• Cellular therapies
• Gastrointestinal disease
• Stem cells

• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Humans
• Adenocarcinoma/genetics
• Adenocarcinoma/pathology
• Tumor Microenvironment
• Disease Progression
• Single-Cell Analysis

• MOH-OFLCG18May-0003 Ministry of Health -Singapore (MOH)
• CIRG23Jul-0035 Ministry of Health -Singapore (MOH)
• Cancer Science Institute of Singapore, National University of Singapore (CSI)
• Duke-NUS Medical School (DukeNUS)

• Antibody specificity
• Immunohistochemistry
• Molecular pathology

• Humans
• Stomach Neoplasms/pathology
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/mortality
• Epithelial Cell Adhesion Molecule/metabolism
• Epithelial Cell Adhesion Molecule/genetics
• Cell Adhesion Molecules/metabolism
• Cell Adhesion Molecules/genetics
• Male
• Female
• Middle Aged
• Antigens, Neoplasm/metabolism
• Antigens, Neoplasm/genetics
• Aged
• Biomarkers, Tumor/metabolism
• Adult
• Prognosis
• Aged, 80 and over
• Immunohistochemistry

• bioinformatics
• biomarker
• circadian rhythm
• machine learning
• melanoma
• prognostic model

• Humans
• Melanoma/genetics
• Melanoma/diagnosis
• Melanoma/mortality
• Machine Learning
• Biomarkers, Tumor/genetics
• Prognosis
• Computational Biology
• Skin Neoplasms/genetics
• Skin Neoplasms/diagnosis
• Skin Neoplasms/mortality
• Circadian Rhythm/genetics
• Gene Expression Regulation, Neoplastic
• Male
• Female
• Gene Regulatory Networks
• Nomograms
• Gene Expression Profiling
• Middle Aged

• Breast cancer
• CAR-T
• Challenges
• Colorectal cancer
• Immunotherapy
• Novel CAR-T targets
• Solid tumor

• Humans
• Female
• Receptors, Chimeric Antigen
• Breast Neoplasms/therapy
• Immunotherapy, Adoptive/methods
• Colorectal Neoplasms/therapy
• Cell- and Tissue-Based Therapy
• Tumor Microenvironment
• Cell Adhesion Molecules
• Receptor Protein-Tyrosine Kinases
• Microfilament Proteins
• Receptors, Cell Surface
• Receptors, Enterotoxin

• Gastric cancer
• Meprin β
• Microbiome

• Humans
• B7-H1 Antigen/genetics
• Stomach Neoplasms/pathology
• Microsatellite Instability
• Mucins/genetics
• Cell Membrane/metabolism

• Universitätsklinikum Schleswig-Holstein - Campus Kiel (6509)

• biomarkers
• gastroenterology
• oncology

• EMT
• biomarkers
• extracellular vesicles
• lung cancer
• tumorigenesis
• β-catenin signaling

• Humans
• beta Catenin/metabolism
• Carcinogenesis
• Cell Line, Tumor
• Cell Movement
• Cell Transformation, Neoplastic
• Epithelial-Mesenchymal Transition
• Extracellular Vesicles/metabolism
• Lung Neoplasms/metabolism
• Signal Transduction

• acute lymphoblastic leukemia
• cell proliferation
• costunolide
• epithelial cell adhesion molecule
• telomerase inhibition

• Cancer
• Cell signaling
• EpCAM
• Extracellular vesicles
• Immune
• Therapy

• 81874065 National Natural Science Foundation of China
• 81372327 National Natural Science Foundation of China
• 2020YQ05 Tongji Hospital (HUST) Foundation for Excellent Young Scientists
• 2018ZX10723204-003-003 State Key Project on Infectious Diseases of China
• 2018YFA0208904 National Key Research and Development Program of China
• 2018ACA137 Major Technological Innovation Projects of Hubei Province
• 2020YFA0710700 National Basic Research Program of China

