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Transcriptomic and Functional Pathway Analysis of Human Cervical Carcinoma Cancer Cells Response to Microtubule Inhibitor.

Wang J, Yan B, Liu SM, Sun H, Pan Y, Guan D, Zhang X, Xu J, Ma H - J Cancer (2015)

Bottom Line: We selected the concentration of vinblastine inducing 30% cell death for analyses assessing the DNA content, gene expression and transcriptional gene regulation of VBL-treated KB-3 cells.Transcriptomic and hierarchical clustering analysis demonstrated that treatment of KB-3 cells with VBL altered the expression of a diverse group of genes with G2/M arrest, which regulated by four oncogenic or tumor suppresser transcription factors (AP1, NFKB1, RELA, and TP53).Northern blots also confirmed that KRT-7, FN14, IER3, and ID1 were deregulated in VBL-treated KB-3 cells.

View Article: PubMed Central - PubMed

Affiliation: 1. Scientific Research Center, Shanghai Public Health Clinical Center, 2901 Caolang Road, Jinshan District, Shanghai 201508, China ; 2. Department of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT

Background: There clearly is a need for effective chemotherapy for early-stage, high-risk patients with human cervical carcinoma. Vinblastine (VBL) is a key microtubule inhibitor, but unproven in its mechanisms as an important antitumor agent in cervical carcinoma.

Methods: We selected the concentration of vinblastine inducing 30% cell death for analyses assessing the DNA content, gene expression and transcriptional gene regulation of VBL-treated KB-3 cells.

Results: Transcriptomic and hierarchical clustering analysis demonstrated that treatment of KB-3 cells with VBL altered the expression of a diverse group of genes with G2/M arrest, which regulated by four oncogenic or tumor suppresser transcription factors (AP1, NFKB1, RELA, and TP53). Functional pathway analysis revealed the disease response to the biological effects of vinblastine in cervical carcinoma chemotherapy including protein ubiquitination pathway, RhoGDI signaling, integrin signaling, agranulocyte adhesion and biapedesis, and actin nucleation pathways. Northern blots also confirmed that KRT-7, FN14, IER3, and ID1 were deregulated in VBL-treated KB-3 cells.

Conclusion: Transcriptional time series profiles and a functional pathway analysis of VBL-treated KB-3 cells will provide a new strategy for improving microtubule inhibitor chemotherapy for cervical carcinoma.

No MeSH data available.


Related in: MedlinePlus

Transcriptional gene regulatory network in VBL-treated KB-3 cell. Triangle nodes represent four TFs AP1, NFKB1, RELA and TP53. Circle nodes refer to target genes of at least two TFs. Orange nodes refer to genes jointly regulated by TP53 and other TFs.
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Figure 4: Transcriptional gene regulatory network in VBL-treated KB-3 cell. Triangle nodes represent four TFs AP1, NFKB1, RELA and TP53. Circle nodes refer to target genes of at least two TFs. Orange nodes refer to genes jointly regulated by TP53 and other TFs.

Mentions: It has been demonstrated that some oncogenic or tumor suppresser TFs are implicated in affecting gene expression programs in cervical cancer, such as NF-κB 14, 15, AP1 4, 14, and TP53 16. In order to elucidate how these cancer-related TFs affect the response of VBL-treated KB-3 cells, we employed a newly developed bioinformatics method to identify their target genes 11. As shown in Table 3, we display the predicted target genes of AP1, NFKB1, RELA, and TP53. Some target genes have been validated in previous studies, for example, CDKN1A (p21), DUSP5, IER3, ITGA5, RPS27L and SOD2 (Table 3). We constructed a transcriptional gene regulatory network controlled by the four TFs (Fig. 4). Noticed is that nine genes are co-targeted by oncogenic (AP1, NFKB1 and RELA) and tumor suppresser TFs (TP53), and involve biological processes apoptosis (CDKN1A and SPHK1), calcium-activated neutral proteinase (CAPN2), epidermis development (EMP1, ACTG1, KRT14, KRT15 and KRT17), and tumor-associated antigen (MAGED2). By contrast, the oncogenic TFs also regulate genes related with ubiquitin-protein modification (PSMD11 and PSMD1), apoptosis (IEG3), and cell adhesion (ITGA5 and MSN). This result indicates a possibility of transcriptional gene regulation that mediates the VBL-induced response in the cancer cells.


