Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Morphogenesis of malignant tumors is characterized by proliferation, invasive growth and metastasis. Although these properties are determined mainly by genetic derangements, their biological behavior within tissues is strictly regulated by tumor microenvironment, which consists of extracellular matrix, proteinases, soluble factors (cytokines/growth factors/chemokines), stromal cells and blood vessels. Thus, modulation of the microenvironment is implicated in morphogenesis in tumorigenesis. ADAMs (a disintegrin and metalloproteinases) are a new gene family of membrane-anchored and secreted proteins that have proteolytic and/or adhesive properties. They are involved in biological events including cell adhesion, cell fusion, membrane protein shedding and proteolysis. We examined the expression of the proteinase-type ADAMs in the invasive breast and lung carcinoma tissues, and found that membrane-anchored ADAM28m and secreted ADAM28s are selectively overexpressed in activated forms by carcinoma cells. The mRNA expression levels directly correlated with the proliferative activity of the carcinoma cells in both carcinomas, and with lymph node metastasis in the lung carcinomas. Our experimental studies showed that ADAM28 plays a key role in cancer cell proliferation through enhancing bioavailability of insulin-like growth factor-I (IGF-I) released from the IGF-I/IGF-binding protein 3 (IGFBP-3) complex by selective cleavage of IGFBP-3. We also identified P-selectin glycoprotein ligand-1 (PSGL-1) as a binding protein to ADAM28 by yeast two-hybrid system, and demonstrated that ADAM28s promotes PSGL-1/P-selectin-mediated HL-60 cell rolling adhesion to endothelial cells and subsequent transendothelial migration into tissue spaces. Altogether, our data suggest the possibility that ADAM28 expressed by cancer cells is involved in cancer cell proliferation and metastases in human cancers through modulation of tumor microenvironment and cell adhesion.
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PMID:Modulation of the microenvironment and adhesion of cancer cells by ADAMs (a disintegrin and metalloproteinase). 1831 93

ADAM28 (a disintegrin and metalloproteinase 28) is abundantly expressed by carcinoma cells in the human breast and non-small cell lung carcinomas, and plays a role in carcinoma cell growth and metastasis. Although Src is an inducer of ADAM28 gene expression through the PI3K/AKT/mTOR and MEK/ERK pathways, direct transcriptional regulators for ADAM28 gene expression remain unknown. In this study, we performed the luciferase reporter assay and found that SOX4 (SRY-related HMG-box 4), an inducer of epithelial-mesenchymal transition (EMT), is a transcriptional activator for the ADAM28 gene. This activation required the SOX4-binding consensus sequence at the 5'-untranslated region of the mouse and human ADAM28 genes. Forced expression of SOX4 promoted the ADAM28 gene expression and migration in human breast and lung carcinoma cell lines. In the human breast and lung carcinoma tissues, ADAM28 and SOX4 were co-expressed at the invasive front of carcinoma cell nests. Our data demonstrate that SOX4 transactivates ADAM28 gene expression through direct binding to the ADAM28 promoter region and suggest the possibility that ADAM28 plays a role in invasion through SOX4-mediated EMT in the human breast and lung carcinomas.
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PMID:SOX4, an epithelial-mesenchymal transition inducer, transactivates ADAM28 gene expression and co-localizes with ADAM28 at the invasive front of human breast and lung carcinomas. 2988 45