CEACAM1

Gene Summary

Gene:CEACAM1; CEA cell adhesion molecule 1
Aliases: BGP, BGP1, BGPI
Location:19q13.2
Summary:This gene encodes a member of the carcinoembryonic antigen (CEA) gene family, which belongs to the immunoglobulin superfamily. Two subgroups of the CEA family, the CEA cell adhesion molecules and the pregnancy-specific glycoproteins, are located within a 1.2 Mb cluster on the long arm of chromosome 19. Eleven pseudogenes of the CEA cell adhesion molecule subgroup are also found in the cluster. The encoded protein was originally described in bile ducts of liver as biliary glycoprotein. Subsequently, it was found to be a cell-cell adhesion molecule detected on leukocytes, epithelia, and endothelia. The encoded protein mediates cell adhesion via homophilic as well as heterophilic binding to other proteins of the subgroup. Multiple cellular activities have been attributed to the encoded protein, including roles in the differentiation and arrangement of tissue three-dimensional structure, angiogenesis, apoptosis, tumor suppression, metastasis, and the modulation of innate and adaptive immune responses. Multiple transcript variants encoding different isoforms have been reported, but the full-length nature of all variants has not been defined. [provided by RefSeq, May 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:carcinoembryonic antigen-related cell adhesion molecule 1
Source:NCBIAccessed: 30 August, 2019

Ontology:

What does this gene/protein do?
Show (11)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • CD Antigens
  • Monoclonal Antibodies
  • Tumor Suppressor Proteins
  • Biomarkers, Tumor
  • Bladder Cancer
  • Transcriptional Activation
  • Transcriptome
  • Sensitivity and Specificity
  • Gene Expression Profiling
  • Tumor Antigens
  • Base Sequence
  • Molecular Weight
  • Glycoproteins
  • Melanoma
  • Lung Cancer
  • Chromosome 19
  • Alternative Splicing
  • Cell Adhesion
  • Cell Proliferation
  • Neoplasm Metastasis
  • Prostate Cancer
  • Vitamin D-Binding Protein
  • Non-Small Cell Lung Cancer
  • Gene Expression
  • Carcinoembryonic Antigen
  • Antigens, Differentiation
  • Down-Regulation
  • Nucleic Acid Regulatory Sequences
  • Immunohistochemistry
  • Cancer Gene Expression Regulation
  • Molecular Sequence Data
  • GPI-Linked Proteins
  • Cell Adhesion Molecules
  • Oligonucleotide Array Sequence Analysis
  • Single-Stranded Conformational Polymorphism
  • Survival Rate
  • Tyrosine
  • Protein Isoforms
  • Colorectal Cancer
  • Precancerous Conditions
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CEACAM1 (cancer-related)

Wu P, Zhou D, Wang Y, et al.
Identification and validation of alternative splicing isoforms as novel biomarker candidates in hepatocellular carcinoma.
Oncol Rep. 2019; 41(3):1929-1937 [PubMed] Related Publications
Alternative splicing (AS) is a transcriptional regulation mechanism that participates in multiple aspects of cancer. The present study aimed to identify differential AS events from tumor and non‑tumor samples and investigate the potential of AS as a source of candidate cancer diagnostic biomarkers. Deep RNA sequencing of three paired hepatocellular carcinoma (HCC) tumors and adjacent non‑tumors was applied to identify AS events. RT‑qPCR was performed on 45 HCC clinical samples to validate the splicing differences. The maximal information coefficient was first used to build an association between clinical features and AS changes. We identified 197 significantly differential skipped exon events, of which only 29% overlapped with the differentially expressed genes. The differentially spliced genes were mainly enriched in HCC‑characterized biological processes and pathways, clearly separating tumors from non‑tumors. We also validated the statistically significant splicing differences of three AS candidates (CEACAM1 exon 7, VPS29 exon 2 and ISOC2 exon 3). Furthermore, a clinicopathological analysis revealed that carcinoembryonic antigen‑related cell adhesion molecule 1 (CEACAM1) exon 7 was significantly correlated with the survival time, and VPS29 exon 2 was associated with cell differentiation stages. In conclusion, the findings of the three AS candidates in the present study could be beneficial in HCC prognosis and new treatment strategies.

Zhong LH, Zhu LY, Zhao YY, et al.
Apoptosis of hepatocarcinoma cells Hepg2 induced by Huaier extract through regulation of HBx and CEACAM1 gene expression..
J Biol Regul Homeost Agents. 2018 Nov-Dec; 32(6):1389-1398 [PubMed] Related Publications
Huaier can effectively inhibit the growth of tumor cells by enhancing the immune system. However, the mechanism of its function is still not clear. The current study aimed to explore the possible mechanism of Huaier in inhibiting human hepatocarcinoma cells by observing its effect on proliferation and invasion in hepatocarcinoma cells, HepG2 and HepG2-X, which stably express the HBx gene, and by comparing the levels of mRNA transcription and protein expression of HBx and CEACAM1 in HepG2 cells and HepG2-X cells when treated with different concentrations of Huaier. HepG2 cells and HepG2-X cells were treated with 0, 1.5, 3.0, and 6.0 g/L-1 Huaier extract

Zhao L, Chi W, Cao H, et al.
Screening and clinical significance of tumor markers in head and neck squamous cell carcinoma through bioinformatics analysis.
Mol Med Rep. 2019; 19(1):143-154 [PubMed] Free Access to Full Article Related Publications
In order to identify potential diagnostic and prognostic biomarkers, and treatment targets for head and neck squamous cell carcinoma (HNSCC), the present study obtained the gene expression profiles in HNSCC through public data mining, and core genes were identified using a series of bioinformatics analysis methods and databases. A total of nine hub genes (SPP1, ITGA6, TMPRSS11D, MMP1, LAMC2, FAT1, ACTA1, SERPINE1 and CEACAM1) were identified to be significantly correlated with HNSCC. Furthermore, overall survival analysis demonstrated that the expression values of hub genes were associated with overall survival in HNSCC. Furthermore, certain of the identified genes, including, TMPRSS11D, ACTA1 and CEACAM1, have not been thoroughly investigated in HNSCC previously. Taken together, the nine hub genes obtained by screening in the present study may serve as potential tumor markers and important prognostic indicators for HNSCC.

