CD30 Regulation of IL-13-STAT6 Pathway in Breast Implant-Associated Anaplastic Large Cell Lymphoma

Marshall E. Kadin, John Morgan, Wei Wei, Zhihui Song, Yibin Yang

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background: Breast implant-Associated anaplastic large cell lymphoma (BIA-ALCL) is a rare, usually indolent CD30+ T-cell lymphoma with tumor cells, often surrounded by eosinophils, expressing IL-13 and pSTAT6. Objectives: The aim of this study was to understand the unique tumor pathology and growth regulation of BIA-ALCL, leading to potential targeted therapies. Methods: We silenced CD30 and analyzed its effect on IL-13 signaling and tumor cell viability. IL-13 signaling receptors of BIA-ALCL cell lines were evaluated by flow cytometry and pSTAT6 detected by immunohistochemistry. CD30 was deleted by CRISPR/Cas9 editing. Effects of CD30 deletion on transcription of IL-13 and IL-4, and phosphorylation of STAT6 were determined by real-Time polymerase chain reaction and western blotting. The effect of CD30 deletion on p38 mitogen-Activated protein kinase (MAPK) phosphorylation was determined. Suppression of IL-13 transcription by a p38 MAPK inhibitor was tested. Tumor cell viability following CD30 deletion and treatment with a pSTAT6 inhibitor were measured in cytotoxicity assays. Results: BIA-ALCL lines TLBR1 and TLBR2 displayed signaling receptors IL-4Rα, IL-13Rα1 and downstream pSTAT6. Deletion of CD30 by CRISPR/Cas9 editing significantly decreased transcription of IL-13, less so Th2 cytokine IL-4, and phosphorylation of STAT6. Mechanistically, we found CD30 expression is required for p38 MAPK phosphorylation and activation, and IL-13-STAT6 signaling was reduced by an inhibitor of p38 MAPK in BIA-ALCL tumor cells. Tumor cell viability was decreased by silencing of CD30, and a specific inhibitor of STAT6, indicating STAT6 inhibition is cytotoxic to BIA-ALCL tumor cells. Conclusions: These findings suggest reagents targeting the IL-13 pathway, pSTAT6 and p38 MAPK, may become useful for treating BIA-ALCL patients.

Original languageEnglish
Pages (from-to)137-146
Number of pages10
JournalAesthetic Surgery Journal
Volume43
Issue number2
DOIs
StatePublished - Feb 1 2023

Keywords

  • Breast Implants/adverse effects
  • Breast Neoplasms/genetics
  • Female
  • Humans
  • Interleukin-13/metabolism
  • Interleukin-4/metabolism
  • Ki-1 Antigen/genetics
  • Lymphoma, Large-Cell, Anaplastic/etiology
  • STAT6 Transcription Factor/genetics
  • p38 Mitogen-Activated Protein Kinases/metabolism

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