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Abstract
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.
LNK is a tumor suppressor in hematopoietic cancers, but its function in melanoma is unclear. Here, the authors show that the overexpression of LNK in melanomas correlate with hyperactive signaling of the RAS-RAF-MEK pathway and LNK enhances melanoma growth and survival and immune evasion by inhibiting IFN signalling.
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1 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431)
2 Melanoma Institute Australia, The University of Sydney, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); Sydney Medical School, The University of Sydney, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X)
3 Melanoma Institute Australia, The University of Sydney, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); Sydney Medical School, The University of Sydney, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); Royal Prince Alfred Hospital, Sydney, Sydney, Australia (GRID:grid.413249.9) (ISNI:0000 0004 0385 0051)
4 Santa Monica-University of California, Los Angeles Medical Center, Los Angeles, USA (GRID:grid.414855.9) (ISNI:0000 0004 0445 0551)
5 Geisel School of Medicine at Dartmouth, Departments of Medical Education and Microbiology/Immunology, Dartmouth, USA (GRID:grid.254880.3) (ISNI:0000 0001 2179 2404)
6 Cedars-Sinai Medical Center, UCLA School of Medicine, Division of Hematology/Oncology, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718)
7 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); Cedars-Sinai Medical Center, UCLA School of Medicine, Division of Hematology/Oncology, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718)