Epiregulin as a marker for the initial steps of ovarian cancer development

Amsterdam, Abraham; Shezen, Elias; Raanan, Calanit; Slilat, Yasmin; Ben-Arie, Alon; Prus, Diana; Schreiber, Letizia

doi:10.3892/ijo.2011.1123

Cited by 16 publications

(14 citation statements)

References 43 publications

(55 reference statements)

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“…oral, lung and ovarian cancers) (25,26), and the upregulation of EREG has been documented in a variety of cancers (e.g. colorectal, lung, pancreatic, oral and ovarian cancers) and in TSC patients (21,27–31). Moreover, EREG has been suggested to be a plausible ‘hamartic’ factor in TSC (21).…”

Section: Discussionmentioning

confidence: 99%

Evidence that TSC2 acts as a transcription factor and binds to and represses the promoter of Epiregulin

Pradhan

Rather

Tiwari

et al. 2014

Nucleic Acids Research

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The TSC2 gene, mutated in patients with tuberous sclerosis complex (TSC), encodes a 200 kDa protein TSC2 (tuberin). The importance of TSC2 in the regulation of cell growth and proliferation is irrefutable. TSC2 in complex with TSC1 negatively regulates the mTOR complex 1 (mTORC1) via RHEB in the PI3K-AKT-mTOR pathway and in turn regulates cell proliferation. It shows nuclear as well as cytoplasmic localization. However, its nuclear function remains elusive. In order to identify the nuclear function of TSC2, a whole-genome expression profiling of TSC2 overexpressing cells was performed, and the results showed differential regulation of 266 genes. Interestingly, transcription was found to be the most populated functional category. EREG (Epiregulin), a member of the epidermal growth factor family, was found to be the most downregulated gene in the microarray analysis. Previous reports have documented elevated levels of EREG in TSC lesions, making its regulatory aspects intriguing. Using the luciferase reporter, ChIP and EMSA techniques, we show that TSC2 binds to the EREG promoter between −352 bp and −303 bp and negatively regulates its expression. This is the first evidence for the role of TSC2 as a transcription factor and of TSC2 binding to the promoter of any gene.

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Section: Discussionmentioning

confidence: 99%

Evidence that TSC2 acts as a transcription factor and binds to and represses the promoter of Epiregulin

Pradhan

Rather

Tiwari

et al. 2014

Nucleic Acids Research

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“…Monoclonal antibodies Methods. Paraffin blocks containing tissues of 3 normal colon and paraffin blocks containing 3 stage I-IV tumor samples at of highly differentiated, moderately differentiated and poorly differentiated cancers were cut at 4-mm thickness and stained with the various antibodies followed by secondary antibodies and staining with hematoxylin for 90 sec (30)(31)(32)(33). For statistical quantification of the number of stem cells in the sections stained with LGR5 of each stage of the tumor and each degree of differentiation, the tissue sections were inspected under a Nikon microscope (Tokyo, Japan) and 4 fields of each patient tissue sample were photographed at a magnification of x400.…”

Section: Methodsmentioning

confidence: 99%

Use of multiple biomarkers for the localization and characterization of colon cancer stem cells by indirect immunocytochemistry

