Association of upregulated GATA-4 transcription factor colorectal adenocarcinoma with metastatic and primary tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15093-e15093
Author(s):  
E. C. Marginean ◽  
G. Torlakovic ◽  
H. Neufeld ◽  
E. Torlakovic
Keyword(s):  
Transcription Factor ◽  
Cancer Progression ◽  
Colonic Mucosa ◽  
Colorectal Adenocarcinoma ◽  
Human Cancer ◽  
Positive Association ◽  
Experimental Models ◽  
Normal Colonic Mucosa ◽  
Chi Square ◽  
Primary Tumors

e15093 Background: GATA-4 zinc finger transcription factor is involved in regulation of cellular development, proliferation, and differentiation and is important in embryonic development of gastrointestinal tract. However, GATA-4 is not expressed in normal adult colonic mucosa. Its protein expression in colonic adenocarcinoma has not been systematically evaluated and small number of samples was previously reported as negative. Nuclear factor-B (NF-B) activation was shown to promote the growth of the colon tumors in experimental models and was correlated with tumor angiogenesis and progression in human colorectal cancer. Methods: Forty cases of colorectal adenocarcinoma were evaluated. The benign colonic mucosa and the matching metastatic tumors of the same patients were also included in the study. TMAs which included 139 samples were evaluated by immunohistochemistry and nuclear and cytoplasmic GATA-4 expression was scored (0–3+). NF-B activation was detected as nuclear reactivity for p65. Results: GATA-4 was expressed in 32% of colorectal adenocarcinoma, but not in benign colonic mucosa (p=0.0001, Chi-Square). GATA-4 was also significantly more expressed in metastatic (41%) than in primary (21%) colorectal adenocarcinoma (p<0.0001, Chi-Square). NF-B activation was not present in any of the samples of benign colonic mucosa, but it was detected in 64% adenocarcinomas (p<0.0001, Chi-Square). While there was no difference in NF-B activation between primary vs. metastatic adenocarcinoma, a strong positive association between GATA-4 expression and NF-B activation (p<0.0001, Linear-by- Linear) was found. Conclusions: GATA-4, a developmental transcription factor is not expressed by normal colonic mucosa, but is present in 1/5 of primary tumors that gave rise to distant metastases and in almost 1/2 of their respective metastases. GATA- 4 is also strongly positively associated with NF-B activation previously described to have a role in human cancer progression. GATA-4 may have a role in colorectal adenocarcinoma development and progression and it should be further evaluated in prospective studies as a putative adverse prognostic factor in colorectal adenocarcinoma. No significant financial relationships to disclose.

Downregulation of RIZ1 protein expression in left-sided versus right-sided primary colorectal carcinomas and their distant metastases and the association with NF-B activation

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15112-e15112
Author(s):  
E. Torlakovic ◽  
E. C. Marginean ◽  
G. Torlakovic ◽  
R. Geyer ◽  
H. Neufeld ◽  
...  
Keyword(s):  
Protein Expression ◽  
Colorectal Adenocarcinoma ◽  
Nuclear Translocation ◽  
Human Cancer ◽  
Distant Metastases ◽  
Normal Mucosa ◽  
Metastatic Carcinoma ◽  
Chi Square ◽  
Primary Tumors ◽  
Molecular Events

e15112 Background: Activation of NF- B leads to enhanced proliferation and the expression of anti-apoptotic proteins, which are cancer phenotypes. RIZ1 inactivation through various molecular events was linked to increased proliferation, migration induction and apoptosis inhibition in human cancer. RIZ1 frameshift mutations were recently reported to be confined to MSI-H colorectal tumors and proximal tumor origin, while its hypermethylation was not limited to MSI-H tumors. However, RIZ1 protein expression has not been evaluated in colorectal carcinoma. Methods: TMAs included 28 left-sided and 12 right-sided primary colorectal adenocarcinomas, their matched normal mucosa and their respective distant metastases. Left-sided tumors were compared to right-sided tumors for expression of RIZ1 protein and NF- B activation. RIZ1 immunostaining was scored semiquantitatively (0–3+). NF- B activation was determined by IHC detecting nuclear translocation of its p65 subunit in more than 30% tumor nuclei. Discrepant results were defined as score difference of 2. Results: RIZ1 was less expressed in tumors than in benign mucosa (p<0.0001, r=- 0.377, Chi-Square). The difference between primary vs. metastatic carcinoma was not significant. Low RIZ1 was associated with NF- B activation (p<0.0001, Linear-by-Linear). Left-sided primary tumors showed less RIZ1 protein expression than right-sided (p=0.03, Chi-Square). NF- B activation was more frequent in left-sided primary tumors and their respective metastases (35% in right vs. 67% in left; p=0.002, Chi-Square Test). RIZ1 expression and NF- B activation were almost identical in primary and their respective metastatic tumors with only 3 discrepant results for NF- B status and 2 discrepant results in RIZ1 expression. Conclusions: While RIZ1 downregulation in colorectal adenocarcinoma due to RIZ1 mutations appears to be associated with MSI-H and proximal origin, its protein expression appears to be downregulated more often in distal tumors. NF- B activation is strongly associated with lower RIZ1 protein expression in colorectal adenocarcinoma. No significant financial relationships to disclose.