Zhao Q, Busch B, Jiménez-Soto LF, et al.
Integrin but not CEACAM receptors are dispensable for Helicobacter pylori CagA translocation.
PLoS Pathog. 2018; 14(10):e1007359 [PubMed] Free Access to Full Article Related Publications
Translocation of the Helicobacter pylori (Hp) cytotoxin-associated gene A (CagA) effector protein via the cag-Type IV Secretion System (cag-T4SS) into host cells is a hallmark of infection with Hp and a major risk factor for severe gastric diseases, including gastric cancer. To mediate the injection of CagA, Hp uses a membrane-embedded syringe-like molecular apparatus extended by an external pilus-like rod structure that binds host cell surface integrin heterodimers. It is still largely unclear how the interaction of the cag-T4SS finally mediates translocation of the CagA protein into the cell cytoplasm. Recently certain carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), acting as receptor for the Hp outer membrane adhesin HopQ, have been identified to be involved in the process of CagA host cell injection. Here, we applied the CRISPR/Cas9-knockout technology to generate defined human gastric AGS and KatoIII integrin knockout cell lines. Although confocal laser scanning microscopy revealed a co-localization of Hp and β1 integrin heterodimers on gastric epithelial cells, Hp infection studies using the quantitative and highly sensitive Hp β-lactamase reporter system clearly show that neither β1 integrin heterodimers (α1β1, α2β1 or α5β1), nor any other αβ integrin heterodimers on the cell surface are essential for CagA translocation. In contrast, deletion of the HopQ adhesin in Hp, or the simultaneous knockout of the receptors CEACAM1, CEACAM5 and CEACAM6 in KatoIII cells abolished CagA injection nearly completely, although bacterial binding was only reduced to 50%. These data provide genetic evidence that the cag-T4SS-mediated interaction of Hp with cell surface integrins on human gastric epithelial cells is not essential for CagA translocation, but interaction of Hp with CEACAM receptors is facilitating CagA translocation by the cag-T4SS of this important microbe.

Horst AK, Najjar SM, Wagener C, Tiegs G
CEACAM1 in Liver Injury, Metabolic and Immune Regulation.
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a transmembrane glycoprotein that is expressed on epithelial, endothelial and immune cells. CEACAM1 is a differentiation antigen involved in the maintenance of epithelial polarity that is induced during hepatocyte differentiation and liver regeneration. CEACAM1 regulates insulin sensitivity by promoting hepatic insulin clearance, and controls liver tolerance and mucosal immunity. Obese insulin-resistant humans with non-alcoholic fatty liver disease manifest loss of hepatic CEACAM1. In mice, deletion or functional inactivation of CEACAM1 impairs insulin clearance and compromises metabolic homeostasis which initiates the development of obesity and hepatic steatosis and fibrosis with other features of non-alcoholic steatohepatitis, and adipogenesis in white adipose depot. This is followed by inflammation and endothelial and cardiovascular dysfunctions. In obstructive and inflammatory liver diseases, soluble CEACAM1 is shed into human bile where it can serve as an indicator of liver disease. On immune cells, CEACAM1 acts as an immune checkpoint regulator, and deletion of

Oliveira-Ferrer L, Goswami R, Galatenko V, et al.
Prognostic Impact of CEACAM1 in Node-Negative Ovarian Cancer Patients.
Dis Markers. 2018; 2018:6714287 [PubMed] Free Access to Full Article Related Publications
The underlying mechanisms of ovarian cancer (OvCa) dissemination are still poorly understood, and novel molecular markers for this cancer type are urgently needed. In search of adhesion molecules with prognostic relevance in OvCa, we compared tumors with good outcome (alive > 3 years) and those with poor outcome (dead < 2 years) within data from The Cancer Genome Atlas (TCGA). The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) turned out as the only gene with differential expression in these groups. In order to further investigation on its role in OvCa, we analyzed CEACAM1 mRNA levels extracted from TCGA microarray data (

Dery KJ, Silver C, Yang L, Shively JE
Interferon regulatory factor 1 and a variant of heterogeneous nuclear ribonucleoprotein L coordinately silence the gene for adhesion protein CEACAM1.
J Biol Chem. 2018; 293(24):9277-9291 [PubMed] Free Access to Full Article Related Publications
The adhesion protein carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is widely expressed in epithelial cells as a short cytoplasmic isoform (S-iso) and in leukocytes as a long cytoplasmic isoform (L-iso) and is frequently silenced in cancer by unknown mechanisms. Previously, we reported that interferon response factor 1 (IRF1) biases alternative splicing (AS) to include the variable exon 7 (E7) in CEACAM1, generating long cytoplasmic isoforms. We now show that IRF1 and a variant of heterogeneous nuclear ribonucleoprotein L (Lv1) coordinately silence the

Kfir-Elirachman K, Ortenberg R, Vizel B, et al.
Regulation of CEACAM1 Protein Expression by the Transcription Factor ETS-1 in BRAF-Mutant Human Metastatic Melanoma Cells.
Neoplasia. 2018; 20(4):401-409 [PubMed] Free Access to Full Article Related Publications
BRAF becomes constitutively activated in 50% to 70% of melanoma cases. CEACAM1 has a dual role in melanoma, including facilitation of cell proliferation and suppression of infiltrating lymphocytes, which are consistent with its value as a marker for poor prognosis in melanoma patients. Here we show that BRAF

