Gene Summary

Gene:EPCAM; epithelial cell adhesion molecule
Aliases: ESA, KSA, M4S1, MK-1, DIAR5, EGP-2, EGP40, KS1/4, MIC18, TROP1, EGP314, HNPCC8, TACSTD1
Summary:This gene encodes a carcinoma-associated antigen and is a member of a family that includes at least two type I membrane proteins. This antigen is expressed on most normal epithelial cells and gastrointestinal carcinomas and functions as a homotypic calcium-independent cell adhesion molecule. The antigen is being used as a target for immunotherapy treatment of human carcinomas. Mutations in this gene result in congenital tufting enteropathy. [provided by RefSeq, Dec 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:epithelial cell adhesion molecule
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: EPCAM (cancer-related)

Cao C, Wang Q, Li Q, et al.
Development and Preliminary Clinical Application of Circulating Tumor Cell Detection System for Prostate Cancer.
J Biomed Nanotechnol. 2019; 15(3):612-620 [PubMed] Related Publications
Real-time detection of circulating tumor cell (CTC) markers that are constantly changing and renewing during disease progression is of great significance for the timely regimen switch or individualized target therapy. The abnormally expressed special AT-rich sequence binding protein 1 (SATB1), a nuclear matrix attachment region binding protein, in various tumors, promotes the growth and metastasis of tumor cells by regulating gene expression. In this paper, a CTC detection system for prostate cancer (PCa) was developed on the basis of epithelial cell adhesion molecule (EpCAM)-targeted immunomagnetic separation and CK-FITC and SATB-1-APC immunofluorescence assay, and the recovery rate of tumor cells in PBS and simulated whole blood by this system was detected. Subsequently, we isolated, identified, and counted SATB-1 ositive CTCs in the peripheral blood and urine samples of 60 tumor-bearing nude mice, 5 healthy volunteers and 13 PCa patients. Combined with the clinicopathological factors, the clinical value of the system was analyzed, and the possibility of SATB-1-positive CTCs in the diagnosis of PCa was evaluated. The results showed that the CTC sorting and identification system for prostate cancer constructed in this study had a recovery rate of more than 85% for CTC in PBS, urine and blood simulation samples. The expression level of SATB-1 was different in different PCa cell lines, which was relatively high in the highly invasive PCa DU-145 cell line. The expression of SATB-1 in CTCs in the blood samples of PCa patients with different clinical characteristics and in the urine samples of a few PCa patients with bone metastases were different, and the detection sensitivity of peripheral blood was higher than that of urine. This study has important clinical reference value for the early diagnosis of PCa and the evaluation of bone metastasis based on the CTC counting and the SATB-1 expression in CTCs.

Cao H, Chu X, Wang Z, et al.
High FOXK1 expression correlates with poor outcomes in hepatocellular carcinoma and regulates stemness of hepatocellular carcinoma cells.
Life Sci. 2019; 228:128-134 [PubMed] Related Publications
AIMS: Forkhead box (FOX) proteins constitute a huge family of transcriptional regulators, which are involved in a wide range of cancers. FOXK1 is a little studied member of FOXK subfamily. This study aimed to investigate the potential prognostic value of FOXK1 in human hepatocellular carcinoma (HCC) and explore potential underlying mechanisms.
MAIN METHODS: We performed bioinformatic analyses to evaluate the prognostic value of FOXK1 expression in human HCC and to reveal the underlying mechanism by which FOXK1 regulates HCC. RT-PCR, FACS analysis and sphere formation assay were carried out to investigate the role of FOXK1 in regulating liver cancer stem cells.
KEY FINDINGS: Our results demonstrated that FOXK1 was overexpressed in human HCC and positively correlated with cancer progression. DNA hypomethylation and gene copy number variation contributed to the overexpression of FOXK1. Importantly, high FOXK1 expression was associated with both low overall survival probability (OS) and low relapse free survival probability (RFS) of HCC patients. Intriguingly, we found that high FOXK1 expression was correlated with activation of stem cell-regulating pathways in human HCC. Knockdown of FOXK1 resulted in downregulation of the cancer stem cell marker EpCAM and ALDH1 and decreased sphere-forming ability of hepatocellular carcinoma cells.
SIGNIFICANCE: Overall, our study identified FOXK1 as a new biomarker for prognosis of HCC patients and revealed its role in regulating stemness of hepatocellular carcinoma cells.

Cini G, Quaia M, Canzonieri V, et al.
Toward a better definition of EPCAM deletions in Lynch Syndrome: Report of new variants in Italy and the associated molecular phenotype.
Mol Genet Genomic Med. 2019; 7(5):e587 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Inherited epimutations of Mismatch Repair (MMR) genes are responsible for Lynch Syndrome (LS) in a small, but well defined, subset of patients. Methylation of the MSH2 promoter consequent to the deletion of the upstream EPCAM gene is found in about 1%-3% of the LS patients and represents a classical secondary, constitutional and tissue-specific epimutation. Several different EPCAM deletions have been reported worldwide, for the most part representing private variants caused by an Alu-mediated recombination.
METHODS: 712 patients with suspected LS were tested for MMR mutation in our Institute. EPCAM deletions were detected by multiplex ligation-dependent probe amplification (MLPA) and then defined by Long-Range polymerase chain reaction (PCR)/Sanger sequencing. A comprehensive molecular characterization of colorectal cancer (CRC) tissues was carried out by immunohistochemistry of MMR proteins, Microsatellite Instability (MSI) assay, methylation specific MLPA and transcript analyses. In addition, somatic deletions and/or variants were investigated by MLPA and next generation sequencing (NGS).
RESULTS: An EPCAM deletion was found in five unrelated probands in Italy: variants c.556-490_*8438del and c.858+1193_*5826del are novel; c.859-1430_*2033del and c.859-670_*530del were previously reported. All probands were affected by CRC at young age; tumors showed MSI and abnormal MSH2/MSH6 proteins expression. MSH2 promoter methylation, as well as aberrant in-frame or out-of-frame EPCAM/MSH2 fusion transcripts, were detected in CRCs and normal mucosae.
CONCLUSION: An EPCAM deletion was the causative variant in about 2% of our institutional series of 224 LS patients, consistent with previously estimated frequencies. Early age and multiple CRCs was the main clinical feature of this subset of patients.

