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CDH17 (cadherin 17, LI cadherin (liver-intestine))

Written2012-06Yiping Rong, Nikki P Lee, John M Luk
pRED China Oncology, Roche R&D Center (China) Ltd, Shanghai, China (YR, JML); Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong (NPL, JML)

(Note : for Links provided by Atlas : click)

Identity

Alias_namescadherin 17
Alias_symbol (synonym)HPT-1
cadherin
Other aliasCDH16
HPT1
HGNC (Hugo) CDH17
LocusID (NCBI) 1015
Atlas_Id 40020
Location 8q22.1  [Link to chromosome band 8q22]
Location_base_pair Starts at 94127166 and ends at 94217303 bp from pter ( according to hg19-Feb_2009)  [Mapping CDH17.png]
Fusion genes
(updated 2016)
CDH17 (8q22.1) / BICD1 (12p11.21)CDH17 (8q22.1) / CDH17 (8q22.1)CDH17 (8q22.1) / DIP2C (10p15.3)
FGGY (1p32.1) / CDH17 (8q22.1)REEP4 (8p21.3) / CDH17 (8q22.1)

DNA/RNA

 
  Figure 1. Cadherin 17 (CDH17) DNA with introns and exons.
Description Human CDH17 DNA contains 90138 bp composed of 18 exons (Gessner and Tauber, 2000; Wendeler et al., 2006).
Transcription Two transcripts (NM_001144663.1 and NM_004063.3) encode the same protein according to Entrez gene. 2499 bp open reading frame.

Protein

 
  Figure 2. A schematic diagram illustrates the structural feature of cadherin-17 (CDH17) in having seven cadherin repeats (EC1-EC7) at the extracellular amino-terminus (NH2), followed by a transmembrane region and a short cytoplasmic domain at the carboxyl-terminus (COOH). Calcium ions (denoted by red dots) are located between cadherin repeats in mammalian CDH17.
Description Cadherins are calcium-dependent cell-cell adhesion molecules which play important roles in organ development, the maintenance of tissue integrity and cancer development (Pokutta and Weis, 2007; Berx and van Roy, 2009). Cadherin 17 (CDH17) is a transmembrane glycoprotein with seven extracellular cadherin repeats. The cytoplasmic domain of human CDH17 only has 23 amino acids, whereas other classical cadherins contain 150 to 160 conserved amino acids forming complexes with catenins (Gessner and Tauber, 2000; Lee et al., 2010). CDH17 belongs to seven-domain (7D) cadherin subfamily which shares low sequence homology with the classical cadherins, such as E-cadherin. The structure difference of CDH17 makes this molecule unique among the known classical cadherin family members (Nollet et al., 2000; Angst et al., 2001). Recent work suggests its role in tumor progression and cancer prognosis (Liu et al., 2009).
Expression In rats, CDH17 is expressed in the liver and small intestine (Berndorff et al., 1994). In mouse and human, CDH17 is highly expressed in the small intestine and colon (Angres et al., 2001; Takamura et al., 2004), but absent or very low level in other organs, such as liver, heart and kidney etc. It is also linked predominantly to a high incidence of tumorigenesis in the human liver, stomach, intestine and pancreas by displaying an aberrant expression in their cancerous state (Lee et al., 2010).
Localisation CDH17 is mainly localized on basolateral cell membrane. Overexpressed CDH17 can also be detected throughout the cytoplasm of liver cancer, gastric cancer and colon cells (Wong et al., 2003; Grötzinger et al., 2001; Takamura et al., 2004).
Function CDH17 was originally cloned from rat liver and identified as a novel cell adhesion molecule (Berndorff et al., 1994). Homotypic trans-interaction of CDH17 is dependent on extracellular calcium concentration. It might serve as a calcium-regulated adhesion switch (Wendeler et al., 2007). CDH17 is also reported as an intestinal peptide transporter. It facilitates the oral absorption of beta-lactam antibiotics and angiotensin-converting enzyme inhibitors from the intestine into enterocytes lining the luminal wall (Dantzig et al., 1994). Knockout CDH17 by a mutant CDH17 deficient mouse showed that CDH17 may also participate in B lymphocyte development (Ohnishi et al., 2005). Recent studies suggested CDH17 important roles in tumorigenesis. Overexpression CDH17 can promote tumor growth, while suppression of CDH17 inhibits cancer cell growth, migration and adhesion (Liu et al., 2009).
Homology Human CDH17 shares ~20-30% sequence identity with other cadherin family members, such as cadherin-16 (30%), cadherin-13 (30%), and cadherin-1 (26%). It also shares ~79% identify with cyno-, mouse-, rat-cadherin-17.