TRIM28, a multi-domain protein, is crucial in the development of mouse embryos and the maintenance of embryonic stem cells’ (ESC) self-renewal potential. As the epigenetic factor modulating chromatin structure, TRIM28 regulates the expression of numerous genes and is associated with progression and poor prognosis in many types of cancer. Because of many similarities between highly dedifferentiated cancer cells and normal pluripotent stem cells, we applied human induced pluripotent stem cells (hiPSC) as a model for stemness studies. For the first time in hiPSC, we analyzed the function of individual TRIM28 domains. Here we demonstrate the essential role of a really interesting new gene (RING) domain and plant homeodomain (PHD) in regulating pluripotency maintenance and self-renewal capacity of hiPSC. Our data indicate that mutation within the RING or PHD domain leads to the loss of stem cell phenotypes and downregulation of the FGF signaling. Moreover, impairment of RING or PHD domain results in decreased proliferation and impedes embryoid body formation. In opposition to previous data indicating the impact of phosphorylation on TRIM28 function, our data suggest that TRIM28 phosphorylation does not significantly affect the pluripotency and self-renewal maintenance of hiPSC. Of note, iPSC with disrupted RING and PHD functions display downregulation of genes associated with tumor metastasis, which are considered important targets in cancer treatment. Our data suggest the potential use of RING and PHD domains of TRIM28 as targets in cancer therapy.

• KAP1
• TRIM28
• cancer
• differentiation
• epigenetics
• iPS
• pluripotency
• self-renewal
• stem cells
• stemness

• Ber-EP4
• MOC-31
• basal cell carcinoma
• prognostic factors
• α-smooth muscle actin

• CAR T cell therapy
• Epstein Barr Virus
• gastric cancer
• immune checkpoint inhibitors
• microsatellite instability
• predictive biomarkers
• tumor mutational burden
• vaccines

• chimeric antigen receptor-T cell
• gastric cancer
• immune checkpoint inhibitors
• immunotherapy
• tumor vaccine

Gastric cancer (GC) is frequently diagnosed and treated in advanced tumour stages with poor prognosis. Recent studies have identified isoform 2 of the tight junction protein claudin-18 (CLDN18.2) as a promising target in GC therapy. In this study, we aimed to outline the expression of CLDN18.2 and its correlation with clinico-pathological patient characteristics in a large and well-characterized cohort of GC patients. The expression of CLDN18.2 was studied in 481 GCs by immunohistochemistry on whole tissue sections. Immunostained GCs were evaluated using the histoscore (H-score) and subsequently divided into two groups: tumours showing any or no expression. CLDN18.2 expression was investigated for correlation with various clinico-pathological patient characteristics, including survival. CLDN18.2 expression was found in 203 GCs (42.2%). Of these tumours, 71 (14.8%) showed solely weak immunostaining. CLDN18.2 expression correlated with mucin phenotype, EBV status, the integrin αvβ5, the EpCAM extracellular domain EpEX, and lysozyme. We found no correlation with survival, Laurén phenotype, or any other clinico-pathological patient characteristic. In conclusion, we demonstrate frequently decreased expression of CLDN18.2 in a GC cohort of appropriate size. Correlating CLDN18.2 expression with clinico-pathological patient characteristics reveals new linkages to αvβ5, EpEX, and lysozyme, which may pave the way for further investigations regarding the role of tight junction proteins in GC progression. Though CLDN18.2 continues to pose an attractive target candidate, we conclude that a rather low overall expression rate challenges its significance in advanced GC therapy and indicates the need for further investigations across different populations.

• Claudin-18.2
• EBV
• Gastric cancer
• Prognosis
• Stomach neoplasms
• Tight junctions

• CD326
• Extramammary Paget's disease
• circulating tumor cell
• distant metastasis
• epithelial cell adhesion molecule
• immunohistochemistry

• Adenoid cystic carcinoma
• Ber-EP4
• EpCAM
• biomarker
• non-salivary gland

• Cytoreductive surgery
• Gastric cancer
• Heated intraperitoneal chemotherapy
• Neoadjuvant intraperitoneal and systemic chemotherapy
• Peritoneal carcinomatosis
• Peritoneal carcinomatosis index