Ahmed A
Prevalence of Her3 in gastric cancer and its association with molecular prognostic markers: a Saudi cohort based study.
Libyan J Med. 2019; 14(1):1574532 [PubMed] Free Access to Full Article Related Publications
Her 3 is a member of epidermal growth factor receptors. Mutated, oncogenic Her3 is reported in gastric and colonic cancers with emerging evidence that Her3 can be a potential target for molecular therapies. There is a paucity of studies regarding Her3 and its prognostic implications in gastric cancer in our region. In this study, we evaluated prevalence of Her3 in gastric cancer, in a Saudi cohort of cases, along with its association with prognostic markers p53 and Ki-67. The study was conducted in Department of Pathology of King Fahd Hospital of Imam Abdulrahman Bin Faisal University, Dammam, KSA. Fifty cases of gastric carcinoma were selected from the pathology files that fulfilled the inclusion criteria. Clinico-pathological parameters, Laurens histological classification, and immunohistochemical staining for Her3, p53, and Ki-67 were done. Her 3 positive cases were also evaluated for Her-2neu co-expression. Her3 positivity was seen in 16% (n = 8) out of a total of 50 cases. The median age of presentation was 44 years. Within Her3 positive cases, a female preponderance of 63% (n = 5), presence of high grade tumors in 75% (n = 6), diffuse gastric carcinoma in 63% (n = 5), diffuse to focal p53 positivity in 63% (n = 5), and a high to moderate Ki-67 proliferation index in 75% (n = 6) of cases was seen. Her3 expression was independent of Her-2neu status. Her3 prevalence of 16% with a median age of 44 years at presentation was less than in other reported studies, highlighting the concept of ethnic and regional variation in tumor characteristics. Her3 association with diffuse gastric carcinoma, high grade tumors, diffuse to focal p53 positivity and high to moderate Ki-67 proliferation index points towards a more aggressive clinical behavior.

Dong J, Zhang RY, Sun N, et al.
Bio-Inspired NanoVilli Chips for Enhanced Capture of Tumor-Derived Extracellular Vesicles: Toward Non-Invasive Detection of Gene Alterations in Non-Small Cell Lung Cancer.
ACS Appl Mater Interfaces. 2019; 11(15):13973-13983 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
Tumor-derived extracellular vesicles (EVs) present in bodily fluids are emerging liquid biopsy markers for non-invasive cancer diagnosis and treatment monitoring. Because the majority of EVs in circulation are not of tumor origin, it is critical to develop new platforms capable of enriching tumor-derived EVs from the blood. Herein, we introduce a biostructure-inspired NanoVilli Chip, capable of highly efficient and reproducible immunoaffinity capture of tumor-derived EVs from blood plasma samples. Anti-EpCAM-grafted silicon nanowire arrays were engineered to mimic the distinctive structures of intestinal microvilli, dramatically increasing surface area and enhancing tumor-derived EV capture. RNA in the captured EVs can be recovered for downstream molecular analyses by reverse transcription Droplet Digital PCR. We demonstrate that this assay can be applied to monitor the dynamic changes of ROS1 rearrangements and epidermal growth factor receptor T790M mutations that predict treatment responses and disease progression in non-small cell lung cancer patients.

Lian S, Xie R, Ye Y, et al.
Simultaneous blocking of CD47 and PD-L1 increases innate and adaptive cancer immune responses and cytokine release.
EBioMedicine. 2019; 42:281-295 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
BACKGROUND: Treatment multiple tumors by immune therapy can be achieved by mobilizing both innate and adaptive immunity. The programmed death ligand 1 (PD-L1; or CD274, B7-H1) is a critical "don't find me" signal to the adaptive immune system. Equally CD47 is a critical "don't eat me" signal to the innate immune system and a regulator of the adaptive immune response.
METHOD: Both of CD47 and PD-L1 are overexpressed on the surface of cancer cells to enable to escape immune-surveillance. We designed EpCAM (epithelial cell adhesion molecule)-targeted cationic liposome (LPP-P4-Ep) containing si-CD47 and si-PD-L1 could target high-EpCAM cancer cells and knockdown both CD47 and PD-L1 proteins.
FINDINGS: Efficient silencing of CD47 and PD-L1 versus single gene silencing in vivo by systemic administration of LPP-P4-Ep could significantly inhibited the growth of solid tumors in subcutaneous and reduced lung metastasis in lung metastasis model. Target delivery of the complexes LPP-P4-Ep increased anti-tumor T cell and NK cell response, and release various cytokines including IFN-γ and IL-6 in vivo and in vitro.
INTERPRETATION: This multi-nanoparticles showed significantly high-EpCAM tumor targeting and lower toxicity, and enhanced immune therapeutic efficacy. Our data indicated that dual-blockade tumor cell-specific innate and adaptive checkpoints represents an improved strategy for tumor immunotherapy. FUND: This research supported by the Ministry of Science and Technology of the People's Republic of China (grant number 2015CB931804); the National Natural Science Foundation of China (NSFC, grant numbers 81703555, U1505225 and 81773063), and the China Postdoctoral Science Foundation (grant number 2017 M620268).

