ADAM23 is downregulated in side population and suppresses lung metastasis of lung carcinoma cells

Abstract

Cancer cells contain a small population of cancer stem cells or cancer initiating cells, which can be enriched in the side population (SP) after fluorescence activated cell sorting. To examine the members of the ADAM, ADAMTS and MMP gene families related to phenotypes of the SP and the main population (MP), we screened the expression of all the members in the propagated SP and MP of A549 lung adenocarcinoma cells, and found that the relative expression ratio of ADAM23 in the MP to the SP is most highly increased, but none of them are increased in the SP. A similar result on the ADAM23 expression was obtained with another cell line, Calu‐3 cells. Overexpression of ADAM23 inhibited colony formation, cell adhesion and migration, and knockdown of ADAM23 by shRNA showed the reverse effects. ADAM23‐mediated suppression of colony formation, cell adhesion and migration was greatly reduced by treatment with neutralizing anti‐ADAM23 antibody, anti‐αvβ3 integrin antibody and/or ADAM23 disintegrin peptide. Expression of cancer stem cell‐related genes, including AKRC1/2, TM4SF1 and NR0B1, was increased by knockdown of ADAM23. In addition, lung metastasis of A549 transfectants with different levels of ADAM23 expression was negatively regulated by the ADAM23 expression levels. Our data provide evidence that ADAM23 plays a role in suppression of cancer cell progression through interaction with αvβ3 integrin, and suggest that downregulation of ADAM23 in SP cells may contribute toward providing a cancer stem cell phenotype by facilitating the activity of integrin αvβ3.

A disintegrin and metalloprotease 23 hypermethylation predicts decreased disease‐free survival in low‐risk breast cancer patients

“…31 Additionally, downregulation of ADAM23 in a side population of lung adenocarcinoma cells contributed to the CSC phenotype, supposedly by promoting activity of α V β 3 integrin. 57 These findings support the hypothesis that by binding to integrins, namely α V β 3 and α4 and/or other cell-surface molecules, ADAM23 can act as a mediator of intercellular association and participate in facilitating EMT in cancer cells. 31,32 To the best of our knowledge, this is the and Ludovit Gaspar for their excellent technical assistance.…”

“…Activation of α V β 3 has been reported to upregulate Slug and facilitate anchorage‐independent growth in pregnant and neoplastic mammary glands whereas ADAM23 knockdown cells showed increased migration and adhesion to classic α V β 3 integrin ligands . Additionally, downregulation of ADAM23 in a side population of lung adenocarcinoma cells contributed to the CSC phenotype, supposedly by promoting activity of α V β 3 integrin . These findings support the hypothesis that by binding to integrins, namely α V β 3 and α4 and/or other cell‐surface molecules, ADAM23 can act as a mediator of intercellular association and participate in facilitating EMT in cancer cells …”

Expression of ADAMTS13 in Normal and Abnormal Placentae and Its Potential Role in Angiogenesis and Placenta Development

“…The disintegrin or cysteine-rich domains in other ADAMTS family members appear to regulate cell adhesion and migration;(42, 43) the active metalloproteinase domain can degrade extracellular matrix components, leading to the release of growth factors and cytokines, and subsequently promote cell proliferation, migration, and angiogenesis. (38, 44, 45) Conversely, the thrombospondin 1 (TSP1) motif is shown to inhibit angiogenesis by regulating interacting with vascular endothelial growth factor (VEGF) receptors, thereby regulating VEGF activity.…”

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

“…PC‐9 cells and MCF‐7 cells transfected with human SOX4 expression vectors or vectors alone (mock) were grown on confluence on six‐well plates (BD Biosciences, Bedford, MA, USA) in the culture media containing 10% FBS and antibiotics. They were scratch‐wounded with a blue pipette tip, and cell migration activity in the media containing 5 mM hydroxyurea (Sigma‐Aldrich) was determined as described previously …”

“…They were scratch-wounded with a blue pipette tip, and cell migration activity in the media containing 5 mM hydroxyurea (Sigma-Aldrich) was determined as described previously. 27…”