High phosphoglycerate dehydrogenase expression induces stemness and aggressiveness in thyroid cancer.

Background:We examined the changes in glucose metabolites of papillary thyroid cancer (PTC) and identified phosphoglycerate dehydrogenase (PHGDH) as a potential target. The role ofPHGDHin the proliferation and tumorigenesis of thyroid cancer cells and its clinical significance were analyzed. Methods:Glucose metabolites of various thyroid tissues were analyzed via targeted metabolomics analysis.In vitroexperiments usingshPHGDHs, inhibitor (NCT503), orPHGDHoverexpression in thyroid cell lines (BCPAP, 8505C, and Nthy-Ori) were performed.In vivoexperiments were performed by usingshPHGDH. Human tissue samples and The Cancer Genome Atlas (TCGA) data were used to validate the experimental findings. Results:PHGDHknockdown in BCPAP and 8505c cell lines significantly inhibited cell viability, colony formation, and tumor spheroid formation compared with the control. In addition, treatment with NCT503 showed similar results.PHGDHinhibition by both knockdown and treatment with NCT503 significantly inhibited the expression of embryonic cancer stemness markers (Oct4,Sox2,KLF4, andNanog).PHGDHoverexpression in Nthy-Ori cells significantly increased cell viability and colony formation. The stemness markers were significantly increased afterPHGDHoverexpression.PHGDHknockdown significantly inhibited tumor growth in anin vivomouse xenograft study using 8505c cells. The protein expression of Oct4 in tumors was significantly reduced afterPHGDHknockdown. The associations betweenPHGDHexpression and stemness markers were confirmed in the TCGA data and human thyroid tissue samples. Positive PHGDH protein expression was associated with metastases of PTC. Conclusions:PHGDHexpression is induced in thyroid cancer and is associated with stemness and aggressiveness of PTC.