Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 120, Issue 18, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2218033120
Keywords
colorectal cancer; interleukin-33; soluble ST2; metastasis; hypoxia
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As a decoy receptor, soluble ST2 (sST2) interferes with the function of IL-33 and decreased sST2 expression in CRC cells promotes tumor growth. Hypoxia reduces sST2 expression and restoration of sST2 in hypoxic tumor regions corrects the inflammatory microenvironment and suppresses tumor growth and lung metastasis.
As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC.
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