Force expression LNK suppresses interferon Gamma signaling

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. mRNA profiles of Control and LNK overexpressing cells were generated by deep sequencing using BGISEQ-500.

LNK（SH2B3）是JAK-STAT信号通路（JAK-STAT signaling）的关键负调控因子，该通路在恶性造血系统疾病中已被广泛研究。本研究发现，LNK在皮肤黑色素瘤（cutaneous melanoma）中显著高表达，且其表达水平与RAS-RAF-MEK通路（RAS-RAF-MEK pathway）的信号过度激活呈正相关。高表达的LNK可增强细胞在不良条件下的生长与存活能力。LNK的强制过表达会抑制干扰素-STAT1信号通路，并阻断干扰素（IFN）诱导的细胞周期阻滞与细胞凋亡。与之相反，通过shRNA或CRISPR-Cas9敲低LNK的表达，则会增强干扰素的杀伤效应。IFN-LNK信号通路受严格的负反馈机制调控：暴露于干扰素的黑色素瘤细胞会上调LNK的表达，以阻止该信号通路的过度激活。本研究揭示了LNK在黑色素瘤中未被关注的功能，并凸显了IFN-STAT1-LNK信号轴（IFN-STAT1-LNK signaling axis）在这一极具破坏性的疾病中的关键作用。LNK有望作为黑色素瘤免疫治疗的潜在治疗靶点开展进一步研究。本研究采用BGISEQ-500平台通过深度测序获取了对照组与LNK过表达细胞的mRNA表达谱。