Abstract
BackgroundWe have previously validated three novel CD44-downstream positively regulated transcriptional targets, including Cortactin, Survivin and TGF-β2, and further characterized the players underlying their separate signaling pathways. In the present study, we identified CD146 as a potential novel target, negatively regulated by CD44. While the exact function of CD146 in breast cancer (BC) is not completely understood, substantial evidence from our work and others support the hypothesis that CD146 is a suppressor of breast tumor progression.MethodsTherefore, using molecular and pharmacological approaches both in vitro and in breast tissues of human samples, the present study validated CD146 as a novel target of CD44-signaling suppressed during BC progression.ResultsOur results revealed that CD44 activation could cause a substantial decrease of CD146 expression with an equally notable converse effect upon CD44-siRNA inhibition. More interestingly, activation of CD44 decreased cellular CD146 and increased soluble CD146 through CD44-dependent activation of MMP.ConclusionHere, we provide a possible mechanism by which CD146 suppresses BC progression as a target of CD44-downstream signaling, regulating neovascularization and cancer cell motility.
Highlights
We have previously validated three novel CD44-downstream positively regulated transcriptional targets, including Cortactin, Survivin and TGF-β2, and further characterized the players underlying their separate signaling pathways
While some reports concluded that CD146 promotes breast cancer (BC) cell growth and metastasis [20, 21], other studies showed that CD146 inhibits BC progression [2, 22, 23]
In order to investigate the relationship between CD44 and CD146, MCF7-B5 cells, which allow the inducible expression of CD44, were stably co-transfected with a construct allowing the constitutive expression of CD146 (MCF7-B5-CD146 [3,4,5], named B4 clone)
Summary
We have previously validated three novel CD44-downstream positively regulated transcriptional targets, including Cortactin, Survivin and TGF-β2, and further characterized the players underlying their separate signaling pathways. Cell adhesion molecules (CAMs) are glycoproteins responsible for promoting cell-cell adhesion and cellextracellular matrix interactions [1]. Most cancerous cells exhibit loss of cell adhesion capability due to alteration in CAMs, which mediate the movement of cancer cells from their tissue of origin to the secondary sites of metastasis [2]. CD44 is a member of the immunoglobulin-like family, known to promote BC metastasis through binding of CD44 to its main ligand hyaluronan (HA), or to other ligands, such as osteopontin, fibronectin, collagen IV, and laminin [6].
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