SOX17, short for SRY-box transcription factor 17, is a pivotal transcription factor. It is crucial in directing the specification and development of the primitive endoderm, primitive germ cells, and definitive endoderm [5]. Subsequently, it is involved in the cardiovascular system and several endoderm-derived organs. It participates in pathways such as Wnt/β -catenin and Notch signaling during development [7]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In colorectal cancer, loss of SOX17 in AKP (Apc -null, KrasG12D and Trp53 -null) tumour-forming organoids reduced their ability to persist in vivo. SOX17 -null tumours had IFNγ -producing effector-like CD8+ T cell infiltrates, while wild-type counterparts had an immune-suppressive microenvironment. SOX17 suppresses tumour cells' ability to sense and respond to IFNγ, preventing anti-tumour T cell responses and engages a fetal intestinal programme to produce immune-evasive LGR5 -tumour cells [1]. In pulmonary hypertension, endothelial SOX17 deficiency in mice, induced by Tie2Cre-mediated Sox17 knockdown or EC-specific Sox17 deletion, led to spontaneously mild pulmonary hypertension and exacerbated hypoxia-induced pulmonary hypertension. Pharmacological inhibition of E2F1, which mediates SOX17 deficiency-induced EC dysfunction, attenuated pulmonary hypertension development [2]. Also, Sox17EC -/- mice had exacerbated chronic hypoxic pulmonary hypertension, while transgenic Tie2 -Sox17 overexpression (Sox17Tg) mice had attenuated symptoms. SOX17 promotes mitochondrial bioenergetics and attenuates PAH via inhibition of HIF2α [3]. SOX17 enhancer knockout in mice reduced lung SOX17 expression, resulting in more severe pulmonary vascular leak and hypoxia-or SU5416/hypoxia-induced pulmonary hypertension [4]. Endothelial knockdown of SOX17 in mice accelerated the progression of SU5416/hypoxia-induced PH, while overexpression attenuated it. SOX17 -associated exosomes blocked HPAECs' proliferation, apoptosis, and inflammation, preventing pulmonary arterial remodeling and PH [6].

In conclusion, SOX17 is essential for normal development and homeostasis. Model-based research, especially using KO/CKO mouse models, has revealed its significant roles in colorectal cancer, where it enables immune evasion, and in pulmonary hypertension, where it affects endothelial function, mitochondrial bioenergetics, and disease progression. Understanding SOX17's functions can provide insights into disease mechanisms and potential therapeutic targets for these diseases.

References:

1. Goto, Norihiro, Westcott, Peter M K, Goto, Saori, Agudo, Judith, Yilmaz, Ömer H. 2024. SOX17 enables immune evasion of early colorectal adenomas and cancers. In Nature, 627, 636-645. doi:10.1038/s41586-024-07135-3. https://pubmed.ncbi.nlm.nih.gov/38418875/

2. Yi, Dan, Liu, Bin, Ding, Hongxu, Fallon, Michael B, Dai, Zhiyu. 2023. E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension. In Hypertension (Dallas, Tex. : 1979), 80, 2357-2371. doi:10.1161/HYPERTENSIONAHA.123.21241. https://pubmed.ncbi.nlm.nih.gov/37737027/

3. Sangam, Shreya, Sun, Xutong, Schwantes-An, Tae-Hwi, Black, Stephen M, Desai, Ankit A. . SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics. In American journal of respiratory and critical care medicine, 207, 1055-1069. doi:10.1164/rccm.202203-0450OC. https://pubmed.ncbi.nlm.nih.gov/36913491/

4. Walters, Rachel, Vasilaki, Eleni, Aman, Jurjan, Zhao, Lan, Rhodes, Christopher J. 2023. SOX17 Enhancer Variants Disrupt Transcription Factor Binding And Enhancer Inactivity Drives Pulmonary Hypertension. In Circulation, 147, 1606-1621. doi:10.1161/CIRCULATIONAHA.122.061940. https://pubmed.ncbi.nlm.nih.gov/37066790/

5. Tan, Daisylyn Senna, Holzner, Markus, Weng, Mingxi, Srivastava, Yogesh, Jauch, Ralf. 2019. SOX17 in cellular reprogramming and cancer. In Seminars in cancer biology, 67, 65-73. doi:10.1016/j.semcancer.2019.08.008. https://pubmed.ncbi.nlm.nih.gov/31419525/

6. Zou, Xiaozhou, Liu, Ting, Huang, Zhongjie, Zhang, Yiwen, Huang, Ping. 2023. SOX17 is a Critical Factor in Maintaining Endothelial Function in Pulmonary Hypertension by an Exosome-Mediated Autocrine Manner. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2206139. doi:10.1002/advs.202206139. https://pubmed.ncbi.nlm.nih.gov/36919784/

7. Zhu, Na, Welch, Carrie L, Wang, Jiayao, Shen, Yufeng, Chung, Wendy K. 2018. Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease. In Genome medicine, 10, 56. doi:10.1186/s13073-018-0566-x. https://pubmed.ncbi.nlm.nih.gov/30029678/