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Regulation of complement-dependent cytotoxicity by TGF-β-induced epithelial-mesenchymal transition
M T Goswami1, A K Reka1, H Kurapati1
1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA.
Oncogene
|July 7, 2015
Summary
Epithelial-mesenchymal transition (EMT) in lung cancer promotes immune evasion and metastasis by increasing CD59 expression. Inhibiting CD59 may enhance cancer therapies and reduce metastasis.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Epithelial-mesenchymal transition (EMT) confers traits like immune evasion and therapy resistance to cancer cells.
- EMT is linked to tumor metastasis and progression.
- The complement cascade is implicated in EMT-associated gene expression changes.
Purpose of the Study:
- To investigate if EMT confers resistance to complement-dependent cytotoxicity (CDC) in lung cancer.
- To determine the role of CD59 in EMT-mediated immune evasion and tumor progression.
- To explore CD59 inhibition as a therapeutic strategy.
Main Methods:
- Transforming growth factor-β (TGF-β)-induced EMT in lung cancer cells.
- Analysis of CD59 expression and its role in complement-dependent cytotoxicity (CDC).
- Smad3 dependency and Smad3 binding to the CD59 promoter via chromatin immunoprecipitation.
Main Results:
- TGF-β-induced EMT increased cell surface CD59 expression.
- CD59 knockdown restored sensitivity to cetuximab-mediated CDC in EMT cells.
- Smad3 directly regulates TGF-β-induced CD59 expression.
- CD59 knockdown inhibited experimental lung cancer metastasis.
Conclusions:
- TGF-β-induced EMT and subsequent CD59 upregulation provide an immune-evasive mechanism for disseminating tumor cells.
- CD59 inhibition can enhance antibody-mediated therapies and inhibit lung cancer metastasis.
- Targeting CD59 represents a potential strategy for improving lung cancer treatment outcomes.
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