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Folate Receptor 1/immunology
• Humans
• Immunotherapy, Adoptive/methods
• Jurkat Cells
• K562 Cells
• Mice
• Receptors, Antigen, T-Cell/immunology
• Receptors, Chimeric Antigen/immunology
• Recombinant Fusion Proteins/immunology
• Stomach Neoplasms/immunology
• Stomach Neoplasms/therapy
• T-Lymphocytes/immunology
• T-Lymphocytes/transplantation
• Xenograft Model Antitumor Assays

• National Research Foundation of Korea

Cancer stem cells (CSCs) are thought as the source of tumor maintaining and many CSCs markers have been identified. Regarding the heterogeneity in gastric cancer (GC), TNM stage is not enough to accurately predict the prognosis. The aim of this study was to investigate the clinical significance of CSCs markers (Lgr5, Oct4, CD133, EpCAM, CD54 and Sox2) and establish a new model based on these markers to accurately predict prognosis of GC. We retrospectively enrolled 377 GC tissues from January 2006 to October 2012 to perform immunohistochemistry (IHC), and 93 pairs of GC tissues and corresponding adjacent normal gastric tissues to perform quantitative PCR (qPCR) from December 2011 to October 2012. The clinicopathological and follow-up characteristics were collected. In IHC, Oct4, CD133 and EpCAM were independently related to tumor progression, while Sox2 were associated with well or moderate differentiation (all p<0.05). Cox regression showed that Oct4-EpCAM was an independently prognostic factor, indicating that double low expression of Oct4-EpCAM group had significantly better prognosis than control group (p=0.035). Regarding qPCR, CD133 was an independent prognostic factor, showing that the prognosis of patients with CD133 high expression was significantly worse than that of patients with CD133 low expression (p<0.001). The prognostic prediction accuracy of nomogram based on Oct4-EpCAM expression in IHC was significantly better than TNM stage alone (p=0.003). Low expressions of Oct4-EpCAM in IHC and CD133 in qPCR were favorable prognostic factors in GC. The nomogram based on Oct4-EpCAM was valuable in prognostic prediction of GC patients.

• cancer stem cells
• gastric cancer
• markers
• nomogram
• prognosis

Epithelial cell adhesion molecule (EpCAM) is known to be highly expressed in a variety of epithelial carcinomas, and it is involved in cell adhesion and proliferation. However, its expression profile and biological function in nasopharyngeal carcinoma (NPC) remains unclear. In this study, higher expression of EpCAM was found in NPC samples compared with non-cancer nasopharyngeal mucosa by qRT-PCR. Additionally, immunohistochemistry (IHC) analysis of NPC specimens from 64 cases showed that high EpCAM expression was associated with metastasis and shorter survival. Multivariate survival analysis identified high EpCAM expression as an independent prognostic factor. Ectopic EpCAM expression in NPC cells promoted epithelial-mesenchymal transition (EMT), induced a cancer stem cell (CSC)-like phenotype, and enhanced metastasis in vitro and in vivo without an effect on cell proliferation. Notably, EpCAM overexpression reduced PTEN expression and increased the level of AKT, mTOR, p70S6K and 4EBP1 phosphorylation. Correspondingly, an AKT inhibitor and rapamycin blocked the effect of EpCAM on NPC cell invasion and stem-like phenotypes, and siRNA targeting PTEN rescued the oncogenic activities in EpCAM knockdown NPC cells. Our data demonstrate that EpCAM regulates EMT, stemness and metastasis of NPC cells via the PTEN/AKT/mTOR pathway.

Brain cytoplasmic RNA 1 (BCYRN1), along non-coding RNA, plays a critical role in various diseases, including some cancers. However, the expression of BCYRN1 and its roles in gastric carcinoma (GC) still remain unidentified. Thus, this study employed RT-qPCR to detect expression of BCYRN1 in 85 paired GC samples and adjacent normal tissues, and performed in vitro studies to explore effects of BCYRN1 in GC cells on cell proliferation, apoptosis and migration. We found BCYRN1 was significantly upregulated in GC samples, and its expression was positively correlated with advanced TNM stage (p = 0.0012) and tumor size (p = 0.027). Functionally, BCYRN1 knockdown by siRNA could inhibit cell proliferation, induce G1/G0 cell cycle arrest, increase apoptosis and impair migratory ability of AGS cells. Moreover, the results of RT-qPCR and western blotting indicated that knockdown of BCYRN1 notably decreased the expression of epithelial cell adhesion molecules (EpCAM). Otherwise, overexpression of BCYRN1 in GC cells (BGC-823 and SGC-7901) could reverse the effects of BCYRN1 knockdown. Taken together, our data indicate for the first time that BCYRN1 acts as an oncogenic lncRNA in GC progression and may be a potential therapeutic target in GC.

