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CEACAM19 (carcinoembryonic antigen related cell adhesion molecule 19)

Written2019-06Dimitra Tsouraki; Christos K. Kontos
Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece / chkontos@biol.uoa.gr

Abstract CEACAM19 is a member of the CEACAM subfamily of genes, described for the first time by Scorilas et al. (2003). Very few studies have been conducted so far concerning the CEACAM19 gene. Consequently, very little is known about it, and its function in either physiological or pathological cellular processes remains poorly elucidated. Here, we present a review on the DNA, mRNA and protein level of the gene and on its implication in various types of human malignancies.

Keywords Carcinoembryonic antigen; Immunoglobulin superfamily; ovarian cancer; breast cancer; gastric cancer; penile cancer; lung adenocarcinoma.

(Note : for Links provided by Atlas : click)

Identity

Alias_namescarcinoembryonic antigen-related cell adhesion molecule 19
Alias_symbol (synonym)CEAL1
Other aliasCEACM19
HGNC (Hugo) CEACAM19
LocusID (NCBI) 56971
Atlas_Id 53540
Location 19q13.31  [Link to chromosome band 19q13]
Location_base_pair Starts at 44671452 and ends at 44684355 bp from pter ( according to hg19-Feb_2009)  [Mapping CEACAM19.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Description The CEACAM19 gene belongs to the CEACAM subfamily of the CEA gene family, which in turn belongs to the Immunoglobulin Superfamily (IgS) (Scorilas et al., 2003). It has a total length of 12,904 nucleotides and consists of 8 exons and 7 intervening introns (Scorilas et al., 2003). It is located downstream of the PVR gene (poliovirus receptor cell adhesion molecule) and upstream of the CEACAM16 gene at the chromosomal location 19q13.31.
Transcription CEACAM19 pre-mRNA is subjected to alternative splicing. According to UniProt, three main splice variants of the gene have been described. The first one, which is referred to as the "canonical" one, consists of 903 nt and encodes for a 300-amino-acid (aa) polypeptide chain (Scorilas et al., 2003). The second splice variant contains one more exon (exon 3) of 134 bp and encodes for a polypeptide chain of 142 aa residues (Scorilas et al., 2003). The third splice variant consists of 900 nt and encodes for a polypeptide chain of 299 aa residues. However, according to the Human Protein Atlas, another five splice variants have also been described.
Pseudogene Not identified so far.

Protein

Description The canonical polypeptide isoform that is encoded by the CEACAM19 gene (isoform 1) consists of 300 aa residues and has a putative molecular weight of 32.6 kDa. (Scorilas et al., 2003). This polypeptide corresponds to a protein with an N-terminal extracellular domain consisting of the aa residues 33-157 and one Ig-like helical transmembrane domain, similar to other members of the same gene family (CEA family), composed of the aa residues 158-178 (Scorilas et al., 2003). The protein carries a hydrophobic N-terminal sequence, which is thought to act as a signal peptide and which is comprised on its whole of the aa residues 1-32 (Scorilas et al., 2003). The signal peptide of the protein is removed. aa residues 179-300 represent the cytoplasmic part of this protein (Figure 1). The CEACAM19 protein bears no constant C2-like domains like the ones seen in other members of the same family (Beauchemin et al., 2013). The protein bears a 9-aa sequence (SAMGQRDIV - from position 92 to 100) that is present in the eIF5A domain of a variety of transcription factors in eukaryotes (Scorilas et al., 2003). Moreover, the CEACAM19 polypeptide is a heavily glycosylated glycoprotein, which carries an ITAM motif (Immunoreceptor Tyrosine-based Activation Motif) in its cytoplasmic tail (as most of the members of the same subfamily) (Beauchemin et al., 2013). Moreover, several putative sites for post-translational modifications, such as O-/N-glycosylation, phosphorylation, N-myristoylation, have been described (Scorilas et al., 2003).
The alternative splicing of CEACAM19 pre-mRNA leads to the production of two other protein isoforms. As described previously, the second splice variant encodes for a polypeptide of 142 aa residues, shorter than the one described as the canonical form of the protein. Besides the fact that the aa residues from position 143 to 300 are missing, this isoform also differs from the canonical one in that the glutamic acid residue in position 142 is replaced by an aspartic acid residue. The third protein isoform is derived from a splice variant of 900 nt and consists of 299 aa residues. In this case, the glutamine residue in position 282 of the canonical form is missing.
As described above, the Human Protein Atlas mentions the existence of another five splice variants of the CEACAM19 gene, which encode for secreted polypeptides and not transmembrane ones (contrary to the three main isoforms described earlier). Four of these polypeptides consist of 56 aa residues and share a common molecular weight of 6.1 kDa each, while one of them consists of 54 amino acids and has a molecular weight of 6 kDa. All these polypeptide chains bear a signal peptide consisting of the amino acids 1-33.
Expression The CEACAM19 gene is widely expressed in a variety of tissues. Based on RNA-seq experiments (Fagerberg et al., 2014), higher expression levels are mainly seen in skin and testis. However, moderate to high expression levels have also been described in the prostate, adrenal gland, endometrium, lung, and ovary.
Localisation The three main CEACAM19 protein isoforms that bear a transmembrane domain are characterized as single-pass type-I membrane proteins. These are proteins that traverse the membrane only once with their N-terminal domain on the extracellular side of it and their signal peptide being removed. However, according to the Human Protein Atlas, the rest of the protein isoforms, which lack transmembrane domains, are predicted to be secreted.
Function The functions of the CEACAM19 protein (either physiological or pathological) have not been elucidated, yet.