Bekes I, Löb S, Holzheu I, et al.
Nectin-2 in ovarian cancer: How is it expressed and what might be its functional role?
Cancer Sci. 2019; 110(6):1872-1882 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
Nectin-2 is an adhesion molecule that has been reported to play a role in tumor growth, metastasis and tumor angiogenesis. Herein, we investigated Nectin-2 in ovarian cancer patients and in cell culture. Tumor as well as peritoneal biopsies of 60 ovarian cancer patients and 22 controls were dual stained for Nectin-2 and CD31 using immunohistochemistry. Gene expression of Nectin-2 was quantified by real-time PCR and differences analyzed in relation to various tumor characteristics. In the serum of patients, vascular endothelial growth factor (VEGF) was quantified by ELISA. Effect of VEGF on Nectin-2 expression as well as permeability was investigated in HUVEC. In tumor biopsies, Nectin-2 protein was mainly localized in tumor cells, whereas in peritoneal biopsies, clear colocalization was found in the vasculature. T3 patients had a significantly higher percentage of positive lymph nodes and this correlated with survival. Nectin-2 was significantly upregulated in tumor biopsies in patients with lymph node metastasis and with residual tumor >1 cm after surgery. Nectin-2 expression was significantly suppressed in the peritoneal endothelium of patients associated with significantly increased VEGF serum levels. In cell culture, VEGF stimulation led to a significant downregulation of Nectin-2 which was reversed by VEGF-inhibition. In addition, Nectin-2 knockdown in endothelial cells was associated with significantly increased endothelial permeability. Nectin-2 expression in ovarian cancer may support tumor cell adhesion, leading to growth and lymph node metastasis. In addition, VEGF-induced Nectin-2 suppression in peritoneal endothelium may support an increase in vascular permeability leading to ascites production.

Kapka-Skrzypczak L, Popek S, Sawicki K, et al.
IL‑6 prevents CXCL8‑induced stimulation of EpCAM expression in ovarian cancer cells.
Mol Med Rep. 2019; 19(3):2317-2322 [PubMed] Related Publications
Epithelial cell adhesion molecule (EpCAM), which is expressed in the majority of epithelial tissues, exhibits tumor growth promoting abilities and is overexpressed in human epithelial ovarian cancer. Therefore, EpCAM is considered to be a promising target for specific immune‑based therapies. The present study evaluated the role of IL‑6 and IL‑8 in the expression of EpCAM in the A2780 human ovarian cancer cell line. Furthermore, the cellular localization of the EpCAM protein in A2780 cells was determined and the effect of EpCAM inhibition on the proliferation of the A2780 cells was investigated. An MTT assay demonstrated that blocking EpCAM with anti‑EPCAM antibodies had no effect on cellular metabolic activity (proliferation). Gene expression analysis revealed that IL‑8 increased EpCAM expression, whereas IL‑6 and the combination of IL‑6/IL‑8 had no effect on EpCAM expression. Immunofluorescence analysis confirmed that EpCAM is expressed on A2780 cell membranes. The present results demonstrated that IL‑8 increased EpCAM expression at the mRNA level in ovarian cancer cells and suggested a potential role of IL‑6 as an inhibitor of IL‑8‑stimulated EpCAM expression.

Qiu J, Du Z, Wang Y, et al.
Weighted gene co-expression network analysis reveals modules and hub genes associated with the development of breast cancer.
Medicine (Baltimore). 2019; 98(6):e14345 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
This study aimed to identify modules associated with breast cancer (BC) development by constructing a gene co-expression network, and mining hub genes that may serve as markers of invasive breast cancer (IBC).We downloaded 2 gene expression datasets from the Gene Expression Omnibus (GEO) database, and used weighted gene co-expression network analysis (WGCNA) to dynamically study the changes of co-expression genes in normal breast tissues, ductal carcinoma in situ (DCIS) tissues, and IBC tissues. Modules that highly correlated with BC development were carried out functional enrichment analysis for annotation, visualization, and integration discovery. The hub genes detected by WGCNA were also confirmed using the Oncomine dataset.We detected 17 transcriptional modules in total and 4 - namely tan, greenyellow, turquoise, and brown - were highly correlated with BC development. The functions of these 4 modules mainly concerned cell migration (tan module, P = 3.03 × 10), the cell cycle (greenyellow module, P = 3.08 × 10), cell-cell adhesion (turquoise module, P = .002), and the extracellular exosome (brown module, P = 1.38 × 10). WGCNA also mined the hub genes, which were highly correlated with the genes in the same module and with BC development. The Oncomine database confirmed that the expressions levels of 6 hub genes were significantly higher in BC tissues than in normal tissues, with fold changes larger than 2 (all P < .05). Apart from the 2 well-known genes EPCAM and MELK, during the development of BC, KRT8, KRT19, KPNA2, and ECT2 also play key roles, and may be used as new targets for the detection or treatment of BC.In summary, our study demonstrated that hub genes such as EPCAM and MELK are highly correlated with breast cancer development. However, KRT8, KRT19, KPNA2, and ECT2 may also have potential as diagnostic and prognostic biomarkers of IBC.

Rask L, Høgdall CK, Kjaer SK, et al.
Association of CD31 and p53 With Survival of Ovarian Cancer Patients.
Anticancer Res. 2019; 39(2):567-576 [PubMed] Related Publications
BACKGROUND/AIM: New markers for ovarian cancer are needed. This study aimed to examine the expression of tumour cell p53 and endothelial cell CD31 proteins and correlate them to clinicopathological factors.
PATIENTS AND METHODS: Expression of proteins was immunohistochemically assessed using tissue sections from 585-599 ovarian cancer patients from the Danish MALOVA study.
RESULTS: High CD31 expression was found in poorly differentiated tumours (p=0.0006), and high p53 expression was found in poorly differentiated cancers (p<0.0001), high clinical stage (p<0.0001), non-radical surgery (p<0.0001) and high serum CA-125 values (p<0.0001). CD31 expression showed no prognostic survival value, but high hazard ratios were found for patients with high p53 expression (HR=2.313, p<0.0001). An interaction was found between p53 and stage of cancer, suggesting a prognostic impact of p53 in low-stage, but not in advanced-stage cancer.
CONCLUSION: More than 5% of p53 tissue expression may predict shorter survival of ovarian cancer patients and may be useful for predicting the risk of disease progression in low-stage patients following primary surgery. CD31 has no strong prognostic value.