Mutations

Note No mutation has been reported for CDH17 so far.
Somatic Alternative mRNA splicing isoform of CDH17 was reported in hepatocellular carcinoma patient samples. The isoform skips exon 7 which leads to open reading frame shift. The mRNA isoform is associated with shorter overall survival time. The functions or mechanisms of the isoform in cancer are unclear (Wang et al., 2005).

Implicated in

Note
  
Entity Hepatocellular carcinoma (HCC)
Prognosis CDH17 overexpression is detected in approximately ~80% of HCC patients (Liu et al., 2009). The elevated level of CDH17 in HCC is correlated to high serum AFP level, microvascular invasion, and advanced stage tumor, associating with shorter overall survival as well as higher incidence of tumor recurrence, of HCC patients. Over half of HCC patients have genomic amplification of CDH17 gene in their tumors. Alternative mRNA splicing of CDH17 was also reported in half of the HCC patient tumor specimens and associated with shorter overall survival time (Ding et al., 2009; Wong et al., 2003; Wang et al., 2006; Kaposi-Novak et al., 2006). The CDH17 overexpression can also be detected in other tumorigenic conditions including gastric cancer (GC). Therefore, CDH17 expression can be a potential biomarker for HCC and GC.
 
Figure 3. CDH17 expression in hepatocellular carcinoma (C) but not in adjacent non-tumor tissues (AT).
Oncogenesis Overexpression of CDH17 can transform premalignant liver progenitor cells to liver carcinomas in mice. RNAi-mediated knockdown of CDH17 inhibited proliferation of both primary and metastatic HCC cell lines in vitro and in vivo. The HCC cell migration, invasion, colony formation and adhesion were also inhibited by CDH17 knockdown. CDH17 shRNA resulted in relocalization of β-catenin to the cytoplasm with the reduction of cyclin D1, and increased caspase 3, Bax and Bcl-xL levels. Therefore, CDH17 is a potential oncogene in HCC by regulating cell cycle and apoptosis via Wnt pathway (Liu et al., 2009).
  
  
Entity Gastric cancer
Prognosis CDH17 expression level in normal human stomach epithelium cells is very low, whereas it is overexpressed in ~60-80% of gastric cancer cells (Grötzinger et al., 2001; Ko et al., 2004). CDH17 level is correlated with advanced stages of gastric cancer, and associated with a poor prognosis and lymph node metastasis. By serial analysis of gene expression (SAGE), CDH17 was found associating with an intestinal type of gastric cancer (Yasui et al., 2009). It was reported as a negative prognostic factor of pN0 gastric cancer and a new biomarker for early detection of gastric intestinal metaplasia (Wang et al., 2012; Grötzinger et al., 2001).
 
Figure 4. CDH17 expression in gastric cancer (C) but not in adjacent non-tumor tissues (AT).
Oncogenesis CDH17 knockdown by siRNA, shRNA or miRNA in gastric cancer cell lines can inhibit the cell proliferation, migration, invasion and adhesion in vitro, as well as tumor growth in xenograft models (Zhang et al., 2011; Liu et al., 2010). Overexpression of CDH17 in gastric cancer cell line MGC-803 cells promotes tumor growth in xenograft mouse model (unpublished data).
  
  
Entity Pancreatic cancer
Prognosis Unlike the normal liver and gastric tissues, CDH17 is found focally expressed in normal pancreatic ducts. In carcinoma, well-differentiated carcinoma cases expressed high level LI-cadherin, whereas less differentiated areas and poorly differentiated carcinoma cases expressed less or were negative. The high CDH17 expression correlated with good survival in pancreatic ductal adenocarcinoma (Takamura et al., 2003).
  
  
Entity Colorectal cancer
Prognosis In normal colorectal epithelial cells, CDH17 immunoreactivity was present at the basolateral plasma membrane. In colorectal carcinoma, the expression of CDH17 is diminished in tumor tissues. It can be observed in well-differentiated adenocarcinoma cells with tight cell-cell adhesion, but expression was reduced in dedifferentiated adenocarcinoma cells. Reduced expression of CDH17 in colorectal cancer tissues correlated with dedifferentiation of tumors and poor survival of patients (Takamura et al., 2004; Kwak et al., 2007; Su et al., 2008). The expression patterns of CDH17 in different cancer types suggest its cell-context dependent roles in organs.
  