et al. 2012

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Abstract. In this study, we used LGR5, γ-synuclein, p53, KRAS and epiregulin antibodies to localize stem cells by indirect immunocytochemistry in paraffin sections of normal and cancerous colon tissues. In the normal colon tissue, no staining of cells with LGR5, γ-synuclein, p53 and KRAS antibodies was observed, apart from a few scattered cells in between the colon villi that were faintly stained with antibodies to LGR5. Staining of highly differentiated cancer tissue with LGR5 antibodies revealed single cells or clusters of up to 4 cells in the interior space of the carcinoma cell layers. Staining of poorly differentiated cancer tissues (stage I-IV) revealed 9-81 clustered stem cells. The number of clustered stem cells increased significantly with the tumor stage, when comparing stage II to stage IV (p<00048). Occasionally, the clustered stem cells appeared in the interphase between the colon stroma and the tumor tissue. Surprisingly, antibodies to p53 clearly stained the clusters of stem cells both in the nuclei and the cytoplasm. The staining of the nuclei of other cells in the undifferentiated tumors was in general weaker, and no staining was found in the cytoplasm. Antibodies to γ-synuclein heavily stained the endothelial cells of the blood vessels and some other scattered cells in the highly differentiated tumors. Antibodies to γ-synuclein heavily stained the stem cells in both the cytoplasm and the nuclei of poorly differentiated tumors. Antibodies to KRAS stained the cytoplasm and the nuclei of stem cells in poorly differentiated tumors and also stained the cytoplasm of some scattered cells. Antibodies to epiregulin stained the cytoplasm of normal colon tissue cells in the crypt-villus axis. The antibodies weakly stained the highly differentiated tumor cells and moderately stained the moderately differentiated tumor cells.Of note, the antibodies intensively stained the clustered stem cells of the poorly differentiated tumor cells. These antibodies also clearly stained the clustered stem cells of poorly differentiated tumors but were not specific as they clearly stained cells in the crypt-villus axis of the normal colon wall. Our results show that LGR5 antibodies can serve as a reliable marker for colon cancer stem cells. Once the colon stem cells are identified, the targeting of specific drugs to kill these cells should be attempted in the future in order to cure this disease. Moreover, the fact that we did not find any stained cells with antibodies to LGR5 in normal tissues apart from a few scattered cells, suggests that the normal colon stem cells differ from the tumor stem cells at least as regards the expression of this protein.In addition, antibodies to γ-synuclein, p53 and KRAS only stained the tumor stem cells and not the normal tissue. Thus, they can serve as multiple biomarkers for the localization of colon cancer stem cells by indirect immunofluorescence.

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“…Ereg is known to be expressed in cancers of the lung (Zhang et al, 2008), colon (Khambata-Ford et al, 2007), prostate (Sauer et al, 2010) and ovary (Amsterdam et al, 2011) in humans. In the mice, increased expressions of Ereg mRNA have been reported in lung tumors induced by vinyl carbamate (Alyaqoub et al, 2008) or UR (Bauer et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Gene expression analysis in the lung of the rasH2 transgenic mouse at week 4 prior to induction of malignant tumor formation by urethane and N-methylolacrylamide

et al. 2015

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-The rasH2 transgenic (Tg) mice are susceptible to genotoxic and some non-genotoxic carcinogens. In carcinogenicity studies carried out using rasH2 Tg mice, the carcinogenic potential of chemicals are evaluated over a 26-week experimental period. In the present study, we examined the comprehensive gene expressions in the lungs of Tg and non-Tg mice prior to the induction of malignant tumors. Urethane (UR), a mutagenic carcinogen, was administered for 4 weeks, and thereafter withdrawn for 22 weeks. N-methylolacrylamide (NMA), a non-mutagenic carcinogen, was administered for 26 weeks. At week 4, gene expression analysis of non-neoplastic part of the lungs demonstrated changes in the expressions of the cell-cycle and inflammation related genes following UR and NMA treatment, respectively, in both the Tg and non-Tg mice. The gene expressions of epireguline, aurora kinase B, and cyclin B1 increased in the UR-treated Tg mice. We also found an increase in the plasma carcinoembryonic antigen level in the UR-treated Tg mice. Although UR treatment induced the formation of adenomas or adenocarcinomas in the lungs in all mice, earlier induction was apparent in the Tg mice. NMA treatment was found to induce the formation of adenomas and adenocarcinomas at week 26 in the Tg mice, but not in the non-Tg mice, and no expressions of specific genes were apparent in either genotype of mice. Our results indicate that analysis of cancer-related gene expressions in the lungs and plasma biomarkers at week 4 in rasH2 Tg mice could be a screening tool for carcinogenicity, especially of mutagenic carcinogens.

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Epiregulin as a marker for the initial steps of ovarian cancer development

Cited by 16 publications

References 43 publications

Evidence that TSC2 acts as a transcription factor and binds to and represses the promoter of Epiregulin

Evidence that TSC2 acts as a transcription factor and binds to and represses the promoter of Epiregulin

Use of multiple biomarkers for the localization and characterization of colon cancer stem cells by indirect immunocytochemistry

Gene expression analysis in the lung of the rasH2 transgenic mouse at week 4 prior to induction of malignant tumor formation by urethane and N-methylolacrylamide

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