Nuclear Factor of Activated T-cell Activity Is Associated with Metastatic Capacity in Colon Cancer

Tripathi, Manish K.; Deane, Natasha G.; Zhu, Jing; An, Hanbing; Mima, Silvana; Wang, Xiaojing; Padmanabhan, Sekhar; Shi, Zhiao; Prodduturi, Naresh; Ciombor, Kristen K.; Chen, Xi; Washington, Mary Kay; Zhang, Bing; Beauchamp, R. Daniel

doi:10.1158/0008-5472.can-14-1592

Cited by 106 publications

(88 citation statements)

References 36 publications

(42 reference statements)

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“…We only included positive correlations in our analysis because we found that a strong negative correlation between two genes did not necessarily correspond to high functional similarity between the genes (supplemental Fig. S1), which is consistent with previous reports (36, 37). …”

Section: Methodssupporting

confidence: 81%

Proteome Profiling Outperforms Transcriptome Profiling for Coexpression Based Gene Function Prediction

Wang

Carr

et al. 2017

Molecular & Cellular Proteomics

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122

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Coexpression of mRNAs under multiple conditions is commonly used to infer cofunctionality of their gene products despite well-known limitations of this “guilt-by-association” (GBA) approach. Recent advancements in mass spectrometry-based proteomic technologies have enabled global expression profiling at the protein level; however, whether proteome profiling data can outperform transcriptome profiling data for coexpression based gene function prediction has not been systematically investigated. Here, we address this question by constructing and analyzing mRNA and protein coexpression networks for three cancer types with matched mRNA and protein profiling data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Our analyses revealed a marked difference in wiring between the mRNA and protein coexpression networks. Whereas protein coexpression was driven primarily by functional similarity between coexpressed genes, mRNA coexpression was driven by both cofunction and chromosomal colocalization of the genes. Functionally coherent mRNA modules were more likely to have their edges preserved in corresponding protein networks than functionally incoherent mRNA modules. Proteomic data strengthened the link between gene expression and function for at least 75% of Gene Ontology (GO) biological processes and 90% of KEGG pathways. A web application Gene2Net (http://cptac.gene2net.org) developed based on the three protein coexpression networks revealed novel gene-function relationships, such as linking ERBB2 (HER2) to lipid biosynthetic process in breast cancer, identifying PLG as a new gene involved in complement activation, and identifying AEBP1 as a new epithelial-mesenchymal transition (EMT) marker. Our results demonstrate that proteome profiling outperforms transcriptome profiling for coexpression based gene function prediction. Proteomics should be integrated if not preferred in gene function and human disease studies.

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Section: Methodssupporting

confidence: 81%

Proteome Profiling Outperforms Transcriptome Profiling for Coexpression Based Gene Function Prediction

Wang

Carr

et al. 2017

Molecular & Cellular Proteomics

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122

104

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“…It has been demonstrated that the sustained activity of NFAT2 is able to induce transformation hallmarks (Fig. 2) (9,49) and is linked to some malignant transformations, such as Burkitt lymphoma, DLBCL, T-cell acute lymphoblastic leukemia ((T-ALL), CLL, melanoma, and pancreatic and colorectal carcinomas (11,(20)(21)(22)(23)50). NFAT2 also regulates genes important for tumorigenesis and tumor development, including those for c-myc, BLyS, and Cox-2 (11,(51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have suggested the oncogenic potential of the NFAT family member NFAT2. NFAT2 was fundamental for pancreatic cancer progression and contributed to the survival of melanoma cells and the metastatic potential of colorectal cancer cells (11,20,21). Furthermore, NFAT2 was activated in 70% of Burkitt lymphoma cases and in ϳ30% of diffuse large B cell lymphoma (DLBCL) cases and was overexpressed and activated in cases of chronic lymphocytic leukemia (CLL) (22,23).…”

mentioning

confidence: 99%

NFAT2 Isoforms Differentially Regulate Gene Expression, Cell Death, and Transformation through Alternative N-Terminal Domains

Lucena

Faget

Pachulec

et al. 2016

Molecular and Cellular Biology

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bThe NFAT (nuclear factor of activated T cells) family of transcription factors is composed of four calcium-responsive proteins (NFAT1 to -4). The NFAT2 (also called NFATc1) gene encodes the isoforms NFAT2␣ and NFAT2␤ that result mainly from alternative initiation exons that provide two different N-terminal transactivation domains. However, the specific roles of the NFAT2 isoforms in cell physiology remain unclear. Because previous studies have shown oncogenic potential for NFAT2, this study emphasized the role of the NFAT2 isoforms in cell transformation. Here, we show that a constitutively active form of NFAT2␣ (CA-NFAT2␣) and CA-NFAT2␤ distinctly control death and transformation in NIH 3T3 cells. While CA-NFAT2␣ strongly induces cell transformation, CA-NFAT2␤ leads to reduced cell proliferation and intense cell death through the upregulation of tumor necrosis factor alpha (TNF-␣). CA-NFAT2␤ also increases cell death and upregulates Fas ligand (FasL) and TNF-␣ in CD4 ؉ T cells. Furthermore, we demonstrate that differential roles of NFAT2 isoforms in NIH 3T3 cells depend on the N-terminal domain, where the NFAT2␤-specific N-terminal acidic motif is necessary to induce cell death. Interestingly, the NFAT2␣ isoform is upregulated in Burkitt lymphomas, suggesting an isoform-specific involvement of NFAT2 in cancer development. Finally, our data suggest that alternative N-terminal domains of NFAT2 could provide differential mechanisms for the control of cellular functions.

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“…Additional supplements were added in the growth medium for YAMC cells as previously described (20). The integrity of cell lines used in this study is described in our recent publications (21). The patient-derived xenograft line, CR-IGR-0034P, was purchased from Oncodesign, France.…”

Section: Methodsmentioning

confidence: 99%

The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer

Wang

Neitzel

et al. 2017

Clinical Cancer Research

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Purpose The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer (CRC). Experimental Design Using a panel of molecularly defined CRC cell lines, we examined the impact of BET inhibition on cellular proliferation and survival as well as MYC activity. We further tested the ability of inhibitors targeting the RAF/MEK/ERK (MAPK) pathway to enhance MYC suppression and circumvent intrinsic resistance to BET inhibitors. Key findings were validated using genetic approaches. Results BET inhibitors as monotherapy moderately reduced CRC cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized CRC cells to BET inhibitors, leading to potent apoptosis and MYC downregulation in vitro and in vivo. A combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous CRC xenografts. Conclusions Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in CRC and propose an effective combination strategy for the treatment of CRC.

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Nuclear Factor of Activated T-cell Activity Is Associated with Metastatic Capacity in Colon Cancer

Cited by 106 publications

References 36 publications

Proteome Profiling Outperforms Transcriptome Profiling for Coexpression Based Gene Function Prediction

Proteome Profiling Outperforms Transcriptome Profiling for Coexpression Based Gene Function Prediction

NFAT2 Isoforms Differentially Regulate Gene Expression, Cell Death, and Transformation through Alternative N-Terminal Domains

The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer

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