Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4.
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.
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
Joseph M
JM
Catanzaro
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
Namratha
N
Sheshadri
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
Ji-An
JA
Pan
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
Yu
Y
Sun
Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.
Chanjuan
C
Shi
Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, New York 11797, USA.
Jinyu
J
Li
Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, New York 11797, USA.
R Scott
RS
Powers
Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida 32224, USA.
Howard C
HC
Crawford
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
Wei-Xing
WX
Zong
D000951:Antigens, Neoplasm / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D015843:Serpins / Q000378:metabolism*; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D016207:Cytokines; D018836:Inflammation Mediators; D015843:Serpins; C051072:squamous cell carcinoma-related antigen; D016283:Proto-Oncogene Proteins p21(ras)