Li JK, Wang C, Gong HD, Li HZ
Coagulation in hindbrain membrane meningioma patients treated with different injections using acute hypervolemic hemodilution.
J Biol Regul Homeost Agents. 2017 Oct-Dec; 31(4):991-996 [PubMed] Related Publications
The aim of this study was to analyze the changes in coagulation in meningioma patients treated with different injections using the method of acute hypervolemic hemodilution (AHH). One hundred fifty hindbrain membrane meningioma patients were randomly divided into 5 groups, 30 per group. The first group were injected 40ml/time with Danhong after anesthesia induction; the second group were injected with 40ml~60ml/time Kangai and combined with interventional chemotherapy and embolization procedure; the third group of AHH were injected with polygeline 15ml/kg; the fourth group were injected with hydroxyethyl starch (130/0.4) sodium chloride in doses of 15ml/kg; the control group underwent basic treatment for lowering blood pressure and lowering blood fat. The changes of coagulation index were recorded before and after surgery and before and after the injection of different medications. Compared to the control group, for the first group of AHH, after being treated for 10 days and 30 days, the concentrations of bone specific alkaline phosphatase (BALP), bone Gla protein (BGP) and pro-collagen carboxy-terminal propeptide (PICP) were higher than that of the control group, the levels of endotoxin (ET) and C-reactive protein (CRP) were decreased compared to the control group (p less than 0.05); for the second group of AHH, after being treated for 10 days, the index of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fg) were not significantly changed, but the related level of vascular endothelial growth factor (VEGF) significantly decreased (p less than 0.05). Comparing the coagulation function index after surgery in the third and fourth groups, there were no significant changes in mean arterial pressure (MAP) level, heart rate (HR) value presented a low decrease, central venous pressure (CVP) level increased and the level of interleukin IL-6 showed a steady state after increasing. Analyzing the levels of interleukin IL-8 and tumor necrosis factor-α (TNF-α) after surgery, it was seen that in the third group they increased and in the fourth group they decreased (p less than 0.05). Danhong injection improved the coagulation function and microcirculation of patients, Kangai injection and interventional chemotherapy and embolization restrained the appearance of tumor angiogenesis, AHH operation with polygeline injection and hydroxyethyl starch (130/0.4) sodium chloride kept blood flow in normal parameters.

Torphy RJ, Schulick RD, Zhu Y
Newly Emerging Immune Checkpoints: Promises for Future Cancer Therapy.
Int J Mol Sci. 2017; 18(12) [PubMed] Free Access to Full Article Related Publications
Cancer immunotherapy has been a great breakthrough, with immune checkpoint inhibitors leading the way. Despite the clinical effectiveness of certain immune checkpoint inhibitors, the overall response rate remains low, and the effectiveness of immunotherapies for many tumors has been disappointing. There is substantial interest in looking for additional immune checkpoint molecules that may act as therapeutic targets for cancer. Recent advances during the last decade have identified several novel immune checkpoint targets, including lymphocyte activation gene-3 (LAG-3), B and T lymphocyte attenuator (BTLA), programmed death-1 homolog (PD-1H), T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIM-3)/carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), and the poliovirus receptor (PVR)-like receptors. The investigations into these molecules have generated promising results in preclinical studies. Herein, we will summarize our current progress and understanding of these newly-characterized immune checkpoints and their potential application in cancer immunotherapy.

Mao CS, Yin H, Ning HB, et al.
Levels of HBx, VEGF, and CEACAM1 in HBV-related hepatocellular carcinoma and their correlation with cancer prognosis.
Eur Rev Med Pharmacol Sci. 2017; 21(17):3827-3833 [PubMed] Related Publications
OBJECTIVE: Hepatitis B virus X protein (HBx), vascular endothelial growth factor (VEGF) and carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), are related to HBV associated hepatocellular carcinoma (HCC). This study recruited HCC patients and employed the SMMC-7721 and L02 liver cell lines, to analyze the expression levels of HBx, VEGF and CEACAM1 in liver cancer and their correlation with the cancer prognosis.
PATIENTS AND METHODS: HBV-related HCC patients were recruited from our hospital. Immunohistochemistry (IHC) and Western blotting assay were used to detect the expression of HBx, VEGF and CEACAM1 in liver tissues. Multi-variant analysis and the correlation analysis between HBx, VEGF, CEACAM1 expression and clinical/pathological features of HCC were performed by using the Cox regression analysis.
RESULTS: In HBV-related HCC tissues, positive expression rates of HBx, CEACAM1, and VEGF, were 80%, 50%, and 65%, respectively. In HBx-positive group, positive rate for CEACAM1 and VEGF were 56.25% and 75%, while in HBx-negative group such figures were 75% and 25% (p<0.05). HCC cells had lower expression of CEACAM1 and higher VEGF levels compared to normal hepatocytes. Those HCC cells transfected with HBx had even lower CEACAM1 and higher VEGF levels compared to un-transfected cells. HBx was negatively correlated with CEACAM1 and positively correlated with VEGF. Expressions of these three factors were all independent risk factors as they were correlated with lesion size, venous infiltration, metastasis, and capsule.
CONCLUSIONS: HBx, VEGF and CEACAM1 were widely expressed in HBV-related HCC. HBx may facilitate occurrence and progression of HBV-related HCC via down-regulating CEACAM1 and up-regulating VEGF.

