Copyright
©The Author(s) 2021.
World J Gastrointest Pathophysiol. Sep 22, 2021; 12(5): 84-105
Published online Sep 22, 2021. doi: 10.4291/wjgp.v12.i5.84
Published online Sep 22, 2021. doi: 10.4291/wjgp.v12.i5.84
Table 1 Summary of anatomical, histomorphological, and molecular characteristics of cholangiocarcinoma subtypes
| Anatomical classification | Histomorphological classification | Molecular specification (gene alterations) | |
| iCCA | Small intrahepatic bile ducts iCCA | Mass forming tumors[17] | IDH1/2, FGFR2, EPHA2, BAP1[14,19] |
| Large intrahepatic bile ducts iCCA | Mass forming, periductal, or intraductal mucinous tumors[17,18] | EPHA2, BAP1, KRAS, TP53, GNAS, NRAS, MRAS, SMAD4[12,14,21] | |
| eCCA | Perihilar CCA | Intraductal mucinous tumors[12,17] | KRAS, TP53, GNAS, NRAS, MRAS, SMAD4, ARID1B, PRKACA, BRAF[14,19,24] |
| Distal CCA | Periductal mucinous tumors[12,17] | KRAS, TP53, GNAS, NRAS, MRAS, SMAD4, ARID1B, PRKACB, BRAF[14,19,24] | |
Table 2 Genetic mutations and polymorphisms associated with cholangiocarcinoma
| Gene (Full name) | Protein (Full name) | Normal function(s) | Ref. |
| ATP8B1 (ATPase Phospholipid Transporting 8B1) | FIC1 (Familial Intrahepatic Cholestasis type 1) | Transmembrane phospholipid transfer | Wadsworth et al[88], 2011 |
| ABCB11 (ATP Binding Cassette Subfamily B Member 11) | BSEP (Bile Salt Exporter Pump) | Transport of cholate conjugates from hepatocytes to bile | Wadsworth et al[88], 2011 |
| ABCC2 (ATP Binding Cassette Subfamily C Member 2) | MRP2 (Multidrug resistance-associated protein 2) | Transport of endogenous and xenobiotic compounds from hepatocytes to bile | Hoblinger et al[89], 2009 |
| ABCB4 (ATP Binding Cassette Subfamily B Member 4) | MDR3 (MHC class I polypeptide-related sequence A) | Transport of lipids from hepatocytes to bile | Khabou et al[90], 2019 |
| COX-2 (Cyclooxygenase 2) | COX-2 (Cyclooxygenase 2) | Inflammatory cytokine | Kim et al[91], 2002 |
| CYP1A2 (Cytochrome P450 1A2) | CYP1A2 (Cytochrome P450 1A2) | Xenobiotic metabolism | Prawan et al[92], 2005 |
| KLRK1 (Killer Cell Lectin Like Receptor K1) | NKG2D (NKG2-D type II integral membrane protein) | Tumor surveillance | Melum et al[93], 2008 |
| MTHFR (Methylenetetrahydrofolate Reductase) | MTHFR (5,10-Methylenetetrahydrofolate reductase) | DNA methylation | Ko et al[94], 2006 |
| NAT2 (N-Acetyltransferase 2) | ARY2(Arylamine N-acetyltransferase 2) | Drug and carcinogen metabolism | Prawan et al[92], 2005 |
| PTGS2 (Prostaglandin-endoperoxide synthase 2) | PTGS2 (Prostaglandin G/H synthase 2) | The key enzyme in prostaglandin biosynthesis, and acts both as a dioxygenase and as a peroxidase | Sakoda et al[95], 2006 |
| XRCC1 (X-ray repair cross complementing 1) | XRCC1 (DNA repair protein XRCC1) | Involved in DNA single-strand break repair by mediating the assembly of DNA break repair protein complexes | Huang et al[96], 2008 |
| GSTO1(Glutathione S-transferase omega-1) | GST01 (Glutathione S-transferase omega-1) | Detoxification of endogenous and xenobiotic compounds | Marahatta et al[97], 2006 |
| MICA (MICA PERB11.1) | MICA (MHC class I polypeptide-related sequence A) | Stress-induced self-antigen and Ligand for the KLRK1/NKG2D receptor | Melum et al[93], 2008 |
| NR1H4(Nuclear Receptor Subfamily 1 Group H Member 4) | BAR (FXR) (Bile acid receptor (Farnesoid X receptor) | Negative feedback inhibitor of bile acid synthesis | Wadsworth et al[88], 2011 |
| TYMS (Thymidylate Synthetase) | TYMS (Thymidylate synthase) | DNA repair | Razumilava et al[61], 2014 |
| XRCC1 (X-Ray Repair Complementing Defective Repair in Chinese Hamster Cells 1) | XRCC1 (DNA repair protein XRCC1) | DNA repair | Gong et al[98], 2015 |