• BCYRN1
• EpCAM
• gastric carcinoma
• lncRNA
• tumor progression

Long non-coding RNAs (lncRNAs) are involved in kinds of human diseases, including colorectal cancer (CRC). TINCR, a 3.7 kb long non coding RNA, was associated with cell differentiation in keratinocyte and gastric cancer cells. However, little is known about the role of TINCR in regulation CRC progression. Here, we showed that lncRNA TINCR was associated with CRC proliferation and metastasis. TINCR was statistically downregulated in CRC tissues and metastatic CRC cell lines compared with their counterparts. TINCR was reversely correlated with CRC progression and promoted tumor cells growth, metastasis in vivo and in vitro. While overexpression of TINCR had opposite effect. In addition, we also found that TINCR specifically bound to EpCAM through RNA IP and RNA pull down assays. Loss of TINCR promoted hydrolysis of EpCAM and then released EpICD, subsequently, activated the Wnt/β-catenin pathway. Further studies shown that c-Myc repressed the expression of TINCR through repressing sp1 transcriptive activity, which established a positive feedback loop controlling c-Myc and TINCR expression. These findings elucidate that loss of TINCR expression promotes proliferation and metastasis in CRC and it could be considered as a potential cancer suppressor gene.

• EpCAM
• TINCR
• c-Myc
• colorectal cancer
• sp1

• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/genetics
• Epithelial Cell Adhesion Molecule/analysis
• Epithelial Cell Adhesion Molecule/genetics
• Gastric Mucosa/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphatic Metastasis/diagnosis
• Lymphatic Metastasis/genetics
• Lymphatic Metastasis/pathology
• Prognosis
• Stomach/pathology
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Up-Regulation

• Natural Science Foundation of Anhui Province
• Anhui Provincial science and technology key projects

Previous study showed that expression of epithelial cell adhesion molecule (EpCAM) was significantly upregulated in porcine induced pluripotent stem cells (piPSCs). However, the regulatory mechanism and the downstream target genes of EpCAM were not well investigated. In this study, we found that EpCAM was undetectable in fibroblasts, but highly expressed in piPSCs. Promoter of EpCAM was upregulated by zygotic activated factors LIN28, and ESRRB, but repressed by maternal factors OCT4 and SOX2. Knocking down EpCAM by shRNA significantly reduced the pluripotent gene expression. Conversely, overexpression of EpCAM significantly increased the number of alkaline phosphatase positive colonies and elevated the expression of endogenous pluripotent genes. As a key surface-to-nucleus factor, EpCAM releases its intercellular domain (EpICD) by a two-step proteolytic processing sequentially. Blocking the proteolytic processing by inhibitors TAPI-1 and DAPT could reduce the intracellular level of EpICD and lower expressions of OCT4, SOX2, LIN28, and ESRRB. We noticed that increasing intracellular EpICD only was unable to improve activity of EpCAM targeted genes, but by blocking GSK-3 signaling and stabilizing beta-catenin signaling, EpICD could then significantly stimulate the promoter activity. These results showed that EpCAM intracellular domain required beta-catenin signaling to enhance porcine cell reprogramming.