Simonetti O, Lucarini G, Rubini C, et al.
Correlation between immunohistochemical staining of CEACAM1 and clinicopathological findings in oral pre-neoplastic lesions and squamous cell carcinoma.
Med Mol Morphol. 2018; 51(1):41-47 [PubMed] Related Publications
Squamous cell carcinoma of the oral cavity represents the sixth most common cancer worldwide and it is often preceded by pre-neoplastic lesions. Sometimes it is still difficult for pathologists to make objective differential diagnoses only on histological characteristics. Tumorigenesis is accompanied by altered expression of cell adhesion molecules, like carcinoembryonic antigen cell adhesion molecule (CEACAM)1. We wanted to investigative CEACAM1 in oral dysplastic lesions, carcinoma in situ (CIS) and oral squamous cell carcinoma (OSCC). We examined immunohistochemical CEACAM1 expression in 50 OSCC, 30 oral CIS and 40 pre-neoplastic lesions and assessed its correlation with clinical and pathological parameters. CEACAM1 was not expressed in normal mucosa, significantly expressed in CIS while it was negative in all the dysplastic lesions. In OSCC, high CEACAM1 expression was associated with tumor grade and inversely correlated with both overall and disease-specific 5-year survival. We showed that CEACAM1 expression is very dynamic: absent in dysplastic lesions, up-regulated in CIS and OSCC. We suggest that CEACAM1 could be a prognostic marker of OSCC and oral CIS. Our most important finding was that it could help pathologists diagnosing oral carcinoma in situ.

Zhou M, Jin Z, Liu Y, et al.
Up-regulation of carcinoembryonic antigen-related cell adhesion molecule 1 in gastrointestinal cancer and its clinical relevance.
Acta Biochim Biophys Sin (Shanghai). 2017; 49(8):737-743 [PubMed] Related Publications
Serum carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is dysregulated in various malignant tumors and has been associated with tumor progression. However, the expression and regulatory mechanisms of serum CEACAM1 in gastrointestinal cancer are still unclear. The expression ratio of the CEACAM1-L and CEACAM1-S isoforms has seldom been investigated in gastrointestinal cancer. In this study, we intended to explore the expression and diagnostic value of CEACAM1 in gastrointestinal cancer. Serum CEACAM1 levels were measured by enzyme-linked immunosorbent assay. The protein expression and distribution of CEACAM1 in tumors were examined by immunohistochemical staining. The expression patterns and ratio of CEACAM1-L/S were analyzed by reverse transcription-polymerase chain reaction. The results showed that serum CEACAM1 levels were significantly higher in cancer patients than in healthy controls. CEACAM1 was found in secreted forms within the neoplastic glands, and its expression was more intense at the tumor invasion front. The CEACAM1-L/S (L:S) ratios were up-regulated during tumorigenesis. Our data suggest that the serum level of CEACAM1 may be used to discriminate gastrointestinal cancer patients from health controls.

Yan F, Ying L, Li X, et al.
Overexpression of the transcription factor ATF3 with a regulatory molecular signature associates with the pathogenic development of colorectal cancer.
Oncotarget. 2017; 8(29):47020-47036 [PubMed] Free Access to Full Article Related Publications
The identification of novel biomarkers of cancer is important for improved diagnosis and prognosis. With an abundant amount of resources in the publicly available database, such as the Cancer Genome Atlas (TCGA) database, an integrative strategy is used to systematically characterize the aberrant patterns of colorectal cancer (CRC) based on RNA-Seq, chromatin immunoprecipitation sequencing (ChIP-Seq), tissue microarray (TMA), gene profiling and molecular signatures. The expression of the transcription factor ATF3 was elevated in human CRC specimens in a TMA by immunochemistry analysis compared to the adjacent normal tissues. In addition, ATF3 overexpression associated with a regulatory molecular signature, and its functions are related to the pathogenic development of CRC. Furthermore, putative ATF3 regulatory elements were identified within the promoters of ATF3 target genes and were confirmed by ChIP-Seq. Critically, in higher ATF3 expression cell lines (HCT116 and RKO) with CRISPR/Cas9 mediated ATF3 knock out, we are able to show that ATF3 target genes such as CEACAM1, DUSP14, HDC, HLF and ULBP2, are required for invasion and proliferation, and they are robustly linked with poor prognosis in CRC. Our findings have important implications for CRC tumorigenesis and may be exploited for diagnostic and therapeutic purposes.

Ueshima C, Kataoka TR, Takei Y, et al.
CEACAM1 long isoform has opposite effects on the growth of human mastocytosis and medullary thyroid carcinoma cells.
Cancer Med. 2017; 6(4):845-856 [PubMed] Free Access to Full Article Related Publications
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed in a number of tumor cell types. The immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing isoforms of this molecule which possess a long cytoplasmic tail (CEACAM1-L) generally play inhibitory roles in cell function by interacting with Src homology 2 domain-containing tyrosine phosphatase (SHP)-1 and/or SHP-2. Src family kinases (SFKs) are also known to bind to and phosphorylate CEACAM1-L isoforms. Here, we report that CEACAM1 was uniquely expressed at high levels in both human neoplastic mast cells (mastocytosis) and medullary thyroid carcinoma cell (MTC) lines, when compared with their expression in nonneoplastic mast cells or nonneoplastic C cells. This expression was mainly derived from CEACAM1-L isoforms based upon assessment of CEACAM1 mRNA expression. CEACAM1 knockdown upregulated cell growth of HMC1.2 cells harboring KIT mutations detected in clinical mastocytosis, whereas downregulated the growth of TT cells harboring RET mutations detected in clinical MTCs. Immunoblotting, ELISA and immunoprecipitaion analysis showed that activated SHP-1 is preferentially associated with CEACAM1 in HMC1.2 cells harboring KIT mutations, whereas Src family kinases (SFKs) are preferentially associated with CEACAM1 in TT cells harboring RET mutations. These studies suggest that the dominantly interacting proteins SHP1 or SFK determine whether CEACAM1-L displays a positive or negative role in tumor cells.