| APC (Adenomatous polyposis coli) | APC (Adenomatous polyposis coli) | Tumor suppressor | Kang et al[99], 1999 |
| ARID1A (AT-Rich Interaction Domain 1A) | ARID1a (AT-rich interactive domain-containing protein 1A) | Transcription factor | Razumilava et al[61], 2014 |
| BAP1 (BRCA1 Associated Protein 1) | BAP1 (Ubiquitin carboxyl-terminal hydrolase BAP1) | Regulates cell growth | Yoshino et al[100], 2020 |
| BCL-2 (B cell Lymphoma-2) | Bcl-2 (B-cell lymphoma 2) | Regulates apoptosis | Fingas et al[101], 2010 |
| BRAF (B Rapidly Accelerated Fibrosarcoma) | B-Raf (B-Rapidly Accelerated Fibrosarcoma) | Proto-oncogene | Sia et al[24], 2013 |
| BRCA1 (Breast Cancer 1) | BRCA1 (Breast cancer type 1 susceptibility protein) | Tumor suppressor and DNA repair | Paradiso et al[102], 2020 |
| BRCA2 (Breast Cancer 2) | BRCA2 (Breast cancer type 2 susceptibility protein) | DNA repair | |
| CCND1(Cyclin D1) | CCND1 (G1/S-specific cyclin-D1) | Regulates cell growth | Yoshino et al[100], 2020 |
| CDH1(Cadherin 1) | E-cadherin (Epithelial cadherin) | Tumor suppressor, cell adhesion | Ross et al[103], 2014 |
| CDK6 (Cyclin-Dependent Kinase 6) | CDK6 (Cyclin-Dependent Kinase 6) | Controls cell cycle and differentiation | |
| CTNNB1 (Catenin Beta 1) | Β-catenin | Proto-oncogene | O'Dell et al[104], 2012 |
| EGFR (ERBB1) (Epidermal Growth Factor Receptor) | EGFR (ErbB-1) (Epidermal Growth Factor Receptor) | Proto-oncogene | |
| ERBB2 (HER2) (Avian Erythroblastosis oncogene B2) | ErbB-2 (HER2) (Receptor tyrosine-protein kinase erbB-2) | Proto-oncogene | |
| FBXW7 (F-Box and WD Repeat Domain Containing 7) | FBXW7 (F-box/WD repeat-containing protein 7) | Component of proteasomal protein degradation pathway | Ross et al[103], 2014 |
| FGF19 (Fibroblast Growth Factor 19) | FGF19 (Fibroblast Growth Factor 19) | Regulation of bile salt synthesis | |
| FGFR2 (Fibroblast Growth Factor Receptor 2) | FGFR2 (Fibroblast Growth Factor Receptor 2) | Cell surface receptor regulating cell proliferation, differentiation, migration and apoptosis | |
| IDH1 (Isocitrate dehydrogenase 1) | Isocitrate de-hydrogenase 1 (Isocitrate dehydrogenase (cytoplasmic)) | Glucose metabolism, indirectly mitigates oxidative stress | Nabeshima et al[105], 2020 |
| IDH2 (Isocitrate dehydrogenase 2) | Isocitrate de-hydrogenase 2 (Isocitrate dehydrogenase (mitochondrial)) | Glucose metabolism, indirectly mitigates oxidative stress | |
| Keap1 (Kelch-like ECH-associated protein 1) | KEAP1 (Kelch-like ECH-associated protein 1) | Prevents Nrf2-driven transcription | Ma et al[106], 2020 |
| KRAS (Kirsten Rat Sarcoma) | K-Ras (Kirsten Rat Sarcoma) | Proto-oncogene | Tannapfel et al[107], 2000 |
| MDM2 (Mouse Double Minute 2) | Mdm2 (E3 ubiquitin-protein ligase Mdm2) | Proto-oncogene, p53 inhibitor | Ross et al[103], 2014 |
| MYC (Avian myelocytomatosis virus oncogene cellular homolog) | Myc (Myc proto-oncogene protein) | Proto-oncogene | Zhou et al[108], 2019 |
| NF1 (Neurofibromin 1) | NF1 (Neurofibromin) | Stimulates Ras activity | Ross et al[103], 2014 |
| PBRM1 (Polybromo 1) | PBRM1 (Protein polybromo-1) | Negative regulator of cell proliferation | Luchini et al[109], 2017 |
| PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) | PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform) | Generates PIP3 that activates signalling cascades for cell growth, survival and motility | Xu et al[110], 2011 |
| PTEN (Phosphatase and Tensin Homolog) | PTEN (Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN) | Tumor suppressor | Zhu et al[111], 2014 |