• Gastric cancer
• Gastrointestinal tract
• Inflammatory fibroid polyp
• Intraepithelial neoplasia
• Neuroendocrine neoplasia
• WHO classification

The chimeric antigen receptor (CAR) is a genetically engineered receptor that combines a scFv domain, which specifically recognizes the tumor-specific antigen, with T cell activation domains. CAR-T cell therapies have demonstrated tremendous efficacy against hematologic malignancies in many clinical trials. Recent studies have extended these efforts to the treatment of solid tumors. However, the outcomes of CAR-T cell therapy for solid tumors are not as remarkable as the outcomes have been for hematologic malignancies. A series of hurdles has arisen with respect to CAR-T cell-based immunotherapy, which needs to be overcome to target solid tumors. The major challenge for CAR-T cell therapy in solid tumors is the selection of the appropriate specific antigen to demarcate the tumor from normal tissue. In this review, we discuss the application of CAR-T cells to gastrointestinal and hepatic carcinomas in preclinical and clinical research. Furthermore, we analyze the usefulness of several specific markers in the study of gastrointestinal tumors and hepatic carcinoma.

• CAR-T cell; Chimeric antigen receptor (CAR)
• gastrointestinal cancer
• hepatic carcinoma
• immunotherapy

• High-fat diet
• Leptin
• Obesity
• Stemness
• Stomach
• β-catenin

• Adenoid cystic carcinoma
• EpCAM
• Mucoepidermoid carcinoma
• Pleomorphic adenomas
• Polymorphous low-grade adenocarcinoma

Epithelial stem cells of gastrointestinal tissues are characterized and controlled by an active Wnt signaling. Recently, the Wnt target gene Troy has been proposed as a neoplastic marker in the murine intestine. In this study, we explored the putative tumor biological significance of Troy in humans by using immunohistochemistry (104 cases), quantitative RT-PCR (50 cases) and cell culture experiments (MKN45, MKN74). In the non-neoplastic gastric mucosa, Troy was expressed by Muc5AC-positive foveolar epithelium, parietal cells, chief cells and cells of the intestinal metaplasia. In gastric cancer, Troy was found in the desmoplastic stroma and tumor cells. The overall staining intensity of the tumor cells was lower compared with the adjacent non-neoplastic mucosa, Troy was found significantly more commonly in intestinal compared with diffuse type gastric cancer (p=0.001) and correlated inversely with tumor grade (p<0.001) and nodal spread (p=0.025). In the intestinal type, loss of Troy-expression was associated with a significantly worse overall survival (p=0.006). Subsequent cell culture experiments showed a Wnt dependent expression of Troy and a reduced colony formation ability of Troy-overexpressing MKN45-cells. Our results lead to the conjecture that Troy is also a negative regulator of WNT signaling in gastric cancer, which affects patient outcome.

• Tnfrsf19 (Troy)
• Wnt signaling
• differentiation
• gastric cancer
• stomach

Identification of patients with oral dysplasia at high risk of cancer development and oral squamous cell carcinoma (OSCC) at increased risk of disease recurrence will enable rigorous personalized treatment. Regulated intramembranous proteolysis of Epithelial cell adhesion molecule (EpCAM) resulting in release of its intracellular domain Ep-ICD into cytoplasm and nucleus triggers oncogenic signaling. We analyzed the expression of Ep-ICD in oral dysplasia and cancer and determined its clinical significance in disease progression and prognosis.

In a retrospective study, immunohistochemical analysis of nuclear and cytoplasmic Ep-ICD and EpEx (extracellular domain of EpCAM), was carried out in 115 OSCC, 97 oral dysplasia and 105 normal oral tissues, correlated with clinicopathological parameters and disease outcome over 60 months for oral dysplasia and OSCC patients. Disease-free survival (DFS) was determined by Kaplan-Meier method and multivariate Cox regression analysis.

In comparison with normal oral tissues, significant increase in nuclear Ep-ICD and membrane EpEx was observed in dysplasia, and OSCC (p = 0.013 and < 0.001 respectively). Oral dysplasia patients with increased overall Ep-ICD developed cancer in short time period (mean = 47 months; p = 0.044). OSCC patients with increased nuclear Ep-ICD and membrane EpEx had significantly reduced mean DFS of 33.7 months (p = 0.018).

Our study provided clinical evidence for Ep-ICD as a predictor of cancer development in patients with oral dysplasia and recurrence in OSCC patients, suggesting its potential utility in enhanced management of those patients detected to have increased risk of progression to cancer and recurrence in OSCC patients.