Transcriptomic and Functional Pathway Analysis of Human Cervical Carcinoma Cancer Cells Response to Microtubule Inhibitor.

Wang J, Yan B, Liu SM, Sun H, Pan Y, Guan D, Zhang X, Xu J, Ma H - J Cancer (2015)

Transcriptional gene regulatory network in VBL-treated KB-3 cell. Triangle nodes represent four TFs AP1, NFKB1, RELA and TP53. Circle nodes refer to target genes of at least two TFs. Orange nodes refer to genes jointly regulated by TP53 and other TFs.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4543753&req=5

Figure 4: Transcriptional gene regulatory network in VBL-treated KB-3 cell. Triangle nodes represent four TFs AP1, NFKB1, RELA and TP53. Circle nodes refer to target genes of at least two TFs. Orange nodes refer to genes jointly regulated by TP53 and other TFs.
Mentions: It has been demonstrated that some oncogenic or tumor suppresser TFs are implicated in affecting gene expression programs in cervical cancer, such as NF-κB 14, 15, AP1 4, 14, and TP53 16. In order to elucidate how these cancer-related TFs affect the response of VBL-treated KB-3 cells, we employed a newly developed bioinformatics method to identify their target genes 11. As shown in Table 3, we display the predicted target genes of AP1, NFKB1, RELA, and TP53. Some target genes have been validated in previous studies, for example, CDKN1A (p21), DUSP5, IER3, ITGA5, RPS27L and SOD2 (Table 3). We constructed a transcriptional gene regulatory network controlled by the four TFs (Fig. 4). Noticed is that nine genes are co-targeted by oncogenic (AP1, NFKB1 and RELA) and tumor suppresser TFs (TP53), and involve biological processes apoptosis (CDKN1A and SPHK1), calcium-activated neutral proteinase (CAPN2), epidermis development (EMP1, ACTG1, KRT14, KRT15 and KRT17), and tumor-associated antigen (MAGED2). By contrast, the oncogenic TFs also regulate genes related with ubiquitin-protein modification (PSMD11 and PSMD1), apoptosis (IEG3), and cell adhesion (ITGA5 and MSN). This result indicates a possibility of transcriptional gene regulation that mediates the VBL-induced response in the cancer cells.

Bottom Line: We selected the concentration of vinblastine inducing 30% cell death for analyses assessing the DNA content, gene expression and transcriptional gene regulation of VBL-treated KB-3 cells.Transcriptomic and hierarchical clustering analysis demonstrated that treatment of KB-3 cells with VBL altered the expression of a diverse group of genes with G2/M arrest, which regulated by four oncogenic or tumor suppresser transcription factors (AP1, NFKB1, RELA, and TP53).Northern blots also confirmed that KRT-7, FN14, IER3, and ID1 were deregulated in VBL-treated KB-3 cells.

View Article: PubMed Central - PubMed

Affiliation: 1. Scientific Research Center, Shanghai Public Health Clinical Center, 2901 Caolang Road, Jinshan District, Shanghai 201508, China ; 2. Department of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT

Background: There clearly is a need for effective chemotherapy for early-stage, high-risk patients with human cervical carcinoma. Vinblastine (VBL) is a key microtubule inhibitor, but unproven in its mechanisms as an important antitumor agent in cervical carcinoma.

Methods: We selected the concentration of vinblastine inducing 30% cell death for analyses assessing the DNA content, gene expression and transcriptional gene regulation of VBL-treated KB-3 cells.

Results: Transcriptomic and hierarchical clustering analysis demonstrated that treatment of KB-3 cells with VBL altered the expression of a diverse group of genes with G2/M arrest, which regulated by four oncogenic or tumor suppresser transcription factors (AP1, NFKB1, RELA, and TP53). Functional pathway analysis revealed the disease response to the biological effects of vinblastine in cervical carcinoma chemotherapy including protein ubiquitination pathway, RhoGDI signaling, integrin signaling, agranulocyte adhesion and biapedesis, and actin nucleation pathways. Northern blots also confirmed that KRT-7, FN14, IER3, and ID1 were deregulated in VBL-treated KB-3 cells.

Conclusion: Transcriptional time series profiles and a functional pathway analysis of VBL-treated KB-3 cells will provide a new strategy for improving microtubule inhibitor chemotherapy for cervical carcinoma.

No MeSH data available.


Related in: MedlinePlus