Zhao XH, Wang ZR, Chen CL, et al.
Molecular detection of epithelial-mesenchymal transition markers in circulating tumor cells from pancreatic cancer patients: Potential role in clinical practice.
World J Gastroenterol. 2019; 25(1):138-150 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
AIM: To evaluate the clinical properties of three subpopulations of circulating tumor cells (CTCs) undergoing epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) patients.
METHODS: We identified CTCs for expression of the epithelial cell marker cytokeratin or epithelial cell adhesion molecule (EpCAM) (E-CTC), the mesenchymal cell markers vimentin and twist (M-CTC), or both (E/M-CTC) using the CanPatrol system. Between July 2014 and July 2016, 107 patients with PDAC were enrolled for CTC evaluation. CTC enumeration and classification were correlated with patient clinicopathological features and outcomes.
RESULTS: CTCs were detected in 78.5% of PDAC patients. The number of total CTCs ranged from 0 to 26 across all 107 patients, with a median value of six. CTC status correlated with lymph node metastasis, TNM stage, distant metastasis, blood lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR). Kaplan-Meier survival analysis showed that patients with ≥ 6 total CTCs had significantly decreased overall survival and progression-free survival compared with patients with < 6 total CTCs. The presence of M-CTCs was positively correlated with TNM stage (
CONCLUSION: Classifying CTCs by EMT markers helps to identify the more aggressive CTC subpopulations and provides useful evidence for determining a suitable clinical approach.

Bagheri V, Abbaszadegan MR, Memar B, et al.
Induction of T cell-mediated immune response by dendritic cells pulsed with mRNA of sphere-forming cells isolated from patients with gastric cancer.
Life Sci. 2019; 219:136-143 [PubMed] Related Publications
Gastric cancer (GC) as the third most common cause of cancer-associated mortality worldwide is one of the cancers with very high heterogeneity. Cancer stem cells (CSCs) as a small subset of cancer cells in solid tumors with the self-renewal, differentiation and tumorigenic ability are responsible for tumor initiation, progression, recurrence, metastasis, and resistance to current treatments. Therefore, eradication of CSCs is very vital to cure cancer. Here, we first isolated and identified sphere-forming cells in tumor tissue from four GC patients and then analyzed T cell responses induced by monocyte-derived dendritic cells (DCs) loaded with total mRNA of sphere-forming cells in terms of interferon-gamma (IFN-γ) gene expression and specific cytotoxicity. Spheroid colonies were formed in serum-free media. Sphere-forming cells dissociated from tumorspheres heterogeneously expressed CD44, CD54, and epithelial cell adhesion molecule (EpCAM) markers and generated one tumor in nude mice. These results demonstrated that gastric CSCs were enriched in tumorspheres. Cytokine-matured DCs loaded with mRNA of sphere-forming cells were able to induce IFN-γ gene expression in T-lymphocytes after a 12-day co-culture. mRNA level of IFN-γ gene in these lymphocytes was more highly expressed compared to stimulated T-lymphocytes by DCs transfected with normal tissue (6.4-9.39 folds). Cytotoxic activity of primed T-lymphocytes with antigens of sphere-forming cells was significantly higher than normal tissue antigens and mock DCs (P ≤ 0.0001). Taken together, DCs loaded with mRNA of sphere-forming cells that elicit effectively specific T cell-mediated immune responses in vitro, may be considered as a promising therapeutic vaccination in GC patients in future.

Martins-Filho SN, Alves VAF, Wakamatsu A, et al.
A phenotypical map of disseminated hepatocellular carcinoma suggests clonal constraints in metastatic sites.
Histopathology. 2019; 74(5):718-730 [PubMed] Related Publications
AIMS: Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterisation of molecular drivers of HCC dissemination, particularly in relation to distant metastases. Biomarker assessment is restricted to early stages, and paired primary-metastatic comparisons between samples from the same patient are difficult.
METHODS AND RESULTS: We report the evaluation of 88 patients with HCC who underwent autopsy, including multiregional sampling of primary and metastatic sites totalling 230 nodules analysed. The study included morphological assessment, immunohistochemistry and mutation status of the TERT promoter, the most frequently mutated gene in HCC. We confirm a strong predilection of HCC for lung dissemination, including subclinical micrometastases (unrecognised during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumour nodule; multinodularity; macrovascular invasion; high histological, nuclear and architectural grades; and cellular crowding were associated with the presence of extrahepatic metastasis. Among the immunohistochemistry markers tested, metastatic nodules had significantly higher K19 and EpCAM expression than primary liver tumours. Morphological and immunohistochemical features showed that metastatic HCC could be traced back to the primary tumour, sometimes to a specific hepatic nodule.
CONCLUSIONS: This study suggests limited heterogeneity in metastatic sites compared to primary tumour sites.

Sui QQ, Jiang W, Wu XD, et al.
A frameshift mutation in exon 19 of MLH1 in a Chinese Lynch syndrome family: a pedigree study.
J Zhejiang Univ Sci B. 2019 Jan.; 20(1):105-108 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
Lynch syndrome (LS), an autosomal dominantly inherited disease previously known as hereditary non-polyposis colorectal cancer (HNPCC), leads to a high risk of colorectal cancer (CRC) as well as malignancy at certain sites including endometrium, ovary, stomach, and small bowel (Hampel et al., 2008; Lynch et al., 2009). Clinically, LS is considered the most common hereditary CRC-predisposing syndrome, accounting for about 3% of all CRC cases (Popat et al., 2005). LS is associated with mutations of DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, PMS2, and EPCAM (Ligtenberg et al., 2009; Lynch et al., 2009), which can trigger a high frequency of replication errors in both microsatellite regions and repetitive sequences in the coding regions of various cancer-related genes. Immunohistochemistry (IHC) tests followed by genetic analysis of these mutations play a significant role in diagnosis, treatment determination, and therapeutic response prediction of LS (Lynch et al., 2009; Alex et al., 2017; Ryan et al., 2017). Here, we report substitution of one base-pair in exon 1 of MLH3 (c.1397C>A) and a frameshift mutation in exon 19 of MLH1 (c.2250_2251ins AA) in a 43-year-old Chinese male with an LS pedigree.

