatsanis A, Papaconstantinou I, Gazouli M, Lyberopoulou A, Polymeneas G, Voros D. Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance. Mol Carcinog 2013; 52 (4) 297-303
• 90 McNally ME, Collins A, Wojcik SE , et al. Concomitant dysregulation of microRNAs miR-151-3p and miR-126 correlates with improved survival in resected cholangiocarcinoma. HPB (Oxford) 2013; 15 (4) 260-264
• 91 Khan SA, Davidson BR, Goldin R , et al; British Society of Gastroenterology. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002; 51 (Suppl. 06) VI1-VI9
• 92 Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990-2009. World J Gastroenterol 2009; 15 (34) 4240-4262
• 93 Shigehara K, Yokomuro S, Ishibashi O , et al. Real-time PCR-based analysis of the human bile microRNAome identifies miR-9 as a potential diagnostic biomarker for biliary tract cancer. PLoS ONE 2011; 6 (8) e23584
• 94 Li L, Masica D, Ishida M , et al. Human bile contains microRNA-laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis. Hepatology 2014; 60 (3) 896-907 [Epub ahead of print]
• 95 Zahm AM, Hand NJ, Boateng LA, Friedman JR. Circulating microRNA is a biomarker of biliary atresia. J Pediatr Gastroenterol Nutr 2012; 55 (4) 366-369
• 96 Krützfeldt J, Kuwajima S, Braich R , et al. Specificity, duplex degradation and subcellular localization of antagomirs. Nucleic Acids Res 2007; 35 (9) 2885-2892
• 97 Krützfeldt J, Rajewsky N, Braich R , et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 2005; 438 (7068) 685-689
• 98 Zhang Y, Wang Z, Gemeinhart RA. Progress in microRNA delivery. J Control Release 2013; 172 (3) 962-974