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MicroRNA-584 and the protein phosphatase and actin regulator 1 (PHACTR1), a new signaling route through which transforming growth factor-? Mediates the migration and actin dynamics of breast cancer cells.

ABSTRACT: TGF-? plays an important role in breast cancer progression as a prometastatic factor, notably through enhancement of cell migration. It is becoming clear that microRNAs, a new class of small regulatory molecules, also play crucial roles in mediating tumor formation and progression. We found TGF-? to down-regulate the expression of the microRNA miR-584 in breast cancer cells. Furthermore, we identified PHACTR1, an actin-binding protein, to be positively regulated by TGF-? in a miR-584-dependent manner. Moreover, we found TGF-?-mediated down-regulation of miR-584 and increased expression of PHACTR1 to be required for TGF-?-induced cell migration of breast cancer cells. Indeed, both overexpression of miR-584 and knockdown of PHACTR1 resulted in a drastic reorganization of the actin cytoskeleton and reduced TGF-?-induced cell migration. Our data highlight a novel signaling route whereby TGF-? silences the expression of miR-584, resulting in enhanced PHACTR1 expression, and further leading to actin rearrangement and breast cancer cell migration.

SUBMITTER: Fils-Aime N

PROVIDER: S-EPMC3636869 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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MicroRNA-584 and the protein phosphatase and actin regulator 1 (PHACTR1), a new signaling route through which transforming growth factor-β Mediates the migration and actin dynamics of breast cancer cells.

Fils-Aimé Nadège N Dai Meiou M Guo Jimin J El-Mousawi Mayada M Kahramangil Bora B Neel Jean-Charles JC Lebrun Jean-Jacques JJ

The Journal of biological chemistry 20130311 17

TGF-β plays an important role in breast cancer progression as a prometastatic factor, notably through enhancement of cell migration. It is becoming clear that microRNAs, a new class of small regulatory molecules, also play crucial roles in mediating tumor formation and progression. We found TGF-β to down-regulate the expression of the microRNA miR-584 in breast cancer cells. Furthermore, we identified PHACTR1, an actin-binding protein, to be positively regulated by TGF-β in a miR-584-dependent m ...[more]

PMID: 23479725

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Project description:Genome-wide association studies (GWAS) have recently identified phosphatase and actin regulator-1 (PHACTR1) as a critical risk gene associated with polyvascular diseases. However, it remains largely unclear how PHACTR1 is involved in endothelial dysfunction. Here, by mining published datasets of human stable and vulnerable/ruptured plaque tissues, we observed upregulated expression of PHACTR1 in vulnerable/ruptured plaques. Congruent with these data, we demonstrated increased Phactr1 gene expression in aortic endothelium from ApoE-/- mice fed a western type diet compared with that in normal C57BL/6J mice. Relevantly, PHACTR1 gene expression was upregulated by pro-inflammatory and pro-atherogenic stimuli, including TNF-α, IL-1β and oxidized LDL (oxLDL). By employing next-generation RNA sequencing, we demonstrate that PHACTR1 overexpression disrupts pathways associated with endothelial homeostasis. Cell biological studies unravel that PHACTR1 mediates endothelial inflammation and monocyte adhesion by activating NF-κB dependent intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) expression. In addition, overexpression of PHACTR1 also reduces the generation of nitric oxide (NO) by inhibiting Akt/eNOS activation. In-house compound screening of vasoprotective drugs identifies several drugs, including lipid-lowering statins, decreases PHACTR1 gene expression. However, PHACTR1 gene expression was not affected by another lipid-lowering drug-fenofibrate. We also performed a proteomic study to reveal PHACTR1 interacting proteins and validated that PHACTR1 can interact with heat shock protein A8 (HSPA8) which was reported to be associated with coronary artery disease and eNOS degradation. Further studies are warranted to confirm the precise mechanism of PHACTR1 in driving endothelial dysfunction. In conclusion, by using systems biology approach and molecular validation, we disclose the deleterious effects of PHACTR1 on endothelial function by inducing endothelial inflammation and reducing NO production, highlighting the potential to prevent endothelial dysfunction and atherosclerosis by targeting PHACTR1 expression. The precise role of endothelial cell PHACTR1 in polyvascular diseases remains to be validated in diseased conditions.

Project description:Changes in intracellular calcium [Ca(2+)](i) levels control critical cytosolic and nuclear events that are involved in the initiation and progression of tumor angiogenesis in endothelial cells (ECs). Therefore, the mechanism(s) involved in agonist-induced Ca(2+)(i) signaling is a potentially important molecular target for controlling angiogenesis and tumor growth. Several studies have shown that blood vessels in tumors differ from normal vessels in their morphology, blood flow and permeability. We had previously reported a key role for arachidonic acid (AA)-mediated Ca(2+) entry in the initial stages of tumor angiogenesis in vitro. In this study we assessed the mechanism involved in AA-induced EC migration. We report that TRPV4, an AA-activated channel, is differentially expressed in EC derived from human breast carcinomas (BTEC) as compared with 'normal' EC (HMVEC). BTEC display a significant increase in TRPV4 expression, which was correlated with greater Ca(2+) entry, induced by AA or 4?PDD (a selective TRPV4 agonist) in the tumor-derived ECs. Wound-healing assays revealed a key role of TRPV4 in regulating cell migration of BTEC but not HMVEC. Knockdown of TRPV4 expression completely abolished AA-induced BTEC migration, suggesting that TRPV4 mediates the pro-angiogenic effects promoted by AA. Furthermore, pre-incubation of BTEC with AA induced actin remodeling and a subsequent increase in the surface expression of TRPV4. This was consistent with the increased plasma membrane localization of TRPV4 and higher AA-stimulated Ca(2+) entry in the migrating cells. Together, the data presented herein demonstrate that: (1) TRPV4 is differentially expressed in tumor-derived versus 'normal' EC; (2) TRPV4 has a critical role in the migration of tumor-derived but not 'normal' EC migration; and (3) AA induces actin remodeling in BTEC, resulting in a corresponding increase of TRPV4 expression in the plasma membrane. We suggest that the latter is critical for migration of EC and thus in promoting angiogenesis and tumor growth.

Dataset Information

MicroRNA-584 and the protein phosphatase and actin regulator 1 (PHACTR1), a new signaling route through which transforming growth factor-? Mediates the migration and actin dynamics of breast cancer cells.

Publications

MicroRNA-584 and the protein phosphatase and actin regulator 1 (PHACTR1), a new signaling route through which transforming growth factor-β Mediates the migration and actin dynamics of breast cancer cells.

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