scholarly journals Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells

2015 ◽  
Vol 112 (25) ◽  
pp. 7743-7748 ◽  
Author(s):  
Muhammad Akhtar Ali ◽  
Shady Younis ◽  
Ola Wallerman ◽  
Rajesh Gupta ◽  
Leif Andersson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Lines ◽  
Differentially Expressed Genes ◽  
Target Genes ◽  
Egf Receptor ◽  
Differentially Expressed ◽  
Striking Difference ◽  
Human Colorectal Cancer ◽  
Chip Sequencing

The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle–related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-β, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.

scholarly journals Hub Genes Related to the Pathogenesis and Progression of Colorectal Cancer and Adenoma by Integrative Bioinformatics Approaches

2021 ◽  
Author(s):  
Yuxuan HUANG ◽  
Ge CUI
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Differentially Expressed Genes ◽  
Protein Interaction ◽  
Biological Networks ◽  
Interaction Network ◽  
Differentially Expressed ◽  
Venn Diagram ◽  
Hub Genes ◽  
Protein Protein Interaction

Abstract Aims: To utilize the bioinformatics to analyze the differentially expressed genes (DEGs), interaction proteins, perform gene enrichment analysis, protein-protein interaction network (PPI) and map the hub genes between colorectal cancer(CRC) and colorectal adenocarcinomas(CA).Methods: We analyzed a microarray dataset (GSE32323 and GSE4183) from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in tumor tissues and non-cancerous tissues were identified using the dplyr and Venn diagram packages of the R Studio software. Functional annotation of the DEGs was performed using the Gene Ontology (GO) website. Pathway enrichment (KEGG) used the WebGestalt to analyze the data and R Studio to generate the graph. We constructed a protein–protein interaction (PPI) network of DEGs using STRING and Cytoscape software was used for visualization. Survival analysis of the hub genes and was performed using the online platform GEPIA to determine the prognostic value of the expression of hub genes in cell lines from CRC patients. The expression of molecules with prognostic values was validated on the UALCAN database. The expression of hub genes was examined using the Human Protein Atlas. Results: Applying the GEO2R analysis and R studio, we identified a total of 471 upregulated and 278 downregulated DEGs. By using the online database WebGestalt, we identified the most relevant biological networks involving DEGs with statistically significant differences in expression were mainly associated with biological processes involved in the cell proliferation, cell cycle transition, cell homeostasis and indicated the role of each DEGs in cell cycle regulation pathways. We found 10 hub genes with prognostic values were overexpressed in the CRC and CA samples.Conclusion: we found out ten hub genes and three core genes closely associated with the pathogenesis and prognosis of CRC and CA, which is of great significance for colorectal tumor early detection and prognosis evaluation.

scholarly journals PI3K p110α Blockade Enhances Anti-Tumor Efficacy of Abemaciclib in Human Colorectal Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2500
Author(s):  
Hyun Jung Lee ◽  
Kui-Jin Kim ◽  
Ji Hea Sung ◽  
Milang Nam ◽  
Koung Jin Suh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Combination Therapy ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Colorectal Cancer ◽  
Colorectal Cancer Cell Lines

Targeting cell cycle regulation in colorectal cancer has not been fully evaluated. We investigated the efficacy of the CDK4/6 inhibitor, abemaciclib, and confirmed a synergistic interaction for PI3K p110α and CDK dual inhibition in colorectal cancer cell lines. Caco-2 and SNU-C4 cell lines were selected to explore the mechanism of action for and resistance to abemaciclib. In vitro and in vivo models were used to validate the anti-tumor activity of abemaciclib monotherapy and BYL719 combination therapy. Abemaciclib monotherapy inhibited cell cycle progression and proliferation in Caco-2 and SNU-C4 cells. CDK2-mediated Rb phosphorylation and AKT phosphorylation appeared to be potential resistance mechanisms to abemaciclib monotherapy. Abemaciclib/BYL719 combination therapy demonstrated synergistic effects regardless of PIK3CA mutation status but showed greater efficacy in the PIK3CA mutated SNU-C4 cell line. Growth inhibition, cell cycle arrest, and migration inhibition were confirmed as mechanisms of action for this combination. In an SNU-C4 mouse xenograft model, abemaciclib/BYL719 combination resulted in tumor growth inhibition and apoptosis with tolerable toxicity. Dual blockade of PI3K p110α and CDK4/6 showed synergistic anti-tumor effects in vivo and in vitro in human colorectal cancer cell lines. This combination could be a promising candidate for the treatment of patients with advanced colorectal cancer.