scholarly journals EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

2016 ◽  
Vol 23 (9) ◽  
pp. 747-758 ◽  
Author(s):  
Zara Zelenko ◽  
Emily Jane Gallagher ◽  
Irini Markella Antoniou ◽  
Deepali Sachdev ◽  
Anupma Nayak ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Mortality Data ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Insulin Resistant ◽  
Human Cancer Cells

Type 2 diabetes (T2D) is associated with increased cancer risk and cancer-related mortality. Data herein show that we generated an immunodeficient hyperinsulinemic mouse by crossing theRag1−/−mice, which have no mature B or T lymphocytes, with the MKR mouse model of T2D to generate theRag1−/−(Rag/WT) andRag1−/−/MKR+/+(Rag/MKR) mice. The female Rag/MKR mice are insulin resistant and have significantly higher nonfasting plasma insulin levels compared with the Rag/WT controls. Therefore, we used these Rag/MKR mice to investigate the role of endogenous hyperinsulinemia on human cancer progression. In this study, we show that hyperinsulinemia in the Rag/MKR mice increases the expression of mesenchymal transcription factors,TWIST1andZEB1, and increases the expression of the angiogenesis marker, vascular endothelial growth factor A (VEGFA). We also show that silencing the insulin receptor (IR) in the human LCC6 cancer cells leads to decreased tumor growth and metastases, suppression of mesenchymal markers vimentin, SLUG, TWIST1 and ZEB1, suppression of angiogenesis markers,VEGFAandVEGFD, and re-expression of the epithelial marker, E-cadherin. The data in this paper demonstrate that IR knockdown in primary tumors partially reverses the growth-promoting effects of hyperinsulinemia as well as highlighting the importance of the insulin receptor signaling pathway in cancer progression, and more specifically in epithelial–mesenchymal transition.

scholarly journals Metabolic Stress Adaptations Underlie Mammary Gland Morphogenesis and Breast Cancer Progression

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2641
Author(s):  
Chun-Chao Wang
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Cancer Progression ◽  
Cancer Metabolism ◽  
Experimental Models ◽  
Premalignant Lesions ◽  
Primary Tumors ◽  
Cancer Subtypes ◽  
Mammary Gland Morphogenesis ◽  
Gland Morphogenesis

Breast cancers display dynamic reprogrammed metabolic activities as cancers develop from premalignant lesions to primary tumors, and then metastasize. Numerous advances focus on how tumors develop pro-proliferative metabolic signaling that differs them from adjacent, non-transformed epithelial tissues. This leads to targetable oncogene-driven liabilities among breast cancer subtypes. Other advances demonstrate how microenvironments trigger stress-response at single-cell resolution. Microenvironmental heterogeneities give rise to cell regulatory states in cancer cell spheroids in three-dimensional cultures and at stratified terminal end buds during mammary gland morphogenesis, where stress and survival signaling juxtapose. The cell-state specificity in stress signaling networks recapture metabolic evolution during cancer progression. Understanding lineage-specific metabolic phenotypes in experimental models is useful for gaining a deeper understanding of subtype-selective breast cancer metabolism.

