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.
Highlights
LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases
Loss of function mutations of JAK1/2 were found in patients with recurrent melanoma who initially responded to PD-1 antibody, or in the primary nonresponder[17]
Compared to either normal skin tissue (Supplementary Fig. 1, RNA sequencing of 473 sun-exposed normal skin samples and 387 non-sunexposed normal skin samples, collected from the GTEX database [https://www.gtexportal.org]) or benign nevi, LNK mRNA was significantly upregulated in the melanoma samples, in advanced stages of the disease and ranked as one of the top 1% overexpressed genes in melanoma (Riker Melanoma, Oncomine database, Fig. 1b)
Summary
LNK expression is significantly elevated in melanoma. We analyzed LNK mRNA expression in the Cancer Cell Line Encyclopedia (CCLE) [http://www.broadinstitute.org/ccle], cBioPortal for Cancer Genomics [www.cbioportal.org/], Oncomine [https:// www.oncomine.org] and NCBI GEO database [https://www.ncbi. nlm.nih.gov/geo/]. Among the >8000 RNA sequencing data from primay cancer samples in The Cancer Genome Atlas (TCGA), melanoma samples expressed the highest LNK mRNA (Fig. 1a, lower panel). We separated the melanoma cell lines based on their driver mutation (BRAF V600E, NRAS Q61K/L, c-KIT or other), and found that LNK expression was significantly higher in cell lines that harbored BRAF and NRAS mutations (Fig. 1f), suggesting that hyperactivated RAS-RAF-MEK signaling may correlate with LNK expression in melanoma.
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