title: STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors.
abstract: Interleukin-6 (IL-6)-Janus kinase (JAK) signaling is viewed as crucial for persistent signal transducer and activator of transcription-3 (STAT3) activation in cancer. However, IL-6-induced STAT3 activation is normally transient. Here we identify a key mechanism for persistent STAT3 activation in tumor cells and the tumor microenvironment. We show that expression of sphingosine-1-phosphate receptor-1 (S1PR1), a G protein-coupled receptor for the lysophospholipid sphingosine-1-phosphate (S1P), is elevated in STAT3-positive tumors. STAT3 is a transcription factor for the S1pr1 gene. Reciprocally, enhanced S1pr1 expression activates STAT3 and upregulates Il6 gene expression, thereby accelerating tumor growth and metastasis in a STAT3-dependent manner. Silencing S1pr1 in tumor cells or immune cells inhibits tumor STAT3 activity, tumor growth and metastasis. S1P-S1PR1-induced STAT3 activation is persistent, in contrast to transient STAT3 activation by IL-6. S1PR1 activates STAT3 in part by upregulating JAK2 tyrosine kinase activity. We show that STAT3-induced S1PR1 expression, as well as the S1P-S1PR1 pathway reciprocal regulation of STAT3 activity, is a major positive feedback loop for persistent STAT3 activation in cancer cells and the tumor microenvironment and for malignant progression.
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Heehyoung
authors.initials: H
authors.lastname: Lee
authors.forename: Jiehui
authors.initials: J
authors.lastname: Deng
authors.forename: Maciej
authors.initials: M
authors.lastname: Kujawski
authors.forename: Chunmei
authors.initials: C
authors.lastname: Yang
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
authors.forename: David
authors.initials: D
authors.lastname: Horne
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological / Q000502:physiology; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D015850:Interleukin-6; D049349:Receptors, Lysosphingolipid; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse