SOX17, SRY-box transcription factor 17, is a crucial transcription factor. It directs the specification and development of the primitive endoderm, primitive germ cells, and definitive endoderm, and is involved in the cardiovascular system and several endoderm-derived organs. It participates in pathways like Wnt/β-catenin and Notch signaling during development [5,7].

In cancer, in vitro-engineered colon cancer organoids with Apc-null, KrasG12D and Trp53-null (AKP) mutations showed strong up-regulation of SOX17 in vivo. SOX17 loss did not impact AKP organoid propagation in vitro but significantly reduced AKP tumour persistence in vivo. SOX17-null tumours had IFNγ-producing effector-like CD8+ T cell infiltrates, unlike the immune-suppressive microenvironment in wild-type counterparts. SOX17 suppresses tumour cells' ability to sense and respond to IFNγ, and engages a fetal intestinal programme to drive differentiation away from LGR5+ tumour cells, producing immune-evasive LGR5-tumour cells with lower MHC-I expression, enabling immune evasion in early colorectal adenomas and cancers [1].

In pulmonary hypertension, SOX17 expression was downregulated in patients' lungs and pulmonary endothelial cells. Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion in mice induced spontaneous mild pulmonary hypertension, and loss of endothelial Sox17 exacerbated hypoxia-induced pulmonary hypertension. SOX17 deficiency led to endothelial dysfunctions, and E2F1 signaling mediated these effects, which could be attenuated by E2F1 inhibitor [2]. Also, Sox17 expression was reduced in PAH tissues. Chronic hypoxic pulmonary hypertension was exacerbated in Sox17EC-/-mice and attenuated in Sox17Tg mice. SOX17 promoted oxidative phosphorylation and mitochondrial function in pulmonary artery endothelial cells, in part via inhibition of HIF2α. 16α-hydroxyestrone (16αOHE) mediated PAH development via down-regulation of SOX17 [3]. Common PAH risk variants upstream of the SOX17 promoter reduced endothelial SOX17 expression through differential binding of HOXA5 and ROR-α, resulting in disturbed endothelial cell function and PAH [4]. Endothelial knockdown of SOX17 accelerated, while overexpression attenuated, SU5416/hypoxia-induced PH in mice. SOX17-associated exosomes blocked HPAECs' proliferation, apoptosis, and inflammation, preventing pulmonary arterial remodeling and PH [6].

In conclusion, SOX17 is vital for embryonic development and tissue homeostasis. Gene-knockout and conditional-knockout mouse models have revealed its role in promoting immune evasion in early colorectal cancers and maintaining endothelial function to prevent pulmonary hypertension. Understanding SOX17's functions provides insights into disease mechanisms and potential therapeutic targets for these diseases.