Implicated in

  
Entity Ovarian cancer
Prognosis CEACAM19 mRNA expression is higher in ovarian cancer tissues, particularly in patients with late stage (stage III) of the disease and patients having been subjected to suboptimal cytoreduction. The sizes of the residual tumors were found to present a statistically significant difference between CEACAM19 mRNA-positive and -negative tumors, with the positive ones exhibiting larger dimensions. No statically significant association has been observed between the expression status of CEACAM19 and patients' age (Scorilas et al., 2003).
  
  
Entity Breast cancer
Prognosis CEACAM19 has been shown to be overexpressed in malignant breast tissue sections, compared to normal counterparts derived from the same patients (Michaelidou et al., 2013), and in breast tumor samples compared to samples derived from normal individuals (Estiar et al., 2016). Furthermore, higher mRNA levels of CEACAM19 have been associated with increased risk of breast cancer in women. The association between CEACAM19 mRNA expression and various clinicopathological parameters linked to aggressive tumor behavior and poor prognosis has also been examined in the aforementioned study. In particular, elevated expression levels have been observed in higher grade (grade III) tumors and those with a high proliferation index. Moreover, it has been shown that the expression of CEACAM19 is elevated in estrogen receptor (ER)-negative tumors and those of premenopausal patients; both these features are associated with poor prognosis (Michaelidou et al., 2013). On the other hand, another study by Estiar et al. (2016) did not support the positive association between CEACAM19 expression and tumor grade, observed by Michaelidou et al. (2013), as described above. In the study of Estiar et al., no significant association was shown between CEACAM19 mRNA expression status and tumor grade. Moreover, the study of Estiar et al. revealed a statistically significant difference in the expression of CEACAM19 between ER/PR-positive and -negative breast cancer patients, with higher mRNA levels in the latter (Estiar et al., 2016).
  
  
Entity Gastric cancer
Prognosis It has been shown that CEACAM19 protein levels are significantly elevated in gastric cancer tissues and cancerous cell lines, compared to normal ones. Similarly, the same study showed that the expression of matrix metallopeptidases 2 and 9 ( MMP2 and MMP9) was also upregulated in gastric cancer cell lines and that knockdown of CEACAM19 via siRNA in the same cells led to the inhibition of their expression. Knockdown of CEACAM19 was also shown to lead to a decrease in proliferation, invasion, and migration of gastric cancer cells. Furthermore, it has been suggested that knockdown of CEACAM19 leads to the inactivation of PI3K/Akt and NF-kB signaling pathways and to the inhibition of tumor growth in vivo, as measured by xenograft experiments in mice (Zhao et al., 2018).
  
  
Entity Penile cancer
Prognosis Differential expression levels of CEACAM19 have been shown in penile cancer cases, with some cancerous tissues exhibiting low and others exhibiting higher expression levels, compared to normal ones. Overexpression of CEACAM19 has been associated with distant and lymph node metastasis in penile cancer and with unfavorable cancer-specific survival of patients, but its prognostic significance is not independent from other predictors of survival. Moreover, it has been shown that knockdown of CEACAM19 in penile cancer cell lines leads to decreased cell growth and that it suppresses colony formation. CEACAM19 knockdown has also been related to the decrease of SMAD2/3 signaling pathway activity and inhibition of MMP2 and MMP9 secretion, which are both associated with invasion and metastasis. Consequently, it has been observed that migration and invasion abilities of the Pen11 cancerous cells were suppressed after CEACAM19 knockdown (Hu et al., 2019).
  
  
Entity Lung adenocarcinoma
Prognosis Kobayashi et al. (2012) examined whether some members of the CEACAM gene family could be used as surrogate markers for tyrosine kinase inhibitor (TKI) sensitivity in lung adenocarcinoma patients. The examined members of the family included CEACAM3, CEACAM5, CEACAM6, CEACAM7, and CEACAM19. The expression patterns of all these genes were found to be associated with TKI sensitivity, in microarray analysis. Moreover, the immunoreactivity of the CEACAMs examined was shown to be significantly higher in patients carrying EGFR mutations than in those carrying the wild-type gene. CEACAM19 immunoreactivity was not found to present statistically significant association with clinicopathological parameters of lung adenocarcinoma patients, such as age, sex, tumor size, stage of the disease, and lymph node metastasis.
  