scholarly journals The Oncogenic Function of PLAGL2 is Mediated via Specific Target Genes Through a Wnt-independent Mechanism in Colorectal Cancer

2020 ◽  
Author(s):  
Anthony D. Fischer ◽  
Daniel A. Veronese-Paniagua ◽  
Shriya Swaminathan ◽  
Hajime Kashima ◽  
Deborah C. Rubin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Transcription Factor ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Bhlh Transcription Factor ◽  
Cycle Progression

ABSTRACTColorectal cancer (CRC) tumorigenesis and progression are linked to common oncogenic mutations, especially in the tumor suppressor APC, whose loss triggers the deregulation of TCF4/β-Catenin activity. CRC tumorigenesis is also driven by multiple epi-mutational modifiers, such as transcriptional regulators. We describe the common (and near-universal) activation of the zinc finger transcription factor and Let-7 target PLAGL2 in CRC and find that it is a key driver of intestinal epithelial transformation. PLAGL2 drives proliferation, cell cycle progression, and anchorage-independent growth in CRC cell lines and non-transformed intestinal cells. Investigating effects of PLAGL2 on downstream pathways revealed very modest effects on canonical Wnt signaling. Alternatively, we find pronounced effects on the direct PLAGL2 target genes IGF2, a fetal growth factor, and ASCL2, an intestinal stem cell-specific bHLH transcription factor. Inactivation of PLAGL2 in CRC cell lines has pronounced effects on ASCL2 reporter activity. Furthermore, ASCL2 expression can partially rescue deficits of proliferation and cell cycle progression caused by depletion of PLAGL2 in CRC cell lines. Thus, the oncogenic effects of PLAGL2 appear to be mediated via core stem cell and onco-fetal pathways, with minimal effects on downstream Wnt signaling.

scholarly journals Expressions of Cell Cycle Regulators in Human Colorectal Cancer Cell Lines

1997 ◽  
Vol 88 (9) ◽  
pp. 855-860 ◽  
Author(s):  
Osamu Tominaga ◽  
Marcelo Eidi Nita ◽  
Hirokazu Nagawa ◽  
Shin Fujii ◽  
Takashi Tsuruo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Colorectal Cancer Cell ◽  
Cell Cycle Regulators ◽  
Human Colorectal Cancer ◽  
Human Colorectal Cancer Cell ◽  
Colorectal Cancer Cell Lines

scholarly journals A tumor suppressive role of lncRNA GAS5 in human colorectal cancer

2016 ◽  
Vol 11 (1) ◽  
pp. 105-109 ◽  
Author(s):  
Yan Lei ◽  
Li Jing-jing ◽  
Zhang Ke-nan ◽  
Tian Qing-zhong ◽  
Li Jin
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Growth ◽  
Cyclin D1 ◽  
Cell Lines ◽  
Growth Arrest ◽  
Cell Cycle Distribution ◽  
Human Colorectal Cancer ◽  
Western Blots

AbstractObjectiveIt is already known that long non-coding RNA growth arrest-specific 5 (GAS5) is downregulated in human colorectal cancer (CRC) cells inhibiting cell proliferation. We further analyzed its involvement in cell cycle distribution and apoptosis induction.MethodsWe measured the expression level of GAS5 in CRC tissues and cell lines with the corresponding non-tumoral cells. We also analyzed the roles of GAS5 in modulation of cell growth, cell cycle distribution and apoptosis by the CCK-8 method and flow cytometry. Western blots were performed to evaluate the protein level of cyclin D1 and p21 after overexpression of GAS5ResultsGAS5 expression was significantly reduced in CRC samples and cell lines. Overexpression of GAS5 induced cell growth arrest and induced cell apoptosis in vitro. Meanwhile, we found that the growth suppressive role of GAS5 might be attributed to the inhibition of G1-S phase transition, reflected by the downregulation of cyclin D1 and upregulation of p21.ConclusionOur results demonstrate that GAS5 is a crucial tumor suppressor in human CRC cells.

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