Dwivedi D, Kasetty S, Tijare MS, et al.
Effect of Conventional and Microwave Tissue Processing Technique on DNA Integrity: A Comparative Molecular Analysis.
Ethiop J Health Sci. 2018; 28(5):615-624 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
Background: Methods of diagnostic molecular biology are routinely applied on formalin-fixed, paraffin-embedded tissues processed via conventional method. Recently, there has been a growing interest to use microwave technology in histopathology laboratories to overcome the deficiencies of the conventional processing method. Thefore, this study was aimed to compare and analyze the quality and quantity of DNA obtained from tissues processed by conventional and microwave tissue processing techniques and to further ascertain the applicability of the latter for PCR (polymerase chain reaction based research).
Methods: Thirty fresh tissues of oral squamous cell carcinoma (OSCC) were included, and each sample was cut into two equivalent halves. One tissue half was processed by conventional manual method whereas the other half was processed using a domestic microwave oven. DNA was obtained from all the tissues which were then subjected to Polymerase chain reaction (PCR) to evaluate GAPDH (Glyceraldehyde-3-phosphate dehydrogenase) gene expression.
Results: The results revealed better DNA yield from microwave processed tissue while the quality of the DNA was alike from both the techniques.
Conclusion: On the basis of the results obtained, it can be concluded that DNA produced by microwave processed tissues was similar to that obtained by conventional processing technique in terms of quantity and quality. Thus, microwave processed tissue samples can be successfully used for further molecular studies and researches.

Mat Yusoff Y, Abu Seman Z, Othman N, et al.
Prevalence of BCR-ABL T315I Mutation in Malaysian Patients with Imatinib-Resistant Chronic Myeloid Leukemia
Asian Pac J Cancer Prev. 2018; 19(12):3317-3320 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
Objective: Chronic Myeloid Leukemia (CML) is caused by a reciprocal translocation between chromosomes 9 and 22, t(9;22) (q34;q11) which encodes for the BCR-ABL fusion protein. Discovery of Imatinib Mesylate (IM) as first line therapy has brought tremendous improvement in the management of CML. However, emergence of point mutations within the BCR-ABL gene particularly T315I mutation, affects a common BCR-ABL kinase contact residue which impairs drug binding thus contribute to treatment resistance. This study aims to investigate the BCR-ABL T315I mutation in Malaysian patients with CML. Methods: A total of 285 patients diagnosed with CML were included in this study. Mutation detection was performed using qualitative real-time PCR (qPCR). Results: Fifteen out of 285 samples (5.26%) were positive for T315I mutations after amplification with real-time PCR assay. From the total number of positive samples, six patients were in accelerated phase (AP), four in chronic phase (CP) and five in blast crisis (BC). Conclusion: Mutation testing is recommended for choosing various tyrosine kinase inhibitors (TKIs) to optimize outcomes for both cases of treatment failure or suboptimal response to imatinib. Therefore, detection of T315I mutation in CML patients are clinically useful in the selection of appropriate treatment strategies to prevent disease progression.

Schmid R, Wolf K, Robering JW, et al.
ADSCs and adipocytes are the main producers in the autotaxin-lysophosphatidic acid axis of breast cancer and healthy mammary tissue in vitro.
BMC Cancer. 2018; 18(1):1273 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
BACKGROUND: Breast cancer is the most common malignancy in women affecting one out of eight females throughout their lives. Autotaxin (ATX) is upregulated in breast cancer which results in increased lysophosphatidic acid (LPA) formation within the tumor. This study's aim was to identify the role of different mammary cell populations within the ATX-LPA axis.
METHODS: Epithelial-cell-adhesion-molecule-positive (EpCAM) and -negative cells from breast tumors, adipose-derived stem cells (ADSCs) of tumor-adjacent and tumor-distant mammary fat were isolated and compared to healthy ADSCs, mammary epithelial cells (HMECs), and mesenchymal cells (MES) of healthy mammary tissue (n = 4 each) and further to well-established breast (cancer) cell lines.
RESULTS: mRNA expression analyses revealed that ADSCs and MES largely expressed LPA receptor 1 (LPAR1) while epithelial cells mainly expressed LPAR6. LPA 18:1 activated all the cell populations and cell lines by rise in cytosolic free calcium concentrations. MES and ADSCs expressed ATX whereas epithelial cells did not. ADSCs revealed the highest expression in ATX with a significant decline after adipogenic differentiation in healthy ADSCs, whereas ATX expression increased in ADSCs from tumor patients. Breast (cancer) cell lines did not express ATX. Transmigration of MES was stimulated by LPA whereas an inhibitory effect was observed in epithelial cells with no differences between tumors and healthy cells. Triple-negative breast cancer (TNBC) cell lines were also stimulated and the transmigration partly inhibited using the LPA receptor antagonist Ki16425.
CONCLUSIONS: We here show that each mammary cell population plays a different role in the ATX-LPA axis with ADSCs and adipocytes being the main source of ATX in tumor patients in our experimental setting. Inhibitors of this axis may therefore present a valuable target for pharmacological therapies.

