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Thy1 (CD90) Expression Is Elevated in Radiation-Induced Periprosthetic Capsular Contracture: Implication for Novel Therapeutics.

ABSTRACT: Capsular contracture is a devastating complication of postmastectomy implant-based breast reconstruction. Unfortunately, capsular contracture rates are drastically increased by targeted radiotherapy, a standard postmastectomy treatment. Thy1 (also called CD90) is important in myofibroblast differentiation and scar tissue formation. However, the impact of radiotherapy on Thy1 expression and the role of Thy1 in capsular contracture are unknown.The authors analyzed Thy1 expression in primary human capsular tissue and primary fibroblast explants by real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. Thy1 was depleted using RNA interference to determine whether Thy1 expression was essential for the myofibroblast phenotype in capsular fibroblasts. Furthermore, human capsular fibroblasts were treated with a new antiscarring compound, salinomycin, to determine whether Thy1 expression and myofibroblast formation were blocked by salinomycin.In this article, the authors show that radiation therapy significantly increased Thy1 mRNA and protein expression in periimplant scar tissue. Capsular fibroblasts explanted from scar tissue retained the ability to make the myofibroblast-produced scar-forming components collagen I and ?-smooth muscle actin. Depletion of Thy1 decreased the fibrotic morphology of capsular fibroblasts and significantly decreased ?-smooth muscle actin and collagen levels. Furthermore, the authors show for the first time that salinomycin decreased Thy1 expression and prevented myofibroblast formation in capsular fibroblasts.These data reveal that ionizing radiation-induced Thy1 overexpression may contribute to increased capsular contracture severity, and fibroblast scar production can be ameliorated through targeting Thy1 expression. Importantly, the authors' new results show promise for the antiscarring ability of salinomycin in radiation-induced capsular contracture.Therapeutic, V.

SUBMITTER: Hansen TC

PROVIDER: S-EPMC5531053 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Thy1 (CD90) Expression Is Elevated in Radiation-Induced Periprosthetic Capsular Contracture: Implication for Novel Therapeutics.

Hansen Trevor C TC Woeller Collynn F CF Lacy Shannon H SH Koltz Peter F PF Langstein Howard N HN Phipps Richard P RP

Plastic and reconstructive surgery 20170801 2

<h4>Background</h4>Capsular contracture is a devastating complication of postmastectomy implant-based breast reconstruction. Unfortunately, capsular contracture rates are drastically increased by targeted radiotherapy, a standard postmastectomy treatment. Thy1 (also called CD90) is important in myofibroblast differentiation and scar tissue formation. However, the impact of radiotherapy on Thy1 expression and the role of Thy1 in capsular contracture are unknown.<h4>Methods</h4>The authors analyze ...[more]

PMID: 28746279

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Project description:We had previously shown that THY1 (CD90) is a tumor suppressor in nasopharyngeal carcinoma (NPC) and that its down-regulation and loss of expression are associated with tumor metastasis, yet the mechanism leading to such effects remains unknown. In this study we show that tumor invasion could be suppressed by THY1 via adherens junction formation in a few NPC cell lines, and knockdown of THY1 would disrupt this cell-cell adhesion phenotype. Mechanistically, the activity of the SRC family kinase (SFK) member, SRC, and canonical Wnt signaling were dramatically reduced when THY1 was constitutively expressed. Previous studies by others have found that high levels of SRC activity in NPCs are associated with EMT and a poor prognosis. We hypothesized that THY1 can suppress tumor invasion in NPC via inhibition of SRC. By gene silencing of SRC, we found that the in vitro NPC cell invasion was significantly reduced and adherens junctions were restored. Through proteomic analysis, we identified that platelet-derived growth factor receptor β (PDGF-Rβ) and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) are novel and potential binding partners of THY1, which were subsequently verified by co-immunoprecipitation (co-IP) analysis. The ligand of PDGF-Rβ (PDGF-BB) could highly induce SRC activation and NPC cell invasion, which could be almost completely suppressed by THY1 expression. On the other hand, the PTPN22 siRNA could enhance both the SRC activities and the cell invasion and could also disrupt the adherens junctions in the THY1-expressing NPC cells; the original THY1-induced phenotypes were reverted when the PTPN22 expression was reduced. Together, our results identified that PTPN22 is essential for THY1 to suppress cell invasion and SRC activity, maintain tight adherens junctions, and prevent NPC metastasis. These results suggested that PDGF-Rβ and SRC can be used as drug targets for suppressing NPC metastasis. Indeed, our in vivo assay using the SRC inhibitor KX2-391, clearly showed that inhibition of SRC signaling can prevent the metastasis of NPC, indicating that targeting SRC can be a promising approach to control the NPC progression.

Dataset Information

Thy1 (CD90) Expression Is Elevated in Radiation-Induced Periprosthetic Capsular Contracture: Implication for Novel Therapeutics.

Publications

Thy1 (CD90) Expression Is Elevated in Radiation-Induced Periprosthetic Capsular Contracture: Implication for Novel Therapeutics.

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