Li Ruowen, Zhao Mingjian, Sun Min, Wu Yongkang, Miao Chengxu, Fangyu Liu, Wu Mengting, Shi Xiaojia, Lu Jinghui, Yue Xuetian
Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong Province, China.
Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
Cancer Cell Int. 2025 Jul 2;25(1):249. doi: 10.1186/s12935-025-03871-2.
Papillary thyroid cancer (PTC) is the most common malignancy of the endocrine system. Collagen prolyl 4-hydroxylase alpha subunit 2 (P4HA2) is a key enzyme involved in collagen metabolism. However, the expression and function of P4HA2 in PTC progression have not been well studied. Our previous proteomic data showed that the differential proteins in human PTC were significantly enriched in metabolic signaling pathways, with P4HA2 being the most up-regulated protein. Here, we found that P4HA2 promotes the proliferation and migration of PTC. The expression of P4HA2 is elevated and its elevation is associated with poor prognosis in human PTC specimens. Functionally, P4HA2 promotes the proliferative and migratory abilities of BHP10-3 and TPC-1 cells. Further studies showed that overexpression of P4HA2 significantly activates the NF-κB signaling pathway. Mechanistically, P4HA2 promotes the ubiquitination and degradation of inhibitor kappa B-alpha (IκBα) by directly binding, leading to activation of NF-κB signaling pathway. Furthermore, BAY 11-7082, an inhibitor of the NF-κB signalling pathway, reversed the promotion of PTC proliferation and metastasis by P4HA2 both in vivo and in vitro. In conclusion, P4HA2 activates the NF-κB signaling pathway by promoting proteasome-dependent degradation of IκBα, which in turn contributes to the proliferation and migration of PTC. Therefore, P4HA2 could be used as a potential therapeutic target for the treatment of PTC patients.
甲状腺乳头状癌（PTC）是内分泌系统最常见的恶性肿瘤。胶原蛋白脯氨酰4-羟化酶α亚基2（P4HA2）是参与胶原蛋白代谢的关键酶。然而，P4HA2在PTC进展中的表达和功能尚未得到充分研究。我们之前的蛋白质组学数据显示，人类PTC中的差异蛋白在代谢信号通路中显著富集，其中P4HA2是上调最明显的蛋白。在此，我们发现P4HA2促进PTC的增殖和迁移。在人类PTC标本中，P4HA2的表达升高，且其升高与预后不良相关。在功能上，P4HA2促进BHP10-3和TPC-1细胞的增殖和迁移能力。进一步研究表明，P4HA2的过表达显著激活NF-κB信号通路。机制上，P4HA2通过直接结合促进抑制蛋白κB-α（IκBα）的泛素化和降解，导致NF-κB信号通路激活。此外，NF-κB信号通路抑制剂BAY 11-7082在体内和体外均逆转了P4HA2对PTC增殖和转移的促进作用。总之，P4HA2通过促进IκBα的蛋白酶体依赖性降解激活NF-κB信号通路，进而促进PTC的增殖和迁移。因此，P4HA2可作为治疗PTC患者的潜在治疗靶点。