Cultrara CN, Kozuch SD, Ramasundaram P, et al.
GRP78 modulates cell adhesion markers in prostate Cancer and multiple myeloma cell lines.
BMC Cancer. 2018; 18(1):1263 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
BACKGROUND: Glucose regulated protein 78 (GRP78) is a resident chaperone of the endoplasmic reticulum and a master regulator of the unfolded protein response under physiological and pathological cell stress conditions. GRP78 is overexpressed in many cancers, regulating a variety of signaling pathways associated with tumor initiation, proliferation, adhesion and invasion which contributes to metastatic spread. GRP78 can also regulate cell survival and apoptotic pathways to alter responsiveness to anticancer drugs. Tumors that reside in or metastasize to the bone and bone marrow (BM) space can develop pro-survival signals through their direct adhesive interactions with stromal elements of this niche thereby resisting the cytotoxic effects of drug treatment. In this study, we report a direct correlation between GRP78 and the adhesion molecule N-cadherin (N-cad), known to play a critical role in the adhesive interactions of multiple myeloma and metastatic prostate cancer with the bone microenvironment.
METHODS: N-cad expression levels (transcription and protein) were evaluated upon siRNA mediated silencing of GRP78 in the MM.1S multiple myeloma and the PC3 metastatic prostate cancer cell lines. Furthermore, we evaluated the effects of GRP78 knockdown (KD) on epithelial-mesenchymal (EMT) transition markers, morphological changes and adhesion of PC3 cells.
RESULTS: GRP78 KD led to concomitant downregulation of N-cad in both tumors types. In PC3 cells, GRP78 KD significantly decreased E-cadherin (E-cad) expression likely associated with the induction in TGF-β1 expression. Furthermore, GRP78 KD also triggered drastic changes in PC3 cells morphology and decreased their adhesion to osteoblasts (OSB) dependent, in part, to the reduced N-cad expression.
CONCLUSION: This work implicates GRP78 as a modulator of cell adhesion markers in MM and PCa. Our results may have clinical implications underscoring GRP78 as a potential therapeutic target to reduce the adhesive nature of metastatic tumors to the bone niche.

Shao M, Yang Q, Zhu W, et al.
LncHOXA10 drives liver TICs self-renewal and tumorigenesis via HOXA10 transcription activation.
Mol Cancer. 2018; 17(1):173 [PubMed] Article available free on PMC after 17/10/2019 Related Publications
BACKGROUND: Liver cancer is one of the most deadly cancers in the world. There are various cells in liver tumor bulk, including liver tumor initiating cells (TICs), which account for liver tumorigenesis, drug resistance, relapse and metastasis. The homeobox (HOX) transcription factors play critical roles in many physiological and pathological processes, while, their roles in liver TICs and liver tumorigenesis remain unknown.
METHODS: An unbiased screening was performed using online-available datasets. Liver TICs were sorted by FACS using surface markers CD133, CD13 and EPCAM, or enriched by oncosphere formation assay. TIC self-renewal was examined by oncosphere formation and tumor initiation assay. Loss of function and gain of function assays were performed to examine the role of lncRNA. RNA pulldown, RNA immunoprecipitation, ChIP, Western blot and double FISH were used to explore the molecular mechanism of lncRNA.
RESULTS: Here, we examined the expression pattern of HOX transcription factors, and found HOXA10 was overexpressed in liver cancer samples. Moreover, a divergent lncRNA of HOXA10 (termed lncHOXA10 hereafter) was also highly expressed in liver cancer and liver TICs. LncHOXA10 drove liver TIC self-renewal and liver tumorigenesis through HOXA10-dependent manner. LncHOXA10 interacted with SNF2L and recruited NURF chromatin remodeling complex to HOXA10 promoter, and thus initiated the transcription of HOXA10. Through HOXA10 transcriptional regulation, lncHOXA10 activated HOXA10 in liver TICs. LncHOXA10-HOXA10 signaling can be targeted to eliminate liver TICs. Altogether, lncHOXA10 drove HOXA10 expression and thus promoted liver TIC self-renewal.
CONCLUSION: HOXA10 was the most highly expressed HOX transcription factor in liver cancer and liver TICs. LncHOXA10 drove the transcriptional activation of HOXA10. This work revealed the important role of HOX transcription factor in liver TIC self-renewal and added a new layer for liver TIC regulation.

Kašubová I, Holubeková V, Janíková K, et al.
Next Generation Sequencing in Molecular Diagnosis of Lynch Syndrome - a Pilot Study Using New Stratification Criteria.
Acta Medica (Hradec Kralove). 2018; 61(3):98-102 [PubMed] Related Publications
The development of the new technologies such as the next-generation sequencing (NGS) makes more accessible the diagnosis of genetically heterogeneous diseases such as Lynch syndrome (LS). LS is one of the most common hereditary form of colorectal cancer. This autosomal dominant inherited disorder is caused by deleterious germline mutations in one of the mismatch repair (MMR) genes - MLH1, MSH2, MSH6 or PMS2, or the deletion in the EPCAM gene. These mutations eventually result in microsatellite instability (MSI), which can be easily tested in tumor tissue. According to the actual recommendations, all patients with CRC that are suspect to have LS, should be offered the MSI testing. When the MSI is positive, these patients should be recommended to genetic counseling. Here we report a pilot study about the application of NGS in the LS diagnosis in patients considered to have sporadic colorectal cancer. The inclusion criteria for the NGS testing were MSI positivity, BRAF V600E and MHL1 methylation negativity. We have used 5 gene amplicon based massive parallel sequencing on MiSeq platform. In one patient, we have identified a new pathogenic mutation in the exon 4 of the MSH6 gene that was previously not described in ClinVar, Human Gene Mutation Database, Ensembl and InSight databases. This mutation was confirmed by the Sanger method. We have shown that the implementation of new criteria for colorectal patients screening are important in clinical praxis and the NGS gene panel testing is suitable for routine laboratory settings.

MacFawn I, Wilson H, Selth LA, et al.
Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers.
Mol Immunol. 2019; 105:137-149 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.