Bibliography

LI-cadherin gene expression during mouse intestinal development.
Angres B, Kim L, Jung R, Gessner R, Tauber R.
Dev Dyn. 2001 Jun;221(2):182-93.
PMID 11376485
 
The cadherin superfamily: diversity in form and function.
Angst BD, Marcozzi C, Magee AI.
J Cell Sci. 2001 Feb;114(Pt 4):629-41. (REVIEW)
PMID 11171368
 
Liver-intestine cadherin: molecular cloning and characterization of a novel Ca(2+)-dependent cell adhesion molecule expressed in liver and intestine.
Berndorff D, Gessner R, Kreft B, Schnoy N, Lajous-Petter AM, Loch N, Reutter W, Hortsch M, Tauber R.
J Cell Biol. 1994 Jun;125(6):1353-69.
PMID 8207063
 
Involvement of members of the cadherin superfamily in cancer.
Berx G, van Roy F.
Cold Spring Harb Perspect Biol. 2009 Dec;1(6):a003129. Epub 2009 Sep 23. (REVIEW)
PMID 20457567
 
Association of intestinal peptide transport with a protein related to the cadherin superfamily.
Dantzig AH, Hoskins JA, Tabas LB, Bright S, Shepard RL, Jenkins IL, Duckworth DC, Sportsman JR, Mackensen D, Rosteck PR Jr, et al.
Science. 1994 Apr 15;264(5157):430-3.
PMID 8153632
 
Liver-intestine cadherin predicts microvascular invasion and poor prognosis of hepatitis B virus-positive hepatocellular carcinoma.
Ding ZB, Shi YH, Zhou J, Shi GM, Ke AW, Qiu SJ, Wang XY, Dai Z, Xu Y, Fan J.
Cancer. 2009 Oct 15;115(20):4753-65.
PMID 19626651
 
Intestinal cell adhesion molecules. Liver-intestine cadherin.
Gessner R, Tauber R.
Ann N Y Acad Sci. 2000;915:136-43. (REVIEW)
PMID 11193569
 
LI-cadherin: a marker of gastric metaplasia and neoplasia.
Grotzinger C, Kneifel J, Patschan D, Schnoy N, Anagnostopoulos I, Faiss S, Tauber R, Wiedenmann B, Gessner R.
Gut. 2001 Jul;49(1):73-81.
PMID 11413113
 
Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype.
Kaposi-Novak P, Lee JS, Gomez-Quiroz L, Coulouarn C, Factor VM, Thorgeirsson SS.
J Clin Invest. 2006 Jun;116(6):1582-95. Epub 2006 May 18.
PMID 16710476
 
Overexpression of LI-cadherin in gastric cancer is associated with lymph node metastasis.
Ko S, Chu KM, Luk JM, Wong BW, Yuen ST, Leung SY, Wong J.
Biochem Biophys Res Commun. 2004 Jun 25;319(2):562-8.
PMID 15178443
 
The prognostic significance of E-cadherin and liver intestine-cadherin expression in colorectal cancer.
Kwak JM, Min BW, Lee JH, Choi JS, Lee SI, Park SS, Kim J, Um JW, Kim SH, Moon HY.
Dis Colon Rectum. 2007 Nov;50(11):1873-80.
PMID 17828401
 
Role of cadherin-17 in oncogenesis and potential therapeutic implications in hepatocellular carcinoma.
Lee NP, Poon RT, Shek FH, Ng IO, Luk JM.
Biochim Biophys Acta. 2010 Dec;1806(2):138-45. Epub 2010 May 24. (REVIEW)
PMID 20580775
 
Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma.
Liu LX, Lee NP, Chan VW, Xue W, Zender L, Zhang C, Mao M, Dai H, Wang XL, Xu MZ, Lee TK, Ng IO, Chen Y, Kung HF, Lowe SW, Poon RT, Wang JH, Luk JM.
Hepatology. 2009 Nov;50(5):1453-63.
PMID 19676131
 
Lentiviral-mediated miRNA against liver-intestine cadherin suppresses tumor growth and invasiveness of human gastric cancer.
Liu QS, Zhang J, Liu M, Dong WG.
Cancer Sci. 2010 Aug;101(8):1807-12. Epub 2010 Apr 23.
PMID 20500517
 
Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members.
Nollet F, Kools P, van Roy F.
J Mol Biol. 2000 Jun 9;299(3):551-72. (REVIEW)
PMID 10835267
 
Lymphocyte-expressed BILL-cadherin/cadherin-17 contributes to the development of B cells at two stages.
Ohnishi K, Melchers F, Shimizu T.
Eur J Immunol. 2005 Mar;35(3):957-63.
PMID 15688343
 
Structure and mechanism of cadherins and catenins in cell-cell contacts.
Pokutta S, Weis WI.
Annu Rev Cell Dev Biol. 2007;23:237-61. (REVIEW)
PMID 17539752
 