Immunodetection of androgen and estrogen a,b receptors in human urinary bladder cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15616-15616
Author(s):  
A. Gómez Pinillos ◽  
G. Bueno Serrano ◽  
S. Sacristán López ◽  
R. García González ◽  
C. Varona Crespo ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Western Blotting ◽  
Cancer Progression ◽  
Transitional Cell ◽  
Urinary Bladder Cancer ◽  
Tumor Grade ◽  
Chi Square ◽  
Primary Tumors ◽  
Female Ratio ◽  
Covalent Modifications

15616 Background: Bladder cancer predominates in males. Loss of androgen receptor (AR) has been associated with invasive and undifferentiated tumors but little is known about the role of hormonal receptors in this type of cancer. Methods: We evaluated samples from 41 nonconsecutive patients treated for bladder transitional cell carcinoma between 2001–2003. Immunohistochemistry was performed using anti-AR and anti-ER a,b antibodies on paraffin-embedded tumors from transurethral resections, nuclear expression was assessed. Western blotting for AR and pAKT were performed in 22 transurethral resections from nonconsecutive bladder cancer patients treated between 2004–2006. Chi-square and U Mann-Witney tests were performed. Results: Immunohistochemistry study: the male/female ratio was 9/1; 61% were noninvasive tumors (pTa, is,1) and 32% were invasive (pT2,3); 22% were G1 and 75% were G2,3. 95% were AR(+), 40% ERa(+) and 94% ERb(+). Significant differences in AR expression were observed between G1 78% and G2,3 tumors 100%, with a high grade tumor prevalence in the AR(+) tumors 81.6% p=0.046. No differences between ERa,b and differentiation were found. G2,3 tumors were predominantly ERb(+). AR was found in 92% noninvasive and in 100% invasive tumors p=0.53. No significant differences were found between invasiveness and ERa,b. Noninvasive tumors showed higher ERa,b expresión (54%, 95% respectively) than invasive tumors (20%, 91% respectively). Western blotting group: 54.5% were primary tumors and 45.5% were recidives. The noninvasive/invasive rate was 59/32%, the G1/G2,3 rate was 4.5/95.5%. 112, 250 and 160 kDa bands were found. AR/pAKT rate was 86.4/100%. 100% of invasive tumors and 86% G2,3 tumors were AR(+). No differences between pAKT, invasiveness, differentiation or AR expression were observed but recidivated tumors had a slight higher median expression level. Conclusions: AR is positively related to tumor grade and might be involved in bladder cancer progression. The profile of AR bands suggest covalent modifications, due to ubiquitin-mediated degradation or to activation mechanisms mediated by SUMO. Nuclear AR and the absence of bands under 90kDa suggest that activated protein is present in bladder cancer. pAKT/AR inhibitors could play a role for bladder cancer therapy. No significant financial relationships to disclose.

scholarly journals FOXA1 defines cancer cell specificity

2016 ◽  
Vol 2 (3) ◽  
pp. e1501473 ◽  
Author(s):  
Gaihua Zhang ◽  
Yongbing Zhao ◽  
Yi Liu ◽  
Li-Pin Kao ◽  
Xiao Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Target Genes ◽  
Human Cancer ◽  
Cell Types ◽  
Human Cancer Cell Lines ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Pioneer Transcription Factor ◽  
Specific Regulation

A transcription factor functions differentially and/or identically in multiple cell types. However, the mechanism for cell-specific regulation of a transcription factor remains to be elucidated. We address how a single transcription factor, forkhead box protein A1 (FOXA1), forms cell-specific genomic signatures and differentially regulates gene expression in four human cancer cell lines (HepG2, LNCaP, MCF7, and T47D). FOXA1 is a pioneer transcription factor in organogenesis and cancer progression. Genomewide mapping of FOXA1 by chromatin immunoprecipitation sequencing annotates that target genes associated with FOXA1 binding are mostly common to these cancer cells. However, most of the functional FOXA1 target genes are specific to each cancer cell type. Further investigations using CRISPR-Cas9 genome editing technology indicate that cell-specific FOXA1 regulation is attributable to unique FOXA1 binding, genetic variations, and/or potential epigenetic regulation. Thus, FOXA1 controls the specificity of cancer cell types. We raise a “flower-blooming” hypothesis for cell-specific transcriptional regulation based on these observations.

