Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF–nuclear IL-33–GATA3 pathway

Menée in vitro et à l'aide de modèles murins de cancer colorectal, cette étude met en évidence un mécanisme par lequel l'hypoxie tumorale induit une baisse du niveau d'expression de la forme soluble du récepteur ST2 via la voie impliquant le facteur HIF, l'interleukine nucléaire IL-33 et le facteur de transcription GATA3

Résumé en anglais

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.