Xu Fangfang, Ye Yingjun, Gao Yueqing, Xu Shaohua
Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
J Cancer. 2024 Aug 13;15(16):5288-5307. doi: 10.7150/jca.98738. eCollection 2024.
In the dynamic landscape of cervical cancer (CC) pathophysiology, this study aimed to elucidate the role of necroptosis in modulating tumor proliferation, invasion, and the immune microenvironment in CC. In this study, the impact of necroptosis on CC was evaluated through a series of bioinformatical analyses and experimental approaches. The impact of necroptosis on CC was illustrated by analyzing its effects on tumor aggression, immune responses, and the JAK2-STAT3 signaling pathway. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), was also evaluated for its potential induction of necroptosis in CC cells and its interaction with necroptosis inhibitors. Additionally, the study assessed the influence of necroptosis on the immune microenvironment, particularly in T-cell-related pathways and the expression of tumor suppressor genes in CC. Necroptosis was found to enhance VEGFA expression through the activation of the JAK2-STAT3 pathway, promoting tumor proliferative and invasive capabilities in CC. Bevacizumab induced necroptosis in CC cells, potentially leading to resistance to therapy. The combination of bevacizumab with necroptosis inhibitors attenuated VEGFA expression, suggesting a novel therapeutic strategy. Additionally, necroptosis activated T-cell-related pathways and promoted the infiltration and activation of Jurkat T cells. CD3D-a tumor suppressor gene in CC-was identified as a critical marker and its expression could be upregulated by necroptosis via the JAK2-STAT3 pathway in Jurkat T cells. Treatment of CC cells with supernatants from necroptosis-induced Jurkat cells resulted in reduced tumor cell proliferation and invasion. This study reveals a complex interaction between necroptosis, tumor progression, and the immune response in CC. The findings propose a nuanced approach to leveraging necroptosis for therapeutic interventions, highlighting the potential of combining necroptosis inhibitors with existing therapies to improve treatment outcomes in CC.
在宫颈癌（CC）病理生理学的动态格局中，本研究旨在阐明坏死性凋亡在调节CC肿瘤增殖、侵袭及免疫微环境中的作用。在本研究中，通过一系列生物信息学分析和实验方法评估了坏死性凋亡对CC的影响。通过分析其对肿瘤侵袭、免疫反应及JAK2-STAT3信号通路的作用，阐明了坏死性凋亡对CC的影响。还评估了靶向血管内皮生长因子（VEGF）的单克隆抗体贝伐单抗在CC细胞中诱导坏死性凋亡的潜力及其与坏死性凋亡抑制剂的相互作用。此外，该研究评估了坏死性凋亡对免疫微环境的影响，特别是在CC中与T细胞相关的信号通路及肿瘤抑制基因的表达。发现坏死性