| RAD51AP1 (RAD51 Associated Protein 1) | RAD51AP1 (RAD51 Associated Protein 1) | DNA damage repair | Liu et al[112], 2021 |
| RASSF1A (Ras association domain family 1 isoform A) | RASSF1A (Ras association domain-containing protein 1 isoform A) | Tumor suppressor | Chen et al[113], 2005 |
| SMAD4 (Small Mothers Against Decapentaplegic 4) | SMAD4 (Small Mothers Against Decapentaplegic 4) | Tumor suppressor, transcription factor | Yoshino et al[100], 2020 |
| SOCS3 (Suppressor of Cytokine Signaling 3) | SOCS3 (Suppressor of Cytokine Signaling 3) | Signal transduction inhibitor | Andersen et al[114], 2012 |
| TP53 (Tumor Protein 53) | p53 (Protein 53) | Tumor suppressor | O'Dell et al[104], 2012 |
Table 3 DNA methylation in the genomic sequences of specific genes that are associated with the pathogenesis of cholangiocarcinoma
| Gene (location) | Function | Epigenetic modification/effect | Outcome | Ref. |
| p16INK4A or CDKN2A (9p21) | Tumor suppressor gene Regulates cell proliferation and oncogenesis | Promoter region hypermethylation of the p16INK4A results in gene inactivation. Common event in PSC-associated CCA | More frequent in ECC cases. More commonly observed in tumors with vascular invasion. Poor clinical outcome | Ueki et al[115], 2004 |
| p14ARF(9p21) | Encoded by the β transcript of CDKN2A (p16/CDKN2A) | Methylation of p14ARF MF = 38 and 25% (32.35); 40.2% liver fluke CCA (37) | Increased tumorigenesis in CCA | Kim et al[116], 2007 |
| p15INK4b or p15 (9p21) | Effecter of TGF-β-mediated cell cycle arrest | Promoter hypermethylation of p15 gene | Increased tumorigenesis in CCA | Yang et al[117], 2005 |
| p73 gene (1p36.3) | Tumor suppressor gene and related to the p53 gene | Promoter region hypermethylation increased tumorigenesis | Increased tumorigenesis in CCA | |
| TMS1/ASC (16p11.2) | Tumor suppressor gene | Aberrant methylation of the TMS1/ASC cause inactivation of gene | Associated with CCA | Liu et al[118], 2006 |
| FHIT (3p14.2) | Tumor suppressor gene | Promoter hypermethylation of the FHIT gene results in epigenetic silencing of the FHIT promoter region | Development of intrahepatic CCAs | Foja et al[119], 2005 |
| RASSF1A (3p21.3) | Tumor suppressor gene induces cell cycle arrest by inhibiting the accumulation of cyclin D1 | Hypermethylation of its CpG island promoter region results in inactivation | Promoter methylation is more common in ECC than | Wong et al[120], 2002 |
| hMLH1 (3p21.3) | DNA mismatch repair gene | Promoter methylation/hypermethylation of the hMLH1 gene | Methylation frequencies vary in sporadic CCA, biliary papillary, neoplasms, and liver fluke-related CCA. Associated with poorly differentiated subtype of CCA with vascular invasion | Yang et al[117], 2005 |
| APC (5q21–q22) | Tumor suppressor gene Controls cell division, cell-cell interactions and cell migration and invasion, and conservation of chromosomal number during cell division | APC gene hypermethylation | Worse clinical outcome in CCA | Yang et al[117], 2005 |
| RAR-β (or HAP, RRB2 and NR1B2) (3p24) | Mediates cellular signaling in embryonic morphogenesis, cell growth and differentiation by regulating gene expression | Gene silencing by promoter region hypermethylation Results in increased tumorigenesis | Increased tumorigenesis in CCA | |
| Epithelial (E) cadherin gene (16q22.1) | Tumor suppressor gene | Hypermethylation of the promoter region of E gene Results in loss of function and contribute to progression of cancer by increasing proliferation, invasion and metastasis | Development of intrahepatic CCA | Lee et al[121], 2002 |