ZKSCAN3, a Novel Zinc Finger Transcription Factor, Regulates Cyclin D2 Expression in Multiple Myeloma (MM) Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 749-749
Author(s):  
Lin Yang ◽  
Robert Z. Orlowski
Keyword(s):  
Transcription Factor ◽  
Cell Lines ◽  
Zinc Finger ◽  
Cancer Progression ◽  
Alternative Pathway ◽  
Cyclin D ◽  
Cyclin D2 ◽  
Primary Tumors ◽  
Zinc Finger Transcription Factor ◽  
Rpmi 8226

Abstract Background: Dysregulation of cyclin D has been proposed to represent an early oncogenic event in MM, and often occurs as a result of chromosomal translocations. Cyclin D2 can be induced as a result of translocations involving c-maf, mafB, and FGFR3/MMSET, but its expression is also increased in hyperdiploid and nonhyperdiploid cells without these translocations through unknown mechanisms. We previously identified a novel zinc finger transcription factor, ZKSCAN3, as a new “driver” of colon cancer progression, and found that the cyclin D2 promoter harbored several ZKSCAN3 binding sites, prompting us to investigate a possible role of ZKSCAN3 in MM pathogenesis. Methods: ZKSCAN3 expression was studied in patient-derived primary tumors and normal cells, as well as in human MM cell lines. Results: Tissue microarray studies showed that ZKSCAN3 was strongly expressed in the neoplastic cells of 7/10 MM patients by immunohistochemistry, while in all samples the surrounding normal bone marrow cells showed only background staining. Real-time polymerase chain reaction (qPCR) analysis revealed some level of ZKSCAN mRNA expression in 5/5 MM cell lines studied (RPMI 8226, U266, KAS-6/1, INA-6, ANBL-6), but not in pooled CD19+ normal B-cells. By Western blotting, ZKSCAN3 was most highly expressed in RPMI 8226 and KAS-6/1 cells, which notably do not bear cyclin D dysregulating translocations, while U266 and ANBL-6, which have such translocations, showed the lowest levels of ZKSCAN3 expression. In RPMI 8226 cells, but not the other MM lines, six copies of the ZKSCAN3 gene were detected, suggesting the presence of a previous amplification event. cisRED analysis predicted that ZKSCAN3 may be transcriptionally regulated by paired box gene 5 (Pax5), an essential factor for maintaining the commitment of the B cell lineage which is inactivated during plasma cell differentiation. Consistent with a role for Pax5 in controlling ZKSCAN3 level, a reporter assay showed that Pax5 inhibited ZKSCAN3 promoter activity, and Pax5 expression negatively correlated with ZKSCAN3 expression. Electrophoretic mobility shift and chromatin immunoprecipitation assays showed direct binding of ZKSCAN3 to the endogenous cyclin D2 promoter in these MM cell lines. Knockdown of ZKSCAN3 using short hairpin RNAs reduced Cyclin D2 mRNA and protein expression in RPMI 8226 and KAS-6/1 cells, and also decreased their proliferative rates. Conclusions: These findings support the possibility that ZKSCAN3 contributes to myeloma pathogenesis by dysregulation of cyclin D2, and that events impacting upon ZKSCAN3 may provide MM cells with an alternative pathway for induction of Cyclin D2 in the absence of an activating translocation. ZKSCAN3 may therefore be an attractive candidate for MM therapy.

scholarly journals Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions

2011 ◽  
Vol 286 (22) ◽  
pp. 19982-19992 ◽  
Author(s):  
Mario Andres Blanco ◽  
Maša Alečković ◽  
Yuling Hua ◽  
Tuo Li ◽  
Yong Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Large Scale ◽  
Staphylococcal Nuclease ◽  
Experimental Models ◽  
Breast Cancer Patients ◽  
Interacting Protein ◽  
Primary Tumors ◽  
Nuclease Domain ◽  
Expression Of Genes

Metastasis is the deadliest and most poorly understood feature of malignant diseases. Recent work has shown that Metadherin (MTDH) is overexpressed in over 40% of breast cancer patients and promotes metastasis and chemoresistance in experimental models of breast cancer progression. Here we applied mass spectrometry-based screen to identify staphylococcal nuclease domain-containing 1 (SND1) as a candidate MTDH-interacting protein. After confirming the interaction between SND1 and MTDH, we tested the role of SND1 in breast cancer and found that it strongly promotes lung metastasis. SND1 was further shown to promote resistance to apoptosis and to regulate the expression of genes associated with metastasis and chemoresistance. Analyses of breast cancer clinical microarray data indicated that high expression of SND1 in primary tumors is strongly associated with reduced metastasis-free survival in multiple large scale data sets. Thus, we have uncovered SND1 as a novel MTDH-interacting protein and shown that it is a functionally and clinically significant mediator of metastasis.