Wegwitz F, Lenfert E, Gerstel D, et al.
CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo.
Oncotarget. 2016; 7(39):63730-63746 [PubMed] Free Access to Full Article Related Publications
We analyzed the molecular basis for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-controlled inhibition of epithelial-mesenchymal transition (EMT) in a mouse model for mammary adenocarcinoma (WAP-T mice). We demonstrate that silencing of CEACAM1 in WAP-T tumor-derived G-2 cells induces epithelial-mesenchymal plasticity (EMP), as evidenced by typical changes of gene expression, morphology and increased invasion. In contrast, reintroduction of CEACAM1 into G-2 cells reversed up-regulation of genes imposing mesenchymal transition, as well as cellular invasion. We identified the Wnt-pathway as target for CEACAM1-mediated repression of EMT. Importantly, β-catenin phosphorylation status and transcriptional activity strongly depend on CEACAM1 expression: CEACAM1high G-2 cells displayed enhanced phosphorylation of β-catenin at S33/S37/T41 and decreased phosphorylation at Y86, thereby inhibiting canonical Wnt/β-catenin signaling. We identified Src-homology 2 domain-containing phosphatase 2 (SHP-2) as a critical binding partner of CEACAM1 that could modulate β-catenin Y86 phosphorylation. Hence, CEACAM1 serves as a scaffold that controls membrane proximal β-catenin signaling. In vivo, mammary tumors of WAP-T/CEACAM1null mice displayed increased nuclear translocation of β-catenin and a dramatically enhanced metastasis rate compared to WAP-T mice. Hence, CEACAM1 controls EMT in vitro and in vivo by site-specific regulation of β-catenin phosphorylation. Survival analyses of human mammary carcinoma patients corroborated these data, indicating that CEACAM1 is a prognostic marker for breast cancer survival.

Zhang L, Wang J, Wei F, et al.
Profiling the dynamic expression of checkpoint molecules on cytokine-induced killer cells from non-small-cell lung cancer patients.
Oncotarget. 2016; 7(28):43604-43615 [PubMed] Free Access to Full Article Related Publications
Immune checkpoints associate with dysfunctional T cells, which have a reduced ability to clear pathogens or cancer cells. T-cell checkpoint blockade may improve patient survival. However, checkpoint molecules on cytokine-induced killer (CIK) cell, a non-specific adoptive immunotherapy, remain unknown. In present study, we detected the dynamic expression of eight major checkpoint molecules (CTLA-4, PD-1, PD-L1, TIM- 3, CEACAM-1, LAG-3, TIGIT and BTLA) on CIK cells from NSCLC patients. The majority of these molecules, except BTLA, were sharply elevated during the early stage of CIK cell culture. Thereafter, PD-1 and TIGIT expressions decreased gradually towards the initial level (day 0). Moreover, CTLA-4 faded away during the later stage of CIK culture. LAG-3 expression decreased but was still significantly higher than the initial level. Of note, PD-L1 remained stably upregulated during CIK culture compared with PD-1, indicating that PD-L1 might act as an inhibitory molecule on CIK cells instead of PD-1. Furthermore, TIM-3 and CEACAM1 were strongly expressed simultaneously during long-term CIK culture and showed a significant and mutually positive correlation. BTLA displayed a distinct pattern, and its expression gradually decreased throughout the CIK culture. These observations suggested that CIK cells might be partly exhausted before clinical transfusion, characterized by the high expression of PD-L1, LAG-3, TIM- 3, and CEACAM-1 and the low expression of TIGIT, BTLA, PD-1, and CTLA-4 compared with initial culture. Our results imply that implementing combined treatment on CIK cells before transfusion via antibodies targeting PD-L1, LAG-3, TIM-3, and CEACAM-1 might improve the efficiency of CIK therapy for NSCLC patients.

Giulietti M, Occhipinti G, Principato G, Piva F
Weighted gene co-expression network analysis reveals key genes involved in pancreatic ductal adenocarcinoma development.
Cell Oncol (Dordr). 2016; 39(4):379-88 [PubMed] Related Publications
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Up till now, the patient's prognosis remains poor which, among others, is due to the paucity of reliable early diagnostic biomarkers. In the past, candidate diagnostic biomarkers and therapeutic targets have been delineated from genes that were found to be differentially expressed in normal versus tumour samples. Recently, new systems biology approaches have been developed to analyse gene expression data, which may yield new biomarkers. As of yet, the weighted gene co-expression network analysis (WGCNA) tool has not been applied to PDAC microarray-based gene expression data.
METHODS: PDAC microarray-based gene expression datasets, listed in the Gene Expression Omnibus (GEO) database, were analysed. After pre-processing of the data, we built two final datasets, Normal and PDAC, encompassing 104 and 129 patient samples, respectively. Next, we constructed a weighted gene co-expression network and identified modules of co-expressed genes distinguishing normal from disease conditions. Functional annotations of the genes in these modules were carried out to highlight PDAC-associated molecular pathways and common regulatory mechanisms. Finally, overall survival analyses were carried out to assess the suitability of the genes identified as prognostic biomarkers.
RESULTS: Using WGCNA, we identified several key genes that may play important roles in PDAC. These genes are mainly related to either endoplasmic reticulum, mitochondrion or membrane functions, exhibit transferase or hydrolase activities and are involved in biological processes such as lipid metabolism or transmembrane transport. As a validation of the applied method, we found that some of the identified key genes (CEACAM1, MCU, VDAC1, CYCS, C15ORF52, TMEM51, LARP1 and ERLIN2) have previously been reported by others as potential PDAC biomarkers. Using overall survival analyses, we found that several of the newly identified genes may serve as biomarkers to stratify PDAC patients into low- and high-risk groups.
CONCLUSIONS: Using this new systems biology approach, we identified several genes that appear to be critical to PDAC development. As such, they may represent potential diagnostic biomarkers as well as therapeutic targets with clinical utility.

