Calcineurin A gamma and NFATc3/SRPX2 axis contribute to human embryonic stem cell differentiation

Abstract

Our understanding of signaling pathways regulating the cell fate of human embryonic stem cells (hESCs) is limited. Calcineurin‐NFAT signaling is associated with a wide range of biological processes and diseases. However, its role in controlling hESC fate remains unclear. Here, we report that calcineurin A gamma and the NFATc3/SRPX2 axis control the expression of lineage and epithelial–mesenchymal transition (EMT) markers in hESCs. Knockdown of PPP3CC, the gene encoding calcineurin A gamma, or NFATC3, downregulates certain markers both at the self‐renewal state and during differentiation of hESCs. Furthermore, NFATc3 interacts with c‐JUN and regulates the expression of SRPX2, the gene encoding a secreted glycoprotein known as a ligand of uPAR. We show that SRPX2 is a downstream target of NFATc3. Both SRPX2 and uPAR participate in controlling expression of lineage and EMT markers. Importantly, SRPX2 knockdown diminishes the upregulation of multiple lineage and EMT markers induced by co‐overexpression of NFATc3 and c‐JUN in hESCs. Together, this study uncovers a previously unknown role of calcineurin A gamma and the NFATc3/SRPX2 axis in modulating the fate determination of hESCs.

SRPX2 promotes cancer cell proliferation and migration of papillary thyroid cancer

“…We found that SRPX2 was overexpressed in PTC and positively correlated with higher histological grade, metastatic lymph node grade, and worse prognosis. Previous studies have found that SRPX2 takes part in human embryonic stem cell differentiation, cognitive impairment, and epileptic activity [ 19 , 30 , 31 ]. Most published data show that SRPX2 has a carcinogenic effect and is abnormally expressed in various tumors [ 15 , 32 , 33 ].…”

“…In addition, inflammation can also promote the expression levels of SRPX2 [ 18 ]. Moreover, SRPX2 is regulated by its upstream molecules including TGFβR1/SMAD3, NFATc3/c-JUN, MAN1 (LEM) domain containing 1 (LEMD1), miR-149, and FOXP2 [ 17 , 19 – 22 ]. The effects of these mechanisms are not only limited to the upregulation of SRPX2 but also regulate the biological behaviors of tumor cell proliferation, migration, and invasion.…”

SRPX2 Promotes Tumor Proliferation and Migration via the FAK Pathway in Papillary Thyroid Carcinoma

“…SRPX2 is a component in an extracellular matrix which involved in tumor formation including colorectal cancer [ 11 ], gastrointestinal cancer [ 12 ], and prostate cancer [ 13 ]. Additionally, SRPX2 exerts essential roles in pan-cancers because of participating in stem cell differentiation of human embryonic [ 14 , 15 ]. In PTC, SRPX2 has also been found significantly overexpressed and correlated with poorer disease-free survival of advanced PTC [ 7 ].…”

The Landscape of the Tumor Microenvironment in Skin Cutaneous Melanoma Reveals a Prognostic and Immunotherapeutically Relevant Gene Signature

“…SRPX2 is invasive by upregulating the FAK/SRC/ERK pathway and can lead to pancreatic cancer drug resistance in PI3K/AKT in lung cancer. Additionally, the NFATc3/SRPX2 axis participates in human embryonic stem cell differentiation, indicating that SRPX2 plays a critical role in pan-cancers (Gao et al, 2020;Li et al, 2020;Chen et al, 2021). SRPX2 is a component of the extracellular matrix, which is important for regulating tumor formation, as demonstrated in diverse tumors, such as colorectal cancer (Øster et al, 2013), gastrointestinal cancer (Tanaka et al, 2012), prostate cancer (Zhang et al, 2018), and pancreatic cancer (Gao et al, 2015).…”