• Dysplasia
• Ep-ICD
• EpCAM
• Oral cancer
• Oral lesion
• Prognosis
• Squamous cell carcinoma

• Colon cancer
• biomarkers
• epcam

AIM: To obtain an accurate evaluation of the association between high expression of epithelial cellular adhesion molecule (EpCAM) and gastric cancer (GC) risk.

METHODS: Studies that had examined the association between high expression of EpCAM and GC risk were identified by searching electronic databases PubMed, EMBASE, Cochrane library and Chinese Biomedical Literature database. Risk ratios (RRs) together with their 95%CIs were used to assess the association between high expression of EpCAM and GC risk. We selected eligible studies based on inclusion criteria. RevMan 5.3 software was used to calculate the pooled values.

RESULTS: A total of 14 studies were included in this meta-analysis. EpCAM-positive cases were significantly associated with tumor size (RR: 1.68, 95%CI: 1.47-1.91, P < 0.00001 fixed-effect), depth of invasion (RR: 1.37, 95%CI: 1.11-1.68, P = 0.003 random-effect), TNM stage (RR: 2.02, 95%CI: 1.35-3.02, P = 0.0007 random-effect), tumor location (RR: 0.80, 95%CI: 0.71-0.91, P = 0.0007 fixed-effect), histologic differentiation (RR: 1.23, 95%CI: 1.13-1.33, P < 0.00001 fixed-effect) and lymph node metastasis (RR: 1.89, 95%CI: 1.28-2.80, P = 0.001 random-effect). However, we did not observe any significant association between the presence of EpCAM with age, gender, distant metastasis, Borrmann type or Lauren classification. Additionally, EpCAM expression was not associated with the overall survival rate. The pooled HR of the overall effect was 1.39 (95%CI: 0.30-6.48, P = 0.67 random-effect).

CONCLUSION: Our meta-analysis indicates that EpCAM contributes to GC risk, which acts as a prognostic factor and a marker of poor outcome.

• Epithelial cellular adhesion molecule
• Gastric cancer
• Prognosis
• Progression
• Meta-analysis

• EpCAM
• bladder cancer
• cadherin
• catenin
• cell adhesion
• stem cells

• Catumaxomab
• EpCAM
• Ovarian cancer
• Polymorphism
• SNP
• TACSTD1

• Ep-CAM
• colorectal cancer
• epidermal growth factor
• vector construction

• Adenocarcinoma/metabolism
• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/metabolism
• Cell Adhesion Molecules/genetics
• Cell Adhesion Molecules/metabolism
• Cell Nucleus/metabolism
• Epithelial Cell Adhesion Molecule
• Humans
• Male
• Neoplasm Recurrence, Local/metabolism
• Prognosis
• Prostate/metabolism
• Prostate/pathology
• Prostatic Neoplasms/metabolism
• Protein Structure, Tertiary/physiology

• Canadian Institutes of Health Research

• ADAM 17
• EGFR
• HB-EGF
• Helicobacter pylori
• Phosphorylation
• TNF-α

Breast cancer stem cells (BCSCs) are the minor population of breast cancer (BC) cells that exhibit several phenotypes such as migration, invasion, self-renewal, and chemotherapy as well as radiotherapy resistance. Recently, BCSCs have been more considerable due to their capacity for recurrence of tumors after treatment. Recognition of signaling pathways and molecular mechanisms involved in stemness phenotypes of BCSCs could be effective for discovering novel treatment strategies to target BCSCs. This review introduces BCSC markers, their roles in stemness phenotypes, and the dysregulated signaling pathways involved in BCSCs such as mitogen-activated protein (MAP) kinase, PI3K/Akt/nuclear factor kappa B (NFκB), TGF-β, hedgehog (Hh), Notch, Wnt/β-catenin, and Hippo pathway. In addition, this review presents recently discovered molecular mechanisms implicated in chemotherapy and radiotherapy resistance, migration, metastasis, and angiogenesis of BCSCs. Finally, we reviewed the role of microRNAs (miRNAs) in BCSCs as well as several other therapeutic strategies such as herbal medicine, biological agents, anti-inflammatory drugs, monoclonal antibodies, nanoparticles, and microRNAs, which have been more considerable in the last decades.