Ashkenazi S, Ortenberg R, Besser M, et al.
SOX9 indirectly regulates CEACAM1 expression and immune resistance in melanoma cells.
Oncotarget. 2016; 7(21):30166-77 [PubMed] Free Access to Full Article Related Publications
As melanoma cells are immunogenic, they instigate an adaptive immune response and production of anti-tumor T-cells. A central factor in this interaction is CEACAM1 (carcinoembryonic antigen cell adhesion molecule 1), a transmembrane glycoprotein previously shown in our lab to protect melanoma cells from T cell-mediated killing. In this study, we examine the role of transcription factor SOX9 in the regulation of CEACAM1 expression and immune resistance in melanoma cells. Knockdown of endogenous SOX9 results in CEACAM1 up-regulation, while its overexpression leads to the opposite effect. We show that SOX9 controls CEACAM1 expression at a transcriptional level, but in an indirect manner, as regulation of the CEACAM1 promoter remains intact even when all eight potential SOX9-binding sites are abolished. A series of promoter truncations localizes the SOX9-controlled area to the proximal 200bp of the promoter. Point mutations in putative Sp1 and ETS1 binding sites identify these transcription factors as the primary SOX9-controlled mediators. Co-immunoprecipitation studies show that SOX9 and Sp1 physically interact in melanoma cells, while silencing of SOX9 down-regulates ETS1, but not Sp1, in the same cells. Finally, knockdown of SOX9 indeed renders melanoma cells resistant to T cell-mediated killing, in line with the increased CEACAM1 expression. In conclusion, we show that SOX9 regulates CEACAM1 expression in melanoma cells, and thereby their immune resistance. As CEACAM1 is a pivotal protein in melanoma biology and immune crosstalk, further understanding of its regulation can provide new insights and contribute to the development of novel approaches to therapy.

Yang C, He P, Liu Y, et al.
Assay of serum CEACAM1 as a potential biomarker for breast cancer.
Clin Chim Acta. 2015; 450:277-81 [PubMed] Related Publications
BACKGROUND: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a widely expressed multi-functional adhesion molecule reported to serve as a serum biomarker in several types of cancer. However, the serum CEACAM1 expression in breast cancer is unclear. We investigated the serum concentrations of CEACAM1 in patients with breast cancer and determine the potential of serum CEACAM1 as a breast cancer biomarker.
METHODS: Serum specimens were obtained from 33 patients with breast cancer, 30 patients with benign breast diseases and 34 healthy donors. The serum CEACAM1 concentrations were examined by an enzyme-linked immunosorbent assay (ELISA).
RESULTS: The serum CEACAM1 concentrations in the malignant group (532 ng/ml) were significantly higher than those of the benign group (423 ng/ml) and healthy control group (386 ng/ml) (both p<0.001). Based on univariable logistic regression, serum CEACAM1 concentrations significantly predicted breast cancer versus normal controls or benign breast diseases. Area under receiver operating characteristic curve (ROC) for serum CEACAM1 was 0.925(95% CI: 0.866-0.984). The optimal cut-off concentration of CEACAM1 was 475.82 ng/ml for discriminating breast cancer from normal controls.
CONCLUSION: Serum concentrations of CEACAM1 may serve as a useful indicator for the presence of breast cancer.

Ullrich N, Löffek S, Horn S, et al.
MITF is a critical regulator of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in malignant melanoma.
Pigment Cell Melanoma Res. 2015; 28(6):736-40 [PubMed] Related Publications
The multifunctional Ig-like carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is neo-expressed in the majority of malignant melanoma lesions. CEACAM1 acts as a driver of tumor cell invasion, and its expression correlates with poor patient prognosis. Despite its importance in melanoma progression, how CEACAM1 expression is regulated is largely unknown. Here, we show that CEACAM1 expression in melanoma cell lines and melanoma tissue strongly correlates with that of the microphthalmia-associated transcription factor (MITF), a key regulator of melanoma proliferation and invasiveness. MITF is revealed as a direct and positive regulator for CEACAM1 expression via binding to an M-box motif located in the CEACAM1 promoter. Taken together, our study provides novel insights into the regulation of CEACAM1 expression and suggests an MITF-CEACAM1 axis as a potential determinant of melanoma progression.

Ilhan-Mutlu A, Siehs C, Berghoff AS, et al.
Expression profiling of angiogenesis-related genes in brain metastases of lung cancer and melanoma.
Tumour Biol. 2016; 37(1):1173-82 [PubMed] Related Publications
Brain metastases (BM) are the most common brain tumors of adults and are associated with fatal prognosis. Formation of new blood vessels, named angiogenesis, was proposed to be the main hallmark of the growth of BM. Previous preclinical evidence revealed that angiogenic blockage might be considered for treatment; however, there were varying responses. In this study, we aimed to characterize the expression pattern of angiogenesis-related genes in BM of lung cancer and melanoma, which might be of importance for the different responses against anti-angiogenic treatment. Fifteen snap-frozen tissues obtained from BM of non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and melanoma patients were analyzed for angiogenesis-related genes using a commercially available gene expression kit. Epilepsy tissue was used as control. Expression values were analyzed using hierarchical clustering investigating relative fold changes and mapping to Omicsnet protein interaction network. CXCL10, CEACAM1, PECAM1, KIT, COL4A2, COL1A1, and HSPG2 genes were more than 50-fold up-regulated in all diagnosis groups when compared to control, whereas genes such as ANGPT4, PDGFRB, and SERPINF1 were down-regulated only in SCLC and melanoma groups, respectively. Using hierarchical clustering, 12 out of 15 cases were allocated to the correct histological primary tumor type. We identified genes with consistent up-regulation in BM of lung cancer and melanoma and other genes with differential expression across BM of these tumor types. Our data may be of relevance for targeted therapy or prophylaxis of BM using anti-angiogenic agents.

