Abstract
TRPV4 belongs to the ‘Transient Receptor Potential’ (TRP) superfamily. It has been identified to profoundly affect a variety of physiological processes, including nociception, heat sensation and inflammation. Unlike other TRP superfamily channels, its role in cancers are unknown until recently when we reported TRPV4 to be required for cancer cell softness that may promote breast cancer cell extravasation and metastasis. Here, we elucidated the molecular mechanisms mediated by TRPV4 in the metastatic breast cancer cells. TRPV4-mediated signaling was demonstrated to involve Ca2+-dependent activation of AKT and downregulation of E-cadherin expression, which was abolished upon TRPV4 silencing. Functionally, TRPV4-enhanced breast caner cell transendothelial migration requires AKT activity while a combination of transcriptional and post-translational regulation contributed to the TRPV4-mediated E-cadherin downregulation. Finally, mass spectrometry analysis revealed that TRPV4 is required for the expression of a network of secreted proteins involved in extracellular matrix remodeling. In conclusion, TRPV4 may regulate breast cancer metastasis by regulating cell softness through the Ca2+-dependent AKT-E-cadherin signaling axis and regulation of the expression of extracellular proteins.
Highlights
Despite the relatively high survival rate of patients with early-stage breast cancers, the 5-year survival rate after diagnosis of stage-4 breast cancer, involving spread of tumor cells to other organs, is considerably low (22%).[1]
Analysis of 761 samples revealed that TRPV4 expression is significantly different between normal, invasive ductal carcinoma (IDC) and metastatic (Mets) lesions
This is consistent with our previous data that implicated a mechanical role of TRPV4 overexpression in metastasis by promoting cancer cell softness and migration.[15] sion is accompanied by an increase in the TRPV4 expression, suggesting a possible link between TRPV4 overexpression and emergence of metastatic traits
Summary
Despite the relatively high survival rate of patients with early-stage breast cancers, the 5-year survival rate after diagnosis of stage-4 breast cancer, involving spread of tumor cells to other organs, is considerably low (22%).[1]. TRPV4 activation induced protein kinase B (PKB/AKT) phosphorylation and downregulation of cell cortex proteins E-cadherin expression.
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