Xu Tongjiang, Zhai Xiaodong, Wang RuiWei, Wu Xiaoben, Zhou ZhiZhen, Shang MiaoMiao, Wang Chongcheng, Qi Tengfei, Yang Wei
Department of Neurosurgery, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
Department of Anesthesiology, Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
Cancer Metab. 2025 Jan 14;13(1):1. doi: 10.1186/s40170-024-00372-0.
Invasiveness of pituitary adenoma is the main cause of its poor prognosis, mechanism of which remains largely unknown. In this study, the differential proteins between invasive and non-invasive pituitary tumors (IPA and NIPA) were identified by TMT labeled quantitative proteomics. The differential metabolites in venous bloods from patients with IPA and NIPA were analyzed by untargeted metabolomics. Proteomic data showed that the top five up-regulated proteins were AD021, C2orf15, PLCXD3, HIST3H2BB and POU1F1, and the top five down-regulated proteins were AIPL1, CALB2, GLUD2, SLC4A10 and GTF2I. Metabolomic data showed that phosphatidylinositol (PI) was most remarkably up-regulated and melibiose was most obviously down-regulated. Further investigation demonstrated that PI stimulation increased the expression of PITPNM1, POU1F1, C2orf15 and LDHA as well as the phosphorylation of AKT and ERK, and promoted the proliferation, migration and invasion of GH3 cells, which were blocked by PITPNM1knockdown. Inhibiting AKT phosphorylation reduced the expression of POU1F1, C2orf15 and LDHA in PI-stimulated cells while activating AKT increased their expression in PITPNM1-silencing cells, which was similar to the function of ERK. POU1F1 silence suppressed the expression of LDHA and C2orf15. Luciferase report assay and ChIP assay demonstrated that POU1F1 positively regulated the transcription of LDHA and C2orf15. In addition, PI propelled the metastasis of GH3 cells in vivo, and elevated the expression of PITPNM1, POU1F1, C2orf15 and LDHA. These results suggested that elevated serum PI might contribute to the proliferation and invasion of pituitary adenoma by regulating the expression of PITPNM1/AKT/ERK/POU1F1 axis.
垂体腺瘤的侵袭性是其预后不良的主要原因，但其机制仍 largely 未知。在本研究中，通过 TMT 标记定量蛋白质组学鉴定侵袭性和非侵袭性垂体肿瘤（侵袭性垂体腺瘤和非侵袭性垂体腺瘤）之间的差异蛋白质。采用非靶向代谢组学分析侵袭性垂体腺瘤和非侵袭性垂体腺瘤患者静脉血中的差异代谢物。蛋白质组学数据显示，上调最显著的前五种蛋白质为 AD021、C2orf15、PLCXD3、HIST3H2BB 和 POU1F1，下调最显著的前五种蛋白质为 AIPL1、CALB2、GLUD2、SLC4A10 和 GTF2I。代谢组学数据显示磷脂酰肌醇（PI）上调最显著，蜜二糖下调最明显。进一步研究表明，PI 刺激增加了 PITPNM1、POU1F1、C2orf15 和 LDHA 的表达以及 AKT 和 ERK 的磷酸化，并促进了 GH3 细胞的增殖、迁移和侵袭，而 PITPNM1 敲低可阻断这些作用。抑制 AKT 磷酸化降低了 PI 刺激细胞中 POU1F1、C2orf15 和 LDHA 的表达，而激活 AKT 则增加了 PITPNM1 沉默细胞中它们的表达，这与 ERK 的功能相似。POU1F1 沉默抑制了 LDHA 和 C2orf15 的表达。荧光素酶报告基因检测和染色质免疫沉淀检测表明，POU1F1 正向调节 LDHA 和 C2orf15 的转录。此外，PI 在体内促进了 GH3 细胞的转移，并提高了 PITPNM1、POU1F1、C2orf15 和 LDHA 的表达。这些结果表明，血清 PI 升高可能通过调节 PITPNM1/AKT/ERK/POU1F1 轴的表达促进垂体腺瘤的增殖和侵袭。
