1. NFAT promotes carcinoma invasive migration through glypican-6
- Author
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Y. Rebecca Chin, Aura Kaunisto, Gary K. Yiu, and Alex Toker
- Subjects
Glypican ,PEI, polyethyleimine ,Biochemistry ,glypican ,p38 Mitogen-Activated Protein Kinases ,COX-2, cyclo-oxygenase-2 ,0302 clinical medicine ,Cell Movement ,10. No inequality ,Wnt Signaling Pathway ,transcription factor ,beta Catenin ,0303 health sciences ,HA, haemagglutinin ,RT, reverse transcription ,Wnt signaling pathway ,NFAT ,TCF, T-cell factor ,3. Good health ,Cell biology ,GAPDH, glyceraldehyde-3-phosphate dehydrogenase ,030220 oncology & carcinogenesis ,shRNA, small-hairpin RNA ,JNK, c-Jun N-terminal kinase ,Female ,cancer invasion ,AP-1, activator protein-1 ,LPA, lysophosphatidic acid ,Research Article ,dox, doxycycline ,Transcriptional Activation ,Beta-catenin ,DYRK, dual-specificity tyrosine-phosphorylated and -regulated kinase ,Breast Neoplasms ,Biology ,EMSA, electrophoretic mobility-shift assay ,Wnt-5a Protein ,03 medical and health sciences ,breast cancer ,Glypicans ,Cell Line, Tumor ,Proto-Oncogene Proteins ,PGE2, prostaglandin E2 ,Gene silencing ,Humans ,Neoplasm Invasiveness ,Molecular Biology ,Transcription factor ,030304 developmental biology ,EGF, epidermal growth factor ,nuclear factor of activated T-cells (NFAT) ,NFATC Transcription Factors ,JNK Mitogen-Activated Protein Kinases ,Cell Biology ,Wnt Proteins ,NFAT, nuclear factor of activated T-cells ,siRNA, small interfering RNA ,Cancer cell ,Cancer research ,biology.protein ,ENPP2, exonucloeotide pyrophosphatase and phosphodiesterase 2 ,GPC, glypican ,MAPK, mitogen-activated protein kinase - Abstract
Invasive migration of carcinoma cells is a prerequisite for the metastatic dissemination of solid tumours. Numerous mechanisms control the ability of cancer cells to acquire a motile and invasive phenotype, and subsequently degrade and invade the basement membrane. Several genes that are up-regulated in breast carcinoma are responsible for mediating the metastatic cascade. Recent studies have revealed that the NFAT (nuclear factor of activated T-cells) is a transcription factor that is highly expressed in aggressive breast cancer cells and tissues, and mediates invasion through transcriptional induction of pro-invasion and migration genes. In the present paper we demonstrate that NFAT promotes breast carcinoma invasion through induction of GPC (glypican) 6, a cell-surface glycoprotein. NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. The mechanism by which GPC6 promotes invasive migration involves inhibition of canonical β-catenin and Wnt signalling, and up-regulation of non-canonical Wnt5A signalling leading to the activation of JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase). Thus GPC6 is a novel NFAT target gene in breast cancer cells that promotes invasive migration through Wnt5A signalling.
- Published
- 2011