LNK suppresses interferon signaling in melanoma.
Ling-Wen DingQiao-Yang SunJarem J EdwardsLucia Torres FernándezXue-Bin RanSi-Qin ZhouRichard A ScolyerJames S WilmottJohn F ThompsonNgan DoanJonathan W SaidNachiyappan VenkatachalamJin-Fen XiaoXin-Yi LohMaren PeinLiang XuDavid W MullinsHenry YangDe-Chen LinH Phillip KoefflerPublished in: Nature communications (2019)
LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases. We found that LNK is significantly elevated in cutaneous melanoma; this elevation is correlated with hyperactive signaling of the RAS-RAF-MEK pathway. Elevated LNK enhances cell growth and survival in adverse conditions. Forced expression of LNK inhibits signaling by interferon-STAT1 and suppresses interferon (IFN) induced cell cycle arrest and cell apoptosis. In contrast, silencing LNK expression by either shRNA or CRISPR-Cas9 potentiates the killing effect of IFN. The IFN-LNK signaling is tightly regulated by a negative feedback mechanism; melanoma cells exposed to IFN upregulate expression of LNK to prevent overactivation of this signaling pathway. Our study reveals an unappreciated function of LNK in melanoma and highlights the critical role of the IFN-STAT1-LNK signaling axis in this potentially devastating disease. LNK may be further explored as a potential therapeutic target for melanoma immunotherapy.
Keyphrases
- high glucose
- dendritic cells
- signaling pathway
- immune response
- poor prognosis
- crispr cas
- cell proliferation
- pi k akt
- cell death
- cell cycle arrest
- emergency department
- magnetic resonance imaging
- epithelial mesenchymal transition
- transcription factor
- bone marrow
- binding protein
- skin cancer
- climate change
- computed tomography
- risk assessment
- long non coding rna
- stress induced