Kaneko S, Nakatani Y, Takezaki T, et al.
Ceacam1L Modulates STAT3 Signaling to Control the Proliferation of Glioblastoma-Initiating Cells.
Cancer Res. 2015; 75(19):4224-34 [PubMed] Related Publications
Glioblastoma-initiating cells (GIC) are a tumorigenic cell subpopulation resistant to radiotherapy and chemotherapy, and are a likely source of recurrence. However, the basis through which GICs are maintained has yet to be elucidated in detail. We herein demonstrated that the carcinoembryonic antigen-related cell adhesion molecule Ceacam1L acts as a crucial factor in GIC maintenance and tumorigenesis by activating c-Src/STAT3 signaling. Furthermore, we showed that monomers of the cytoplasmic domain of Ceacam1L bound to c-Src and STAT3 and induced their phosphorylation, whereas oligomerization of this domain ablated this function. Our results suggest that Ceacam1L-dependent adhesion between GIC and surrounding cells play an essential role in GIC maintenance and proliferation, as mediated by signals transmitted by monomeric forms of the Ceacam1L cytoplasmic domain.

Cheng L, Ruan Z
Tim-3 and Tim-4 as the potential targets for antitumor therapy.
Hum Vaccin Immunother. 2015; 11(10):2458-62 [PubMed] Free Access to Full Article Related Publications
Both Tim-3 and Tim-4 belong to the T-cell immunoglobulin and mucin domain (Tim) gene family, which plays a critical role in immunoregulation. Tim-3 has been suggested as a negative regulator of anti-tumor immunity due to its function on inducing T cells exhaustion in cancer. In addition to its expression on exhausted T cells, Tim-3 also has been reported to up-regulate on nature killer (NK) cells and promote NK cells functionally exhausted in cancer. While Tim-3 selectively expression on most types of leukemia stem cells, it promotes the progression of acute myeloid leukemia. Recently, data from experimental models of tumor discovered that Tim-3 and Tim-4 up-regulation on tumor associated dendritic cells and macrophages attenuated the anti-tumor effects of cancer vaccines and chemotherapy. Moreover, co-blockage of Tim-3 and PD-1, Tim-3 and CD137, Tim-3 and carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) could enhance cell-mediated immunity in advanced tumor, and combined treatment with anti-Tim-3 and anti-Tim-4 mAbs further increase the efficacy of cancer vaccines. The therapeutic manipulation of TIM-3 and TIM-4 may provide a novel strategy to improve the clinical efficacy of cancer immunotherapy.

Cai X, Luo J, Yang X, et al.
In vivo selection for spine-derived highly metastatic lung cancer cells is associated with increased migration, inflammation and decreased adhesion.
Oncotarget. 2015; 6(26):22905-17 [PubMed] Free Access to Full Article Related Publications
We developed a murine spine metastasis model by screening five metastatic non-small cell lung cancer cell lines (PC-9, A549, NCI-H1299, NCI-H460, H2030). A549 cells displayed the highest tendency towards spine metastases. After three rounds of selection in vivo, we isolated a clone named A549L6, which induced spine metastasis in 80% of injected mice. The parameters of the A549L6 cell spinal metastatic mouse models were consistent with clinical spine metastasis features. All the spinal metastatic mice developed symptoms of nerve compression after 40 days. A549L6 cells had increased migration, invasiveness and decreased adhesion compared to the original A549L0 cells. In contrast, there was no significant differences in cell proliferation, apoptosis and sensitivity to chemotherapeutic agents such as cisplatin. Comparative transcriptomic analysis and real-time PCR analysis showed that expression of signaling molecules regulating several tumor properties including migration (MYL9), metastasis (CEACAM6, VEGFC, CX3CL1, CST1, CCL5, S100A9, IGF1, NOTCH3), adhesion (FN1, CEACAM1) and inflammation (TRAF2, NFκB2 and RelB) were altered in A549L6 cells. We suggest that migration, adhesion and inflammation related genes contribute to spine metastatic capacity.

Arabzadeh A, Dupaul-Chicoine J, Breton V, et al.
Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells.
Gut. 2016; 65(5):821-9 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Nearly 20%-29% of patients with colorectal cancer (CRC) succumb to liver or lung metastasis and there is a dire need for novel targets to improve the survival of patients with metastasis. The long isoform of the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1-L or CC1-L) is a key regulator of immune surveillance in primary CRC, but its role in metastasis remains largely unexplored. We have examined how CC1-L expression impacts on colon cancer liver metastasis.
DESIGN: Murine MC38 transfected with CC1-L were evaluated in vitro for proliferation, migration and invasion, and for in vivo experimental liver metastasis. Using shRNA silencing or pharmacological inhibition, we delineated the role in liver metastasis of Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) downstream of CC1-L. We further assessed the clinical relevance of these findings in a cohort of patients with CRC.
RESULTS: MC38-CC1-L-expressing cells exhibited significantly reduced in vivo liver metastasis and displayed decreased CCL2 chemokine secretion and reduced STAT3 activity. Down-modulation of CCL2 expression and pharmacological inhibition of STAT3 activity in MC38 cells led to reduced cell invasion capacity and decreased liver metastasis. The clinical relevance of our findings is illustrated by the fact that high CC1 expression in patients with CRC combined with some inflammation-regulated and STAT3-regulated genes correlate with improved 10-year survival.
CONCLUSIONS: CC1-L regulates inflammation and STAT3 signalling and contributes to the maintenance of a less-invasive CRC metastatic phenotype of poorly differentiated carcinomas.