Bibliography

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis
Beauchemin N, Arabzadeh A
Cancer Metastasis Rev 2013 Dec;32(3-4):643-71
PMID 23903773
 
High expression of CEACAM19, a new member of carcinoembryonic antigen gene family, in patients with breast cancer
Estiar MA, Esmaeili R, Zare AA, Farahmand L, Fazilaty H, Zekri A, Jafarbeik-Iravani N, Majidzadeh-A K
Clin Exp Med 2017 Nov;17(4):547-553
PMID 27909883
 
Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics
Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlén M
Mol Cell Proteomics 2014 Feb;13(2):397-406
PMID 24309898
 
Aberrant CEACAM19 expression is associated with metastatic phenotype in penile cancer
Hu X, Chen M, Li Y, Wang Y, Wen S, Jun F
Cancer Manag Res 2019 Jan 14;11:715-725
PMID 30679925
 
Carcinoembryonic antigen-related cell adhesion molecules as surrogate markers for EGFR inhibitor sensitivity in human lung adenocarcinoma
Kobayashi M, Miki Y, Ebina M, Abe K, Mori K, Narumi S, Suzuki T, Sato I, Maemondo M, Endo C, Inoue A, Kumamoto H, Kondo T, Yamada-Okabe H, Nukiwa T, Sasano H
Br J Cancer 2012 Nov 6;107(10):1745-53
PMID 23099808
 
The expression of the CEACAM19 gene, a novel member of the CEA family, is associated with breast cancer progression
Michaelidou K, Tzovaras A, Missitzis I, Ardavanis A, Scorilas A
Int J Oncol 2013 May;42(5):1770-7
PMID 23525470
 
Molecular characterization of a new gene, CEAL1, encoding for a carcinoembryonic antigen-like protein with a highly conserved domain of eukaryotic translation initiation factors
Scorilas A, Chiang PM, Katsaros D, Yousef GM, Diamandis EP
Gene 2003 May 22;310:79-89
PMID 12801635
 
Knockdown of CEACAM19 suppresses human gastric cancer through inhibition of PI3K/Akt and NF-κB
Zhao H, Xu J, Wang Y, Jiang R, Li X, Zhang L, Che Y
Surg Oncol 2018 Sep;27(3):495-502
PMID 30217308
 

Citation

This paper should be referenced as such :
Tsouraki D, Kontos CK
CEACAM19 (carcinoembryonic antigen related cell adhesion molecule 19);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/CEACAM19ID53540ch19q13.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]