Weng CC, Ding PY, Liu YH, et al.
Mutant Kras-induced upregulation of CD24 enhances prostate cancer stemness and bone metastasis.
Oncogene. 2019; 38(12):2005-2019 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Prostate cancer (PCA), one of the most common malignant tumors in men, is the second leading cause of cancer deaths in males worldwide. We report here that PCA models harboring conditional LSL/Kras

Barkeer S, Chugh S, Karmakar S, et al.
Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells.
BMC Cancer. 2018; 18(1):1157 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Glycosylation plays a critical role in the aggressiveness of pancreatic cancer (PC). Emerging evidences indicate significant involvement of cancer stem cells (CSCs) in PC aggressiveness. However, the importance of glycosylation in pancreatic cancer stem cells (PCSCs) is yet to be addressed. Hence, we evaluated the potential role of glycosylation in maintenance of stemness of PCSCs.
METHODS: Effect of glycosylation specific inhibitors on growth and PCSCs of PC cells was assessed by MTT assay and Side Population (SP) analysis. Isolated PCSCs/SP were characterized using molecular and functional assays. Expression of tumor-associated carbohydrate antigens (TACAs) was analyzed in PCSCs by western blotting. Effect of tunicamycin on PCSCs was analyzed by tumorsphere, clonogenicity, migration assay and immunoblotting for CSCs markers. The differential expression of glycogenes in PCSCs compared to non-CSCs were determined by RT-qPCR, immunoblotting and immunofluorescence. Co-expression of GALNT3 and B3GNT3 with CD44v6 was assessed in progression stages of Kras
RESULTS: Inhibition of glycosylation decreased growth and CSCs/SP in PC cells. PCSCs overexpressed CSC markers (CD44v6, ESA, SOX2, SOX9 and ABCG2), exhibited global expressional variation of TACAs and showed higher self-renewal potential. Specifically, N-glycosylation inhibition, significantly decreased tumorsphere formation, migration, and clonogenicity of PCSCs, as well as hypo-glycosylated CD44v6 and ESA. Of note, glycosyltransferases (GFs), GALNT3 and B3GNT3, were significantly overexpressed in PCSCs and co-expressed with CD44v6 at advanced PDAC stages in KC and KPC tumors. Further, GALNT3 and B3GNT3 knockdown led to a decrease in the expression of cell surface markers (CD44v6 and ESA) and self-renewal markers (SOX2 and OCT3/4) in PCSCs. Interestingly, CD44v6 was modified with sialyl Lewis a in PCSCs. Finally, CRISPR/Cas9-mediated GALNT3 KO significantly decreased self-renewal, clonogenicity, and migratory capacity in PCSCs.
CONCLUSIONS: Taken together, for the first time, our study showed the importance of glycosylation in mediating growth, stemness, and maintenance of PCSCs. These results indicate that elevated GALNT3 and B3GNT3 expression in PCSCs regulate stemness through modulating CSC markers.

Ni J, Cozzi P, Beretov J, et al.
Epithelial cell adhesion molecule (EpCAM) is involved in prostate cancer chemotherapy/radiotherapy response in vivo.
BMC Cancer. 2018; 18(1):1092 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Development of chemo-/radioresistance is a major challenge for the current prostate cancer (CaP) therapy. We have previously demonstrated that epithelial cell adhesion molecule (EpCAM) is associated with CaP growth and therapeutic resistance in vitro, however, the role of EpCAM in CaP in vivo is not fully elucidated. Here, we aimed to investigate how expression of EpCAM is involved in CaP growth and chemo-/radiotherapy response in NOD/SCID mouse models in vivo and to validate its role as a therapeutic target for CaP therapy.
METHODS: EpCAM was knocked down in PC-3 CaP cell line using short hairpin RNA (shRNA). The effect of EpCAM-knockdown (KD) on tumour growth, chemo-/radiotherapy response and animal survival was evaluated on subcutaneous (s.c) and orthotopic mouse models.
RESULTS: We found that KD of EpCAM significantly inhibited tumour growth, increased xenograft sensitivity to chemotherapy/radiotherapy, and prolonged the survival of tumour-bearing mice. In addition, we demonstrated that KD of EpCAM is associated with downregulation of the PI3K/Akt/mTOR pathway.
CONCLUSIONS: In conclusion, our data confirms that CaP growth and chemo-/radioresistance in vivo is associated with over-expression of EpCAM, which serves both a functional biomarker and promising therapeutic target.

Yang C, Cai WC, Dong ZT, et al.
lncARSR promotes liver cancer stem cells expansion via STAT3 pathway.
Gene. 2019; 687:73-81 [PubMed] Related Publications
Liver cancer stem cells (CSCs) have important functions in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). lncARSR has been reported to play an important role in the maintenance and self-renewal of renal cancer stem cells, but its role in liver cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of lncARSR in chemoresistant hepatocellular carcinomas (HCCs). A remarkable increase of lncARSR expression in EpCAM or CD133-positive liver CSCs as well as in CSC-enriched hepatoma spheres. Interference lncARSR suppressed liver CSC expansion by inhibiting the dedifferentiation of hepatoma cells and decreasing the self-renewal ability of liver CSCs. Mechanistically, we found STAT3 as the downstream of lncARSR in HCC cells. The special STAT3 inhibitor S3I-201 abolished the discrepancy in liver CSC proportion and the self-renewal capacity between lncARSR knockdown hepatoma cells and control cells, which further confirmed that STAT3 was required in lncARSR promoted liver CSCs expansion. More importantly, interference lncARSR HCC cells were more sensitive to sorafenib or cisplatin treatment. This maybe means that patients with low lncARSR levels benefited from cisplatin or sorafenib treatment, but patients with high lncARSR expression did not. Conclusion: lncARSR was upregulated in liver CSCs and could promote HCC cells dedifferentiation and liver CSCs expansion by targeting STAT3 signaling.

Cheng Z, Lei Z, Yang P, et al.
Long non-coding RNA THOR promotes liver cancer stem cells expansion via β-catenin pathway.
Gene. 2019; 684:95-103 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs), which participate in tumor invasion, therapeutic resistance, and tumor relapse leading to poor outcome and limited therapeutic options. Recently, a novel lncRNA, THOR (testis-associated highly conserved oncogenic long non-coding RNA), was characterized in human cancers and shown to exhibit an oncogenic role. However, the role of THOR in liver cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of THOR in chemoresistant hepatocellular carcinomas (HCCs). A remarkable increase of THOR expression in OV6 or EpCAM-positive liver CSCs as well as in CSC-enriched hepatoma spheres. Interference THOR suppressed liver CSC expansion by inhibiting the dedifferentiation of hepatoma cells and decreasing the self-renewal ability of liver CSCs. Mechanistically, we found β-catenin as the downstream of THOR in HCC cells. The special β-catenin inhibitor FH535 abolished the discrepancy in liver CSC proportion and the self-renewal capacity between THOR knockdown HCC cells and control cells, which further confirmed that β-catenin was required in THOR promoted liver CSCs expansion. Moreover, interference THOR hepatoma cells were more sensitive to sorafenib treatment, indicates that HCC patients with low THOR expression may benefit from sorafenib treatment. Collectively, THOR was upregulated in liver CSCs and could promote HCC cells dedifferentiation and liver CSCs expansion by targeting β-catenin signaling.