Cadherin-17 is a useful diagnostic marker for adenocarcinomas of the digestive system.
Su MC, Yuan RH, Lin CY, Jeng YM.
Mod Pathol. 2008 Nov;21(11):1379-86. Epub 2008 Jun 13.
PMID 18552820
 
Reduced expression of liver-intestine cadherin is associated with progression and lymph node metastasis of human colorectal carcinoma.
Takamura M, Ichida T, Matsuda Y, Kobayashi M, Yamagiwa S, Genda T, Shioji K, Hashimoto S, Nomoto M, Hatakeyama K, Ajioka Y, Sakamoto M, Hirohashi S, Aoyagi Y.
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PMID 15279905
 
The predictive effect of cadherin-17 on lymph node micrometastasis in pN0 gastric cancer.
Wang J, Yu JC, Kang WM, Wang WZ, Liu YQ, Gu P.
Ann Surg Oncol. 2012 May;19(5):1529-34. Epub 2011 Oct 19.
PMID 22009269
 
Liver intestine-cadherin (CDH17) haplotype is associated with increased risk of hepatocellular carcinoma.
Wang XQ, Luk JM, Garcia-Barcelo M, Miao X, Leung PP, Ho DW, Cheung ST, Lam BY, Cheung CK, Wong AS, Lau SS, So MT, Yu WC, Cai Q, Liu KS, Hui CK, Lau GK, Poon RT, Wong J, Fan ST.
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PMID 16951245
 
Intestinal LI-cadherin acts as a Ca2+-dependent adhesion switch.
Wendeler MW, Drenckhahn D, Gessner R, Baumgartner W.
J Mol Biol. 2007 Jul 6;370(2):220-30. Epub 2007 May 1.
PMID 17512947
 
Identification of liver-intestine cadherin in hepatocellular carcinoma--a potential disease marker.
Wong BW, Luk JM, Ng IO, Hu MY, Liu KD, Fan ST.
Biochem Biophys Res Commun. 2003 Nov 21;311(3):618-24.
PMID 14623315
 
Transcriptome dissection of gastric cancer: identification of novel diagnostic and therapeutic targets from pathology specimens.
Yasui W, Oue N, Sentani K, Sakamoto N, Motoshita J.
Pathol Int. 2009 Mar;59(3):121-36. (REVIEW)
PMID 19261089
 
Blockade of proliferation and migration of gastric cancer via targeting CDH17 with an artificial microRNA.
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Citation

This paper should be referenced as such :
Rong, Y ; Lee, NP ; Luk, JM
CDH17 (cadherin 17, LI cadherin (liver-intestine))
Atlas Genet Cytogenet Oncol Haematol. 2012;16(12):884-888.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CDH17ID40020ch8q22.html


