RGC-32 Mediates Transforming Growth Factor-β-induced Epithelial-Mesenchymal Transition in Human Renal Proximal Tubular Cells

Huang, Wenyan; Li, Zuguo; Rus, Horea; Wang, Xiaoyan; José, Pedro A.; Chen, Shiyou

doi:10.1074/jbc.m900039200

Cited by 67 publications

(82 citation statements)

References 48 publications

(35 reference statements)

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“…The phase II metabolizing enzyme SULT1C2, which was upregulated by at least 20 chemicals in vitro (fold change >3) and revealed significantly increased expression levels in diseased liver tissue, provides one example of a gene that is deregulated in both the in vitro and the in vivo situation. Similarly, CYP3A7, the predominant cytochrome P450 in human fetal liver (Pang et al 2012) and the p53-induced gene RGCC (Huang et al 2009;Saigusa et al 2007) were increased by chemical exposure in vitro and in at least two of the studied human liver conditions. Genes that were downregulated by at least 20 chemicals (more than threefold compared to controls) and showed significantly lower expression levels in at least two liver diseases include the aldehyde dehydrogenase family members ALDH8A1 and ADH4, the steroland fatty acid-metabolizing cytochrome P450 isoenzymes CYP8B1 and CYP4A11, the urea cycle enzyme CPS1, the gluconeogenesis key enzyme PCK1, the membrane-associated ATP-binding cassette transporter ABCA8, and the glucose transporter SLC2A2.…”

Section: Overrepresented Gene Ontology Groups and Transcription Factomentioning

confidence: 88%

“…Relatively little is known about this gene. It was previously reported to cause epithelial to mesenchymal transition in kidney cells (Huang et al 2009), and to represent a p53 Fig. 10 Overlap between genes altered by the test compounds (a SV20 genes, b SV3 genes) and genes altered by the human liver diseases non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular cancer (HCC).…”

Section: Human Disease Genesmentioning

confidence: 99%

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Toxicogenomics directory of chemically exposed human hepatocytes

et al. 2014

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A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge this gap, we used the Open TG-GATES database with Affymetrix files of cultivated human hepatocytes incubated with chemicals, further sets of gene array data with hepatocytes from human donors generated in this study, and publicly available genome-wide datasets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 143 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics directory (http://wiki.toxbank.net/toxicogenomics-map/) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The directory also informs about the following key features of chemically influenced genes: (1) Stereotypical stress response. When chemicals induce strong expression alterations, this usually includes a complex but highly reproducible pattern named 'stereotypical response.' On the other hand, more specific expression responses exist that are induced only by individual compounds or small numbers of compounds. The directory differentiates if the gene is part of the stereotypical stress response or if it represents a more specific reaction. (2) Liver disease-associated genes. Approximately 20 % of the genes influenced by chemicals are up- or downregulated, also in liver disease. Liver disease genes deregulated in cirrhosis, HCC, and NASH that overlap with genes of the aforementioned stereotypical chemical stress response include CYP3A7, normally expressed in fetal liver; the phase II metabolizing enzyme SULT1C2; ALDH8A1, known to generate the ligand of RXR, one of the master regulators of gene expression in the liver; and several genes involved in normal liver functions: CPS1, PCK1, SLC2A2, CYP8B1, CYP4A11, ABCA8, and ADH4. (3) Unstable baseline genes. The process of isolating and the cultivation of hepatocytes was sufficient to induce some stress leading to alterations in the expression of genes, the so-called unstable baseline genes. (4) Biological function. Although more than 2,000 genes are transcriptionally influenced by chemicals, they can be assigned to a relatively small group of biological functions, including energy and lipid metabolism, inflammation and immune response, protein modification, endogenous and xenobiotic metabolism, cytoskeletal organization, stress response, and DNA repair. In conclusion, the introduced toxicotranscriptomics directory offers a basis for a rationale choice of candidate genes for biomarker evaluation studies and represents an easy to use source of background information on chemically infl...

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Section: Overrepresented Gene Ontology Groups and Transcription Factomentioning

confidence: 88%

Section: Human Disease Genesmentioning

confidence: 99%

Toxicogenomics directory of chemically exposed human hepatocytes

et al. 2014

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“…These include angiogenesis, invasion and metastasis, suppression of antitumor CD8 + T-cells (77), and epithelial-to-mesenchymal transition (EMT) in numerous tumor types (77). Intriguingly, one of the downstream targets of TGF-β seems to be RGC-32, which has also been shown to regulate EMT (80,81). Not only has RGC-32 been implicated in control of the cell cycle and cancer (58-60) but it also shows upstream control by complement proteins, similar to TGF-β.…”

Section: Complement Sustains Tumorigenesismentioning

confidence: 99%

Cancer and the Complement Cascade

Rutkowski

Sughrue

Kane

et al. 2010

Molecular Cancer Research

219

245

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Despite significant research on the role of inflammation and immunosurveillance in the immunologic microenvironment of tumors, little attention has been given to the oncogenic capabilities of the complement cascade. The recent finding that complement may contribute to tumor growth suggests an insidious relationship between complement and cancer, especially in light of evidence that complement facilitates cellular proliferation and regeneration. We address the hypothesis that complement proteins promote carcinogenesis and suggest mechanisms by which complement can drive the fundamental features of cancer. Evidence shows that this diverse family of innate immune proteins facilitates dysregulation of mitogenic signaling pathways, sustained cellular proliferation, angiogenesis, insensitivity to apoptosis, invasion and migration, and escape from immunosurveillance. Given that the traditionally held functions for the complement system include innate immunity and cancer defense, our review suggests a new way of thinking about the role of complement proteins in neoplasia.

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“…1). We have reported that the response gene to complement 32 (RGC-32) is a downstream target of TGF-␤ signaling, which mediates the EMT in renal proximal tubule cells (9,16,19). The SMAD cascade is not implicated in the TGF-␤ effect on Cx43 expression in the mammary gland (26).…”

mentioning

confidence: 99%