Horst AK, Najjar SM, Wagener C, Tiegs G
CEACAM1 in Liver Injury, Metabolic and Immune Regulation.
Int J Mol Sci. 2018; 19(10) [PubMed] Article available free on PMC after 01/01/2020 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

Lu W, Ding Z
Identification of key genes in prostate cancer gene expression profile by bioinformatics.
Andrologia. 2019; 51(1):e13169 [PubMed] Related Publications
The aim of this study was to identify key candidate genes in prostate cancer. The gene expression profiles of GSE32448, GSE45016, GSE46602 and GSE104749 were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) between prostate cancer and normal samples were identified by R language. The gene ontology functional and pathway enrichment analyses of DEGs were performed by the Database for Annotation, Visualization and Integrated Discovery software followed by the construction of protein-protein interaction network. Hub gene identification was performed by the plug-in cytoHubba in Cytoscape software. The 217 DEGs were significantly enriched in biological processes including epithelial cell differentiation, response to estradiol and several pathways, mainly associated with protein digestion and absorption pathway in prostate cancer. Epithelial cell adhesion molecule, twist family basic helix-loop-helix transcription factor 1, CD38 molecule and vascular endothelial growth factor A were identified as hub genes. The expression levels of hub genes were consistent with data obtained in The Cancer Genome Atlas for prostate adenocarcinoma. These hub genes may be used as potential targets for prostate cancer diagnosis and treatment.

Nastały P, Filipska M, Morrissey C, et al.
ALDH1-positive intratumoral stromal cells indicate differentiated epithelial-like phenotype and good prognosis in prostate cancer.
Transl Res. 2019; 203:49-56 [PubMed] Related Publications
Aldehyde dehydrogenase 1 (ALDH1) characterizes tumor-initiating cells in solid tumors; however, little is known about its expression in intratumoral stromal cells. Herein, we aimed to dissect its potential dual relevance in prostate cancer (PCa). ALDH1 expression was evaluated immunohistochemically in tumor and stromal cells in primary PCa and metastases. It was correlated to clinico-pathologic parameters, patients' outcome, and selected proteins (CK5/6, CK14, CK8/18, CK19, EpCAM, Ki-67, E-cadherin, N-cadherin, and vimentin). ALDH1 protein was detected in tumor and stromal cells in 16% and 67% of 348 primary PCa, respectively. Tumor cell ALDH1 expression was associated with advanced T stage (P = 0.009), higher Gleason score (P = 0.016), shorter time to biochemical recurrence (TBR P = 0.010) and CK14 expression (P = 0.023). Stromal cell ALDH1 expression correlated to lower T stage (P = 0.008) and Gleason score (P = 0.016), N0 stage (P = 0.017), and longer TBR (P = 0.017). It occurred to be an independent predictor of good prognosis in the subgroup of d'Amico high-risk patients (multivariate analysis, P = 0.050). ALDH1-positive stromal cells were found in tumors characterized frequently by CK8/18 (P = 0.033) or EpCAM expression (P < 0.001) and rarely by epithelial-mesenchymal transition defined as CK8/18(-)vimentin(+) phenotype (P = 0.003). ALDH1-positive tumor and stromal cells were detected in 33% and 41% of hormone naive lymph node metastases (n = 63), 52% and 24% of castration resistant bone metastases, as well as 89% and 28% of castration resistant visceral metastases (n = 21), respectively. We have determined that contrary to tumor cell ALDH1, the presence of stromal ALDH1 is associated with epithelial phenotype of primary PCa, improved clinical outcome, and is less frequent in PCa metastases.

Rodrigues MFSD, Miguita L, De Andrade NP, et al.
GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma.
Int J Oncol. 2018; 53(6):2458-2472 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Oral squamous cell carcinoma (OSCC) is an extremely aggressive disease associated with a poor prognosis. Previous studies have established that cancer stem cells (CSCs) actively participate in OSCC development, progression and resistance to conventional treatments. Furthermore, CSCs frequently exhibit a deregulated expression of normal stem cell signalling pathways, thereby acquiring their distinctive abilities, of which self-renewal is an example. In this study, we examined the effects of GLI3 knockdown in OSCC, as well as the differentially expressed genes in CSC-like cells (CSCLCs) expressing high (CD44high) or low (CD44low) levels of CD44. The prognostic value of GLI3 in OSCC was also evaluated. The OSCC cell lines were sorted based on CD44 expression; gene expression was evaluated using a PCR array. Following this, we examined the effects of GLI3 knockdown on CD44 and ESA expression, colony and sphere formation capability, stem-related gene expression, proliferation and invasion. The overexpression of genes related to the Notch, transforming growth factor (TGF)β, FGF, Hedgehog, Wnt and pluripotency maintenance pathways was observed in the CD44high cells. GLI3 knockdown was associated with a significant decrease in different CSCLC fractions, spheres and colonies in addition to the downregulation of the CD44, Octamer-binding transcription factor 4 (OCT4; also known as POU5F1) and BMI1 genes. This downregulation was accompanied by an increase in the expression of the Involucrin (IVL) and S100A9 genes. Cellular proliferation and invasion were inhibited following GLI3 knockdown. In OSCC samples, a high GLI3 expression was associated with tumour size but not with prognosis. On the whole, the findings of this study demonstrate for the first time, at least to the best of our knowledge, that GLI3 contributes to OSCC stemness and malignant behaviour. These findings suggest the potential for the development of novel therapies, either in isolation or in combination with other drugs, based on CSCs in OSCC.

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