IGF2BP2-driven serine metabolism promotes the progression of thyroid carcinoma via m⁶A-PHGDH

Thyroid cancer (TC) is one of the most common malignant tumors of the endocrine system, and patients with advanced and metastatic TC have a poor prognosis. Serine metabolism is an important component of tumor cell metabolic reprogramming. However, the molecular mechanism underlying the upregulation of serine metabolism in TC remains poorly understood.

Immunohistochemistry was performed to observe the expression of IGF2BP2 and its target molecules in TC and adjacent tissues. RNA interference and lentivirus infection of TPC-1 and 8505 C cells were used to downregulate and overexpress key molecules, respectively. CCK8, colony formation, EdU incorporation, transwell migration and invasion, scratch wound-healing and flow cytometry assays were performed to detect the changes in cell function among the different groups. LC‒MS was used to detect serine and related metabolites in TC cells. Transcriptome sequencing, RIP, m⁶A-RIP, FISH, RNA stability and luciferase reporter assays were performed to explore the molecular mechanism of IGF2BP2 and its targets. Finally, the molecular axis was validated in a mouse model.

We observed high expression of IGF2BP2 in TC tissues, and its expression increased with the tumor stage and was associated with a poor prognosis. The inhibition of IGF2BP2 suppressed proliferation, invasion, migration and serine synthesis and metabolism in TC cells. Additionally, supplementation with serine partially rescued the proliferation defect in IGF2BP2-knockdown cells. RNA-seq indicated that PHGDH is a target of IGF2BP2, and its expression was positively correlated with IGF2BP2 expression in TC. Moreover, RIP, m⁶A-RIP, FISH, RNA stability, LC‒MS and luciferase reporter assays showed that IGF2BP2 can increase serine synthesis and metabolism by promoting PHGDH expression in an m⁶A-dependent manner. The overexpression of PHGDH partially rescued the IGF2BP2 knockdown-induced attenuation of TC cell proliferation. Finally, mouse experiments verified that the IGF2BP2-PHGDH axis promoted the formation of TC.

Our results further reveal the pathogenesis of TC and provide new insights for controlling the progression of TC from the perspective of tumor metabolism in clinical practice.