| DAPK (9q34.1) | Tumor suppressor gene Positive mediator of interferon-γ (IFN-γ)-induced programmed cell death | DAPK gene hypermethylation | Associated with poorly differentiated CCAs and with a poor prognosis | Tozawa et al[122], 2004 |
| CHFR gene (12q24.33) | Tumor suppressor gene Delays the entry into the metaphase | Gene silencing by promoter hypermethylation | Increased tumorigenesis in CCA | |
| RUNX3 gene (Ip36) | Tumor suppressor gene Regulate proliferation of the biliary tract epithelium | Methylation of RUNX3 results in gene silencing | Associated with poorer survival | |
| GSTP gene (1q43) | Regulate drug and xenobiotic. metabolism | Promoter region hypermethylation | Hypermethylation more frequent in ICCA than in ECC | Lee et al[121], 2002 |
| MGMT gene (10q26) | Responsible for repairing alkylation. DNA damage inhibits estrogen receptor-mediated cell proliferation | Methylation of discrete regions of the MGMT CpG island, results in heterochromatinization of the MGMT transcription start site and silencing of the gene | Increased frequency of GC to AT transitions in oncogenes and tumor suppressor genes and a poor prognosis | Koga et al[123], 2005 |
| BLU gene (3p21.3) | Tumor suppressor gene | Gene methylation | Increased tumorigenesis in CCA | Tischoff et al[124], 2005 |
| SEMA3B (3p21.3) | Tumor suppressor gene by inducing apoptosis. Plays a critical role in the guidance of growth cones during neuronal development | Methylation of SEMA3B gene | Increased tumorigenesis in CCA | |
| TIMP3 gene (22q12.3) | Plays a role in the induction of apoptosis | CpG island methylation of TIMP3 gene | Associated with worse survival | Lee et al[121], 2002 |
| RIZ1 | Tumor suppressor gene | Methylation of RIZ1 Results in chromatin compaction and gene silencing MF = 38% liver fluke CCA (47) | Increased proliferation and migration of CCA cell line | Khaenam et al[125], 2010 |
| OPCML | Tumor suppressor gene | Hypermethylation of OPCML | Increased tumorigenesis in CCA | Sriraksa et al[126], 2011 |
| GSTP1 | Tumor suppressor gene | Methylation of GSTP1 | Increased tumorigenesis in CCA | Yang et al[117], 2005 |
| COX-2/PTGS2 (1q25.2–q25.3) | Acts both as a dioxygenase and as a peroxidase | Methylation of COX-2 gene | Increased tumorigenesis in CCA | Lee et al[121], 2002 |
| THBS1 gene (15q15) | Mediates cell-to-cell and cell-to-matrix interactions and play roles in platelet aggregation, angiogenesis and tumorigenesis | Hypermethylation in the promoter region of THBS1 gene | Increased tumorigenesis in CCA | Tischoff et al[124], 2005 |
| SOCS3 | responsible for sustained IL-6/STAT-3 signaling and enhanced Mcl-1 expression in cholangiocarcinoma | Hypermethylation in the promoter region of SOCS3 gene | Increased tumorigenesis in CCA | Zhang et al[127], 2012 |
Table 4 Unique microRNAs that were identified to promote the pathogenesis of cholangiocarcinoma
| miRNAs | Target gene | Correlation with CCA tumorigenesis | Upregulated/downregulated | Ref. |
| miR-26a | GSK-3b | Tumor growth | Upregulated | Zhang et al[127], 2012 |
| miR-24 | MEN1(11q13) | Tumor suppressor gene | Upregulated | Ehrlich et al[128], 2017 |
| miR-29b | MCL-1 | Tumor suppressor gene | Downregulated | Stutes et al[129], 2007 |
| let-7a | NF2 | Tumor suppressor gene | Upregulated | |
| miR-148a | DNMT-1 | Regulate methyltransferase | Downregulated | Braconi et al[130], 2010 |
| miR-124 | SMYD3 | Migration and invasion of CCA cells | Downregulated | Zeng et al[131], 2012 |
| miR-21 | PTEN | Tumor suppressor gene | Upregulated | Meng et al[132], 2006 |
| miR-152 | DNMT-1 | Regulate methyltransferase | Downregulated | Braconi et al[130], 2010 |
| miR-200b | PTPN12 | Tumor suppressor gene | Upregulated | Meng et al[132], 2006 |