Solid Tumors TT_t0719q31q13ID107487 TT_t1719p13q13ID102891


External links

Nomenclature
HGNC (Hugo)CEACAM19   31951
Cards
AtlasCEACAM19ID53540ch19q13.txt
Entrez_Gene (NCBI)CEACAM19  56971  carcinoembryonic antigen related cell adhesion molecule 19
AliasesCEACM19; CEAL1
GeneCards (Weizmann)CEACAM19
Ensembl hg19 (Hinxton)ENSG00000186567 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000186567 [Gene_View]  ENSG00000186567 [Sequence]  chr19:44671452-44684355 [Contig_View]  CEACAM19 [Vega]
ICGC DataPortalENSG00000186567
TCGA cBioPortalCEACAM19
AceView (NCBI)CEACAM19
Genatlas (Paris)CEACAM19
WikiGenes56971
SOURCE (Princeton)CEACAM19
Genetics Home Reference (NIH)CEACAM19
Genomic and cartography
GoldenPath hg38 (UCSC)CEACAM19  -     chr19:44671452-44684355 +  19q13.31   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CEACAM19  -     19q13.31   [Description]    (hg19-Feb_2009)
GoldenPathCEACAM19 - 19q13.31 [CytoView hg19]  CEACAM19 - 19q13.31 [CytoView hg38]
ImmunoBaseENSG00000186567
Mapping of homologs : NCBICEACAM19 [Mapview hg19]  CEACAM19 [Mapview hg38]
OMIM606691   
Gene and transcription
Genbank (Entrez)AK027157 AK128234 AK291588 AL390165 AY358394
RefSeq transcript (Entrez)NM_001127893 NM_020219
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CEACAM19
Cluster EST : UnigeneHs.416925 [ NCBI ]
CGAP (NCI)Hs.416925
Alternative Splicing GalleryENSG00000186567
Gene ExpressionCEACAM19 [ NCBI-GEO ]   CEACAM19 [ EBI - ARRAY_EXPRESS ]   CEACAM19 [ SEEK ]   CEACAM19 [ MEM ]
Gene Expression Viewer (FireBrowse)CEACAM19 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)56971
GTEX Portal (Tissue expression)CEACAM19
Human Protein AtlasENSG00000186567-CEACAM19 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ7Z692   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ7Z692  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ7Z692
Splice isoforms : SwissVarQ7Z692
PhosPhoSitePlusQ7Z692
Domains : Interpro (EBI)Ig-like_dom_sf    Ig-like_fold    Ig_V-set   
Domain families : Pfam (Sanger)V-set (PF07686)   
Domain families : Pfam (NCBI)pfam07686   
Conserved Domain (NCBI)CEACAM19
DMDM Disease mutations56971
Blocks (Seattle)CEACAM19
SuperfamilyQ7Z692
Human Protein Atlas [tissue]ENSG00000186567-CEACAM19 [tissue]
Peptide AtlasQ7Z692
HPRD16229
IPIIPI00376238   IPI00419809   
Protein Interaction databases
DIP (DOE-UCLA)Q7Z692
IntAct (EBI)Q7Z692
FunCoupENSG00000186567
BioGRIDCEACAM19
STRING (EMBL)CEACAM19
ZODIACCEACAM19
Ontologies - Pathways
QuickGOQ7Z692
Ontology : AmiGOprotein binding  integral component of membrane  
Ontology : EGO-EBIprotein binding  integral component of membrane  
NDEx NetworkCEACAM19
Atlas of Cancer Signalling NetworkCEACAM19
Wikipedia pathwaysCEACAM19
Orthology - Evolution
OrthoDB56971
GeneTree (enSembl)ENSG00000186567
Phylogenetic Trees/Animal Genes : TreeFamCEACAM19
HOGENOMQ7Z692
Homologs : HomoloGeneCEACAM19
Homology/Alignments : Family Browser (UCSC)CEACAM19
Gene fusions - Rearrangements
Fusion : MitelmanEMC6/CEACAM19 [17p13.2/19q13.31]  [t(17;19)(p13;q13)]  
Fusion : MitelmanZNF277/CEACAM19 [7q31.1/19q13.31]  [t(7;19)(q31;q13)]  
Fusion PortalTMEM93 CEACAM19 19q13.31 OV
Fusion PortalZNF277 7q31.1 CEACAM19 19q13.31 KIRC
Fusion : FusionGDB11525    28372    29697    43160   
Fusion : Fusion_HubFOPNL--CEACAM19    LRRC68--CEACAM19    MAP3K6--CEACAM19    PPP1R37--CEACAM19    PVR--CEACAM19    PVRL2--CEACAM19    RP11-1407O15.2--CEACAM19    TMEM93--CEACAM19    TOMM40--CEACAM19    TPM1--CEACAM19    ZMIZ2--CEACAM19    ZNF277--CEACAM19   
Fusion : QuiverCEACAM19
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCEACAM19 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CEACAM19
dbVarCEACAM19
ClinVarCEACAM19
1000_GenomesCEACAM19 
Exome Variant ServerCEACAM19
ExAC (Exome Aggregation Consortium)ENSG00000186567
GNOMAD BrowserENSG00000186567
Varsome BrowserCEACAM19
Genetic variants : HAPMAP56971
Genomic Variants (DGV)CEACAM19 [DGVbeta]
DECIPHERCEACAM19 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCEACAM19 
Mutations
ICGC Data PortalCEACAM19 
TCGA Data PortalCEACAM19 
Broad Tumor PortalCEACAM19
OASIS PortalCEACAM19 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCEACAM19  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DCEACAM19
Mutations and Diseases : HGMDCEACAM19
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 CEACAM19
DgiDB (Drug Gene Interaction Database)CEACAM19
DoCM (Curated mutations)CEACAM19 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CEACAM19 (select a term)
intoGenCEACAM19
NCG5 (London)CEACAM19
Cancer3DCEACAM19(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606691   
Orphanet
DisGeNETCEACAM19
MedgenCEACAM19
Genetic Testing Registry CEACAM19
NextProtQ7Z692 [Medical]
TSGene56971
GENETestsCEACAM19
Target ValidationCEACAM19
Huge Navigator CEACAM19 [HugePedia]
snp3D : Map Gene to Disease56971
BioCentury BCIQCEACAM19
ClinGenCEACAM19
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD56971
Chemical/Pharm GKB GenePA142672133
Clinical trialCEACAM19
Miscellaneous
canSAR (ICR)CEACAM19 (select the gene name)
DataMed IndexCEACAM19
Probes
Litterature
PubMed9 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCEACAM19
EVEXCEACAM19
GoPubMedCEACAM19
iHOPCEACAM19
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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