Catanzaro Joseph M, Sheshadri Namratha, Pan Ji-An, Sun Yu, Shi Chanjuan, Li Jinyu, Powers R Scott, Crawford Howard C, Zong Wei-Xing
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.
Nat Commun. 2014 Apr 23;5:3729. doi: 10.1038/ncomms4729.
Mounting evidence indicates that oncogenic Ras can modulate cell autonomous inflammatory cytokine production, although the underlying mechanism remains unclear. Here we show that squamous cell carcinoma antigens 1 and 2 (SCCA1/2), members of the Serpin family of serine/cysteine protease inhibitors, are transcriptionally upregulated by oncogenic Ras via MAPK and the ETS family transcription factor PEA3. Increased SCCA expression leads to inhibition of protein turnover, unfolded protein response, activation of NF-κB and is essential for Ras-mediated cytokine production and tumour growth. Analysis of human colorectal and pancreatic tumour samples reveals a positive correlation between Ras mutation, enhanced SCCA expression and IL-6 expression. These results indicate that SCCA is a Ras-responsive factor that plays an important role in Ras-associated cytokine production and tumorigenesis.
越来越多的证据表明，致癌性Ras可调节细胞自主分泌炎性细胞因子，但其潜在机制仍不清楚。在此我们表明，丝氨酸/半胱氨酸蛋白酶抑制剂丝氨酸蛋白酶抑制剂家族成员鳞状细胞癌抗原1和2（SCCA1/2）通过MAPK和ETS家族转录因子PEA3被致癌性Ras转录上调。SCCA表达增加导致蛋白质周转抑制、未折叠蛋白反应、NF-κB激活，并且对于Ras介导的细胞因子产生和肿瘤生长至关重要。对人类结直肠癌和胰腺肿瘤样本的分析揭示了Ras突变、SCCA表达增强与IL-6表达之间的正相关。这些结果表明，SCCA是一种Ras反应因子，在Ras相关的细胞因子产生和肿瘤发生中起重要作用。
