LNK suppresses interferon signaling in melanoma.

Autor: Ding LW; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Sun QY; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. qiaoyangsun@gmail.com., Edwards JJ; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, 2065, Australia.; Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia., Fernández LT; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Ran XB; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Zhou SQ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Scolyer RA; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, 2065, Australia.; Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia.; Royal Prince Alfred Hospital, Sydney, Sydney, NSW, 2050, Australia., Wilmott JS; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, 2065, Australia.; Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia., Thompson JF; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, 2065, Australia.; Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia.; Royal Prince Alfred Hospital, Sydney, Sydney, NSW, 2050, Australia., Doan N; Santa Monica-University of California, Los Angeles Medical Center, Los Angeles, CA, 90095, USA., Said JW; Santa Monica-University of California, Los Angeles Medical Center, Los Angeles, CA, 90095, USA., Venkatachalam N; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Xiao JF; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Loh XY; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Pein M; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Xu L; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Mullins DW; Departments of Medical Education and Microbiology/Immunology, Geisel School of Medicine at Dartmouth, Dartmouth, MA, 03755, USA., Yang H; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Lin DC; Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, 90048, USA., Koeffler HP; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.; Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, 90048, USA.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 May 20; Vol. 10 (1), pp. 2230. Date of Electronic Publication: 2019 May 20.
DOI: 10.1038/s41467-019-09711-y
Abstrakt: 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.
Databáze: MEDLINE