Zippel D, Barlev H, Ortenberg R, et al.
A longitudinal study of CEACAM1 expression in melanoma disease progression.
Oncol Rep. 2015; 33(3):1314-8 [PubMed] Related Publications
The present study characterized the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression profile in a longitudinal study during melanoma progression, in lesions obtained from the same patients: a primary skin lesion, a lymph node and a distant metastasis. The present study is expected to increase our understanding of the expression patterns of CEACAM1 in melanoma development. We identified 20 patients who could be analyzed for CEACAM1 expression over the course of disease progression. The pathology blocks were cut, and two slides were generated for each specimen. One underwent standard hematoxylin and eosin (H&E) staining and a corresponding slide underwent immunohistochemical staining for the detection of CEACAM1. For 13 patients who were able to be followed up serially from primary lesion, lymph node and distant metastasis, a borderline significant increase in the staining of the membrane was noted (P=0.06). In contrast, there was no equivalent increase in cytoplasmic CEACAM1 in the same group of patients. For the cohort of 20 patients with primary and distant metastasis, a significant increase in the membrane staining was noted (P=0.026) and again, no equivalent significant increase in cytoplasmic staining was observed. We report that CEACAM1 expression increases along the course of disease development and progression of a patient. CEACAM1 represents a novel area of research which may have profound influence in future methods of harnessing cellular immunity to combat this disease. The results of the present study confirm that CEACAM1 is potentially an extremely useful target in arresting melanoma progression.

Gebauer F, Wicklein D, Horst J, et al.
Carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1, 5 and 6 as biomarkers in pancreatic cancer.
PLoS One. 2014; 9(11):e113023 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aim of this study was to assess the biological function in tumor progression and metastatic process carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1, 5 and 6 in pancreatic adenocarcinoma (PDAC).
EXPERIMENTAL DESIGN: CEACAM knock down cells were established and assessed in vitro and in a subcutaneous and intraperitoneal mouse xenograft model. Tissue and serum expression of patients with PDAC were assessed by immunohistochemistry (IHC) and by enzyme linked immunosorbent assays.
RESULTS: Presence of lymph node metastasis was correlated with CEACAM 5 and 6 expression (determined by IHC) and tumor recurrence exclusively with CEACAM 6. Patients with CEACAM 5 and 6 expression showed a significantly shortened OS in Kaplan-Meier survival analyses. Elevated CEACAM6 serum values showed a correlation with distant metastasis and. Survival analysis revealed a prolonged OS for patients with low serum CEACAM 1 values. In vitro proliferation and migration capacity was increased in CEACAM knock down PDAC cells, however, mice inoculated with CEACAM knock down cells showed a prolonged overall-survival (OS). The number of spontaneous pulmonary metastasis was increased in the CEACAM knock down group.
CONCLUSION: The effects mediated by CEACAM expression in PDAC are complex, though overexpression is correlated with loco-regional aggressive tumor growth. However, loss of CEACAM can be considered as a part of epithelial-mesenchymal transition and is therefore of rather importance in the process of distant metastasis.

Pattabiraman C, Hong S, Gunasekharan VK, et al.
CD66+ cells in cervical precancers are partially differentiated progenitors with neoplastic traits.
Cancer Res. 2014; 74(22):6682-92 [PubMed] Free Access to Full Article Related Publications
Cervical cancers, a malignancy associated with oncogenic papilloma viruses, remain a major disease burden in the absence of effective implementation of preventive strategies. CD66(+) cells have previously been identified as a tumor-propagating subset in cervical cancers. We investigated the existence, differentiation state, and neoplastic potential of CD66(+) cells in a precancer cell line harboring HPV31b episomes. The gene expression profile of CD66(high) cells overlaps with differentiated keratinocytes, neoplastic mesenchymal transition, cells of the squamocolumnar junction, and cervical cancer cell line-derived spheroids. There is elevated expression of DNMT1, Notch1, and the viral gene product E1⁁E4 in CD66(high) cells. Thus, CD66(high) cells, in the absence of differentiating signals, express higher levels of key regulators of keratinocytes stemness, differentiation, and the viral life cycle, respectively. We also find a striking association of neoplastic traits, including migration, invasion, and colony formation, in soft agar with CD66(high) cells. These properties and a distinct G2-M-enriched cell-cycle profile are conserved in cells from cervical cancers. Principally, using a precancerous cell line, we propose that CD66(high) cells have an intermediate differentiation state, with a cellular milieu connected with both viral replication and neoplastic potential, and validate some key features in precancer lesions. Such pathophysiologically relevant systems for defining cellular changes in the early phases of the disease process provide both mechanistic insight and potential therapeutic strategies. Collectively, our data provide a rationale for exploring novel therapeutic targets in CD66(+) subsets during cancer progression.

Wakabayashi-Nakao K, Hatakeyama K, Ohshima K, et al.
Carcinoembryonic antigen-related cell adhesion molecule 4 (CEACAM4) is specifically expressed in medullary thyroid carcinoma cells.
Biomed Res. 2014; 35(4):237-42 [PubMed] Related Publications
Carcinoembryonic antigen (CEA), an oncofetal cell surface glycoprotein, has been widely used as a human tumor marker due to its high expression in tumors and secretion to serum. It belongs to the immunoglobulin superfamily named CEA-related cell adhesion molecule (CEACAM) family. Members of this family are detected in various cancers and have been shown to be involved in cancer growth and invasion. In this study, we examined the mRNA expression profiles of CEACAM family members including CEACAM1, CEACAM3, CEACAM4, CEACAM5 (CEA), CEACAM6, CEACAM7, and CEACAM8 in various tumor cell lines. Our screening data indicated that the mRNA expression patterns of CEACAMs in TT cells, which are derived from medullary thyroid carcinoma (MTC), were distinct from other tumor cell lines. Additionally, CEACAM4 was only expressed in TT cells, in which two novel splice variants of CEACAM4 were expressed. These findings suggested that production of CEA and CEA-related molecules in MTC may be distinct from other tumor-based production of those molecules and that the specific expression of CEACAM4 would make possible to differentiate between MTC and other CEA-producing tumors.

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