scholarly journals The transcription factor ZEB1 (δEF1) represses Plakophilin 3 during human cancer progression

FEBS Letters ◽  
2007 ◽  
Vol 581 (8) ◽  
pp. 1617-1624 ◽  
Author(s):  
Kirsten Aigner ◽  
Luise Descovich ◽  
Mario Mikula ◽  
Aneesa Sultan ◽  
Brigitta Dampier ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cancer Progression ◽  
Human Cancer ◽  
Plakophilin 3

Translational and Functional Oncogenomics. From Cancer-Oriented Genomic Screenings to New Diagnostic Tools and Improved Cancer Treatment

2008 ◽  
Vol 94 (2) ◽  
pp. 172-178
Author(s):  
Enzo Medico ◽  
Keyword(s):  
Candidate Genes ◽  
Cancer Progression ◽  
Human Cancer ◽  
Function Analysis ◽  
Functional Characterization ◽  
Experimental Models ◽  
Diagnostic Tools ◽  
Cancer Genes ◽  
Loss Of Function ◽  
Diagnostic Potential

We present here an experimental pipeline for the systematic identification and functional characterization of genes with high potential diagnostic and therapeutic value in human cancer. Complementary competences and resources have been brought together in the TRANSFOG Consortium to reach the following integrated research objectives: 1) execution of cancer-oriented genomic screenings on tumor tissues and experimental models and merging of the results to generate a prioritized panel of candidate genes involved in cancer progression and metastasis; 2) setup of systems for high-throughput delivery of full-length cDNAs, for gain-of-function analysis of the prioritized candidate genes; 3) collection of vectors and oligonucleotides for systematic, RNA interference-mediated down-regulation of the candidate genes; 4) adaptation of existing cell-based and model organism assays to a systematic analysis of gain and loss of function of the candidate genes, for identification and preliminary validation of novel potential therapeutic targets; 5) proteomic analysis of signal transduction and protein-protein interaction for better dissection of aberrant cancer signaling pathways; 6) validation of the diagnostic potential of the identified cancer genes towards the clinical use of diagnostic molecular signatures; 7) generation of a shared informatics platform for data handling and gene functional annotation. The results of the first three years of activity of the TRANSFOG Consortium are also briefly presented and discussed.

scholarly journals A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression

2021 ◽  
Vol 23 (1) ◽  
pp. 445
Author(s):  
Arka Saha ◽  
Sanith Cheriyamundath ◽  
Anmol Kumar ◽  
Nancy Gavert ◽  
Thomas Brabletz ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Liver Metastasis ◽  
Cancer Progression ◽  
Colonic Mucosa ◽  
Culture Medium ◽  
Target Genes ◽  
Normal Colonic Mucosa ◽  
Cellular Processes ◽  
Colon Cancer Progression ◽  
Cell Adhesion Receptor

Aberrant activation of Wnt/β-catenin signaling and downstream β-catenin-TCF target genes is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin-like cell adhesion receptor L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. Overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis, and liver metastasis, and L1 is exclusively localized at invasive areas of human CRC tissue. Several genes are induced after L1 transfection into CRC cells by a mechanism involving the L1-ezrin-NF-κB pathway. We conducted a secretomic analysis of the proteins in the culture medium of L1-overexpressing CRC cells. We detected a highly increased level of biglycan, a small leucine-rich ECM component, and a signaling molecule. We found that induction of biglycan is required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis, and liver metastasis. The suppression of endogenous biglycan levels or a point mutation in the L1 ectodomain that regulates cell–cell adhesion mediated by L1 blocked the enhanced tumorigenic properties conferred by L1. The mechanism of biglycan induction by L1 involves the L1-NF-κB pathway. Blocking NF-κB signaling in L1 expressing cells suppressed the induction of biglycan and the tumorigenic properties conferred by L1. Biglycan expression was undetectable in the normal colonic mucosa, but expressed at highly increased levels in the tumor tissue, especially in the stroma. The therapeutic strategies to target biglycan expression might provide a useful approach for CRC treatment in L1-overexpressing tumors.

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