External links

Nomenclature
HGNC (Hugo)CDH17   1756
Cards
AtlasCDH17ID40020ch8q22
Entrez_Gene (NCBI)CDH17  1015  cadherin 17
AliasesCDH16; HPT-1; HPT1
GeneCards (Weizmann)CDH17
Ensembl hg19 (Hinxton)ENSG00000079112 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000079112 [Gene_View]  chr8:94127166-94217303 [Contig_View]  CDH17 [Vega]
ICGC DataPortalENSG00000079112
TCGA cBioPortalCDH17
AceView (NCBI)CDH17
Genatlas (Paris)CDH17
WikiGenes1015
SOURCE (Princeton)CDH17
Genetics Home Reference (NIH)CDH17
Genomic and cartography
GoldenPath hg38 (UCSC)CDH17  -     chr8:94127166-94217303 -  8q22.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CDH17  -     8q22.1   [Description]    (hg19-Feb_2009)
EnsemblCDH17 - 8q22.1 [CytoView hg19]  CDH17 - 8q22.1 [CytoView hg38]
Mapping of homologs : NCBICDH17 [Mapview hg19]  CDH17 [Mapview hg38]
OMIM603017   
Gene and transcription
Genbank (Entrez)AI566493 AK130441 AK300638 AK301001 AK312873
RefSeq transcript (Entrez)NM_001144663 NM_004063
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CDH17
Cluster EST : UnigeneHs.591853 [ NCBI ]
CGAP (NCI)Hs.591853
Alternative Splicing GalleryENSG00000079112
Gene ExpressionCDH17 [ NCBI-GEO ]   CDH17 [ EBI - ARRAY_EXPRESS ]   CDH17 [ SEEK ]   CDH17 [ MEM ]
Gene Expression Viewer (FireBrowse)CDH17 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1015
GTEX Portal (Tissue expression)CDH17
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ12864   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ12864  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ12864
Splice isoforms : SwissVarQ12864
PhosPhoSitePlusQ12864
Domaine pattern : Prosite (Expaxy)CADHERIN_1 (PS00232)    CADHERIN_2 (PS50268)   
Domains : Interpro (EBI)Cadherin    Cadherin-like    Cadherin_CS   
Domain families : Pfam (Sanger)Cadherin (PF00028)   
Domain families : Pfam (NCBI)pfam00028   
Domain families : Smart (EMBL)CA (SM00112)  
Conserved Domain (NCBI)CDH17
DMDM Disease mutations1015
Blocks (Seattle)CDH17
SuperfamilyQ12864
Human Protein AtlasENSG00000079112
Peptide AtlasQ12864
HPRD04312
IPIIPI00290089   IPI00909102   IPI00983182   IPI00982507   
Protein Interaction databases
DIP (DOE-UCLA)Q12864
IntAct (EBI)Q12864
FunCoupENSG00000079112
BioGRIDCDH17
STRING (EMBL)CDH17
ZODIACCDH17
Ontologies - Pathways
QuickGOQ12864
Ontology : AmiGOgerminal center B cell differentiation  marginal zone B cell differentiation  integrin binding  transporter activity  proton-dependent oligopeptide secondary active transmembrane transporter activity  calcium ion binding  nucleus  plasma membrane  transport  oligopeptide transport  cell adhesion  homophilic cell adhesion via plasma membrane adhesion molecules  integrin-mediated signaling pathway  cell surface  integral component of membrane  basolateral plasma membrane  calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules  cell junction  positive regulation of integrin activation by cell surface receptor linked signal transduction  adherens junction organization  oligopeptide transmembrane transport  spleen development  
Ontology : EGO-EBIgerminal center B cell differentiation  marginal zone B cell differentiation  integrin binding  transporter activity  proton-dependent oligopeptide secondary active transmembrane transporter activity  calcium ion binding  nucleus  plasma membrane  transport  oligopeptide transport  cell adhesion  homophilic cell adhesion via plasma membrane adhesion molecules  integrin-mediated signaling pathway  cell surface  integral component of membrane  basolateral plasma membrane  calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules  cell junction  positive regulation of integrin activation by cell surface receptor linked signal transduction  adherens junction organization  oligopeptide transmembrane transport  spleen development  
REACTOMEQ12864 [protein]
REACTOME PathwaysR-HSA-418990 [pathway]   
NDEx NetworkCDH17
Atlas of Cancer Signalling NetworkCDH17
Wikipedia pathwaysCDH17
Orthology - Evolution
OrthoDB1015
GeneTree (enSembl)ENSG00000079112
Phylogenetic Trees/Animal Genes : TreeFamCDH17
HOVERGENQ12864
HOGENOMQ12864
Homologs : HomoloGeneCDH17
Homology/Alignments : Family Browser (UCSC)CDH17
Gene fusions - Rearrangements
Fusion : MitelmanFGGY/CDH17 [1p32.1/8q22.1]  [t(1;8)(p32;q22)]  
Fusion: TCGAFGGY 1p32.1 CDH17 8q22.1 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCDH17 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CDH17
dbVarCDH17
ClinVarCDH17
1000_GenomesCDH17 
Exome Variant ServerCDH17
ExAC (Exome Aggregation Consortium)CDH17 (select the gene name)
Genetic variants : HAPMAP1015
Genomic Variants (DGV)CDH17 [DGVbeta]
DECIPHERCDH17 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCDH17 
Mutations
ICGC Data PortalCDH17 
TCGA Data PortalCDH17 
Broad Tumor PortalCDH17
OASIS PortalCDH17 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCDH17  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCDH17
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CDH17
DgiDB (Drug Gene Interaction Database)CDH17
DoCM (Curated mutations)CDH17 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CDH17 (select a term)
intoGenCDH17
NCG5 (London)CDH17
Cancer3DCDH17(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM603017   
Orphanet
MedgenCDH17
Genetic Testing Registry CDH17
NextProtQ12864 [Medical]
TSGene1015
GENETestsCDH17
Target ValidationCDH17
Huge Navigator CDH17 [HugePedia]
snp3D : Map Gene to Disease1015
BioCentury BCIQCDH17
ClinGenCDH17
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1015
Chemical/Pharm GKB GenePA26290
Clinical trialCDH17
Miscellaneous
canSAR (ICR)CDH17 (select the gene name)
Probes
Litterature
PubMed50 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCDH17
EVEXCDH17
GoPubMedCDH17
iHOPCDH17
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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