Sun Jingfu, Zhu Qing, Shan Liqun, Liu Jianing
Thyroid Surgery, The Second Hospital of Shandong University, No. 247, Beiyuan Street, Jinan City, Shandong Province, 250033, P. R. China.
Department of General Surgery, Taicang Loujiang New City Hospital, No. 666 Shanghai East Road, Taicang, Jiangsu, 215400, China.
J Physiol Biochem. 2025 Aug 5. doi: 10.1007/s13105-025-01114-6.
Emerging evidence suggests that prolyl-4-hydroxylase α subunit 2 (P4HA2) plays critical roles in cancer progression through multiple mechanisms. Notably, P4HA2 has been implicated in modulating glycolytic pathways in malignancies. Phosphofructokinase (PFKP), a key glycolytic enzyme, exhibits significant overexpression in thyroid cancer. This study investigates the functional of P4HA2 in thyroid cancer and elucidates the P4HA2/PFKP axis in regulating cancer cell glycolysis. Bioinformatics analysis using GEPIA website revealed P4HA2 expression patterns in thyroid cancer samples. P4HA2 protein levels were detected in thyroid cancer cell lines by western blot assay. Functional characterization was performed through siRNA-mediated P4HA2 knockdown followed by evaluation of proliferative capacity, cell cycle progression, migratory/invasive potential, and glycolytic activity. Rescue experiments employing PFKP overexpression were conducted to delineate molecular interactions. Significant P4HA2 up-regulation was observed in thyroid cancer tissues and cell lines. P4HA2 silencing marked inhibited cellular proliferation, suppressed cell cycle regulators, and attenuated metastatic potential. Glycolytic parameters including glucose consumption, lactate production, and ATP synthesis were significantly compromised following P4HA2 knockdown. Mechanistically, P4HA2 depletion down-regulated PFKP expression, while PFKP overexpression partially rescued the oncogenic phenotype. Our data indicated that P4HA2 promoted cell proliferation, cell cycle, migration, invasion, glycolysis and tumor growth, suggesting that it might be a valuable therapeutic target for thyroid cancer.
新出现的证据表明，脯氨酰-4-羟化酶α亚基2（P4HA2）通过多种机制在癌症进展中发挥关键作用。值得注意的是，P4HA2已被证明与调节恶性肿瘤中的糖酵解途径有关。磷酸果糖激酶（PFKP）是一种关键的糖酵解酶，在甲状腺癌中显著过表达。本研究调查了P4HA2在甲状腺癌中的功能，并阐明了P4HA2/PFKP轴在调节癌细胞糖酵解中的作用。使用GEPIA网站进行的生物信息学分析揭示了甲状腺癌样本中P4HA2的表达模式。通过蛋白质印迹分析检测甲状腺癌细胞系中的P4HA2蛋白水平。通过小干扰RNA介导的P4HA2敲低进行功能表征，随后评估增殖能力、细胞周期进程、迁移/侵袭潜力和糖酵解活性。进行了采用PFKP过表达的挽救实验以描述分子相互作用。在甲状腺癌组织和细胞系中观察到P4HA2显著上调。P4HA2沉默显著抑制细胞增殖，抑制细胞周期调节因子，并减弱转移潜力。P4HA2敲低后，包括葡萄糖消耗、乳酸产生和ATP合成在内的糖酵解参数显著受损。从机制上讲，P4HA2的缺失下调了PFKP的表达，而PFKP的过表达部分挽救了致癌表型。我们的数据表明，P4HA2促进细胞增殖、细胞周期、迁移、侵袭、糖酵解和肿瘤生长，提示它可能是甲状腺癌的一个有价值的治疗靶点。
