Zhang Jie, Dong Wei, Yang Qin, Liu Li-Na, Cai Xi-Lun, Wang Dan, Yan Guo-Ji, Xiyang Yan-Bin, Hu Tao, Zhang Jie
Department of Medical Genetics, Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases, National Health Commission Key Laboratory of Preconception Health Birth in Western China, the First People's Hospital of Yunnan Province, Kunming 650100, P. R. China.
Department of Obstetrics and Gynecology, The First People's Hospital of Yunnan Province, Kunming 650100, P. R. China.
Carcinogenesis. 2025 Apr 3;46(2). doi: 10.1093/carcin/bgaf005.
High-risk human papillomavirus (HPV) infection is strongly linked to the initiation and progression of cervical cancer (CC), yet the precise molecular mechanisms involved remain partially understood. This investigation examined differential protein expression profiles in various cohorts, including healthy controls and HPV-positive CC patients with different expression levels of glucose-6-phosphate dehydrogenase (G6PD), shedding light on the dysregulation of oncogenic proteins by HPV. Proteomic analysis of cervical tissues revealed specific protein signatures, indicating significant upregulation of HPV E6, G6PD, STAT3, phosphorylated STAT3, and procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in HPV-infected CC tissues and cell lines. Functional experiments, involving the manipulation of G6PD and STAT3 activities in CC cells with HPV E6 modulation, demonstrated that dysregulated G6PD enhanced cell proliferation, migration, and invasion while suppressing apoptosis, primarily through the STAT3/PLOD2 pathway. Integrating these findings with the existing literature underscores the role of G6PD as an oncogene, potentially under STAT3 regulation, and highlights the role of PLOD2 as a pivotal factor in CC progression. This study also proposed a mechanism in which HPV E6-induced dysregulation of G6PD activates the STAT3-PLOD2 axis to promote CC progression. Understanding the intricate interplay between HPV E6, G6PD, STAT3, and PLOD2 offers valuable insights into the molecular landscape of CC. These findings may pave the way for targeted therapeutic approaches aimed at disrupting this axis to mitigate the progression of CC.
高危型人乳头瘤病毒（HPV）感染与宫颈癌（CC）的发生和发展密切相关，但其具体分子机制仍未完全明确。本研究检测了不同队列中的差异蛋白表达谱，包括健康对照以及葡萄糖-6-磷酸脱氢酶（G6PD）表达水平不同的HPV阳性CC患者，以揭示HPV对致癌蛋白的失调作用。宫颈组织的蛋白质组学分析揭示了特定的蛋白特征，表明HPV感染的CC组织和细胞系中HPV E6、G6PD、信号转导和转录激活因子3（STAT3）、磷酸化STAT3以及脯氨酸赖氨酸2-酮戊二酸5-双加氧酶2（PLOD2）显著上调。功能实验通过在HPV E6调控下操纵CC细胞中的G6PD和STAT3活性，证明失调的G6PD主要通过STAT3/PLOD2途径增强细胞增殖、迁移和侵袭，同时抑制细胞凋亡。将这些发现与现有文献相结合，强调了G6PD作为一种癌基因在STAT3调控下的潜在作用，并突出了PLOD2在CC进展中的关键作用。本研究还提出了一种机制，即HPV E6诱导的G6PD失调激活STAT3-PLOD2轴以促进CC进展。了解HPV E6、G6PD、STAT3和PLOD2之间复杂的相互作用，为深入了解CC的分子格局提供了有价值的见解。这些发现可能为旨在破坏该轴以减轻CC进展的靶向治疗方法铺平道路。
