Microenvironmental Regulation of Epithelial–Mesenchymal Transitions in Cancer

Gao, Dingcheng; Vahdat, Linda T.; Wong, Stephen T.C.; Chang, Jenny C.; Mittal, Vivek

doi:10.1158/0008-5472.can-12-1223

Cited by 272 publications

(256 citation statements)

References 70 publications

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“…Interestingly, we observe an initial down-regulation of VCAN upon immortalization (FPKM 3 to 0.3) and a subsequent up-regulation in the metastasizing cells (FPKM 1.4 to 5.4). It has previously been shown that VCAN can promote metastatic processes (34), and our results indicate that VCAN may have a dual role, both early and late in tumorigenesis.…”

Section: Validation Of Differentially Expressed Genes On the Protein supporting

confidence: 73%

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson

Skogs

Huss

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The transformation of normal cells to malignant, metastatic tumor cells is a multistep process caused by the sequential acquirement of genetic changes. To identify these changes, we compared the transcriptomes and levels and distribution of proteins in a fourstage cell model of isogenically matched normal, immortalized, transformed, and metastatic human cells, using deep transcriptome sequencing and immunofluorescence microscopy. The data show that ∼6% (n = 1,357) of the human protein-coding genes are differentially expressed across the stages in the model. Interestingly, the majority of these genes are down-regulated, linking malignant transformation to dedifferentiation. The up-regulated genes are mainly components that control cellular proliferation, whereas the down-regulated genes consist of proteins exposed on or secreted from the cell surface. As many of the identified gene products control basic cellular functions that are defective in cancers, the data provide candidates for follow-up studies to investigate their functional roles in tumor formation. When we further compared the expression levels of four of the identified proteins in clinical cancer cohorts, similar differences were observed between benign and cancer cells, as in the cell model. This shows that this comprehensive demonstration of the molecular changes underlying malignant transformation is a relevant model to study the process of tumor formation.C ancer development is a multistep process where genetic changes are accumulated, thus progressively transforming cells into a cancerous phenotype (1, 2). Over the last decades, numerous investigators have studied the underlying molecular mechanisms for malignant transformation. This has resulted in many models that explain the development of a malignant phenotype of human cells, for instance the "hallmarks of cancer" by Hanahan and Weinberg (3,4).With new technologies for deep sequencing, novel opportunities to study the underlying molecular events leading to cancers have emerged. A large number of investigations have analyzed mutations occurring in tumors, such as the analysis of mRNA expression, microRNA expression, and DNA copy number in a large number of tumors in the Cancer Genome Atlas (5). Similarly, the Human Protein Atlas project (6) studies human cancers using a proteome-wide collection of antibodies, resulting in publicly available immunohistochemistry images covering 20 different human cancer types.An interesting approach to studying the molecular mechanisms underlying cancer is to use an isogenically matched cell model in which normal cells are progressively transformed into malignant cells. There are several studies where genetic elements such as oncogenes have been introduced to different types of cells in an accumulative order as an attempt to mimic the natural steps of transformation (7,8). One such cell model is the fourstage model based on BJ fibroblasts developed by the Weinberg group, in which primary fibroblast cells were immortalized with telomerase reverse transcriptase (...

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Section: Validation Of Differentially Expressed Genes On the Protein supporting

confidence: 73%

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson

Skogs

Huss

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…32,37,38,50,51 Our findings that the TLR2 coregulates with TLR6 in MAM led us to the hypothesis that versican may be the relevant TLR2/6 ligand in myeloma BM. However, there are no reports in the literature regarding the role, or even the presence, of versican in the myeloma microenvironment.…”

Section: Resultsmentioning

confidence: 99%

“…Versican is a large extracellular matrix proteoglycan previously shown to enhance carcinoma metastasis through TLR2/6-mediated nonautonomous activation of myeloid cells in the metastatic niche. [32][33][34][35][36][37][38] However, versican had not previously been implicated in myeloma pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

TPL2 kinase regulates the inflammatory milieu of the myeloma niche

Hope

Ollar

Héninger

et al. 2014

Blood

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“…Thus, activation of the EMT is known to endow the invasive and metastatic properties upon cancer cells for the successful colonization of distal target organs (26). Previous studies also revealed that EMT is crucial in drug resistance to EGFR inhibitor in NSCLC (27) and promotes the cell invasion and metastatic property.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells

et al. 2013

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Abstract. Although ZNF746, also known as Parkin-interacting substrate (PARIS), has been reported to suppress peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and its target gene NRF-1 leading to the neurodegeneration in Parkinson's disease, its function in tumorigenesis has yet to be investigated. Thus, in the present study, the role of ZNF746 in the invasion and epithelial to mesenchymal transition (EMT) in H460 non-small cell lung cancer (NSCLC) cells was investigated. Invasion assay showed that inhibition of ZNF746 using siRNA transfection inhibited the invasion of H460 NSCLC cells using Boyden chamber. Quantitative PCR (qPCR) analysis revealed that the silencing of ZNF746 attenuated the expression of matrix metalloproteinase (MMP)1, MMP2 and MMP9, but not MMP7, in H460 NSCLC cells. Immunoblotting assay revealed that the expression of E-cadherin and β-catenin of epithelial phenotype was upregulated, while Slug was downregulated in ZNF746 siRNA-transfected H460 NSCLC cells. Accordingly, the mRNA expression of E-cadherin was upregulated while vimentin or Slug, Twist, ZEB as EMT key transcriptional factors were suppressed in ZNF746 siRNAtransfected H460 NSCLC cells. Also, mRNA expression of transcriptional marker Nanog and Octamer-binding transcription factor 4 (OCT4), known to enhance malignancy and metastasis in lung adenocarcinoma, was suppressed in ZNF746 siRNA-transfected H460 NSCLC cells. Notably, the endogenous expression of ZNF746 was induced in parallel with Twist at the protein level during hypoxia. Overall, our findings suggest that inhibition of ZNF746 suppresses the invasion and EMT molecules in H460 NSCLC cells and ZNF746 may be an important target molecule in lung tumorigenesis.

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Microenvironmental Regulation of Epithelial–Mesenchymal Transitions in Cancer

Cited by 272 publications

References 70 publications

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

TPL2 kinase regulates the inflammatory milieu of the myeloma niche

Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells

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