| miR-429 | CDH-6 | Tumor suppressor gene | Upregulated | Goeppert et al[133], 2016 |
| miR-122, miR-145, miR-200c, miR-221, and miR-222 | Multiple | Associated with tumorigenesis of ICCA | Downregulated | Karakatsanis et al[134], 2013 |
| miR-21, miR-31, and miR-223 | Multiple | No association with clinic-pathological parameters of CCA | Upregulated | |
| miR-370 | MAP3K8 | Tumor suppressor gene | Downregulated | Stutes et al[129], 2007 |
| miR-141 | CLOCK | Tumor suppressor gene | Upregulated | Meng et al[132], 2006 |
| miR-214 | Twist | Oncogene | Downregulated | Li et al[135], 2012 |
Table 5 Upregulated long non-coding RNAs that are reported in cholangiocarcinomas
| LncRNA | Possible mechanism | Clinical relevance | Ref. |
| AFAP1-AS1 | (1) Decreasing the expression of c-Myc, Cyclin D1, MMP-2 and MMP-9; and (2) Decreasing the AFAP1 expression and promoting cell stress filament integrity | Unfavorable prognostic biomarker; potential therapeutic target | Lu et al[136], 2017 |
| CCAT2 | - | Unfavorable prognostic biomarker; potential therapeutic target | Xu et al[137], 2018 |
| HULC | Activating CXCR4 by sponging to miR-372/miR-373 as ceRNA | Potential therapeutic target | Wang et al[138], 2016 |
| ASAP1-IT1 | Interacting with hedgehog signaling pathway | Unfavorable prognostic biomarker; potential therapeutic target | Guo et al[139], 2018 |
| CPS1IT1 | Coexpressed with host gene CPS1 | Unfavorable prognostic biomarker; potential therapeutic target | Lu et al[136], 2017 |
| EPIC1 | Directly interacting with Mys | - | Li et al[140], 2018 |
| H19 | Activating IL-6 by sponging to let-7a/let-7b as ceRNA | Unfavorable prognostic biomarker; potential therapeutic target | Xu et al[141], 2017 |
| CCAT1 | Sponging to miR-152 as ceRNA | Independent prognostic factor; potential therapeutic target | Jiang et al[142], 2017 |
| LINC01296 | Modulating MYCN transcription by sponge miR-5095 as ceRNA | Potential therapeutic target | Jiang et al[142], 2017 |
| PCAT1 | Enhancing Wnt/β-catenin signaling through miR-122 repression and WNT1 expression | Potential therapeutic target | Zhang et al[143], 2017 |
| SNHG1 | Modulating cancer-related gene like CDKN1A by co-operating with chromatin-modifying enzymes as EZH2 | Unfavorable prognostic biomarker; potential therapeutic target | Yu et al[144], 2018 |
| MALAT1 | (1) Activating PI3K/Akt pathway; and (2) miR-204-dependent CXCR4 regulation as ceRNA | Unfavorable prognostic biomarker; potential therapeutic target | Tan et al[145], 2017 |
| PVT1 | Binding to epigenetic modification complexes, adjusting the expression of ANGPTL4 | Potential therapeutic target | Yang et al[146], 2018 |
| UCA1 | (1) Facilitating apoptosis via Bcl-2/caspase-3 pathway; (2) Activating AKT/GSK-3β/CCND1 axis; and (3) Upregulating MMP-9 | Unfavorable prognostic biomarker; potential therapeutic target | Xu et al[147], 2017 |
| SPRY4-IT1 | Recruiting EZH2, LSD1 or DNMT1 via sponging to miR-101-3p | Unfavorable prognostic biomarker; potential therapeutic target | Xu et al[148], 2018 |
| T-UCRs | Downstream of Wnt pathway and sponging to miR-193b | Unfavorable prognostic biomarker; potential therapeutic target | Carotenuto et al[149], 2017 |
- Citation: Safarpour AR, Askari H, Ejtehadi F, Azarnezhad A, Raeis-Abdollahi E, Tajbakhsh A, Abazari MF, Tarkesh F, Shamsaeefar A, Niknam R, Sivandzadeh GR, Lankarani KB, Ejtehadi F. Cholangiocarcinoma and liver transplantation: What we know so far? World J Gastrointest Pathophysiol 2021; 12(5): 84-105
- URL: https://www.wjgnet.com/2150-5330/full/v12/i5/84.htm
- DOI: https://dx.doi.org/10.4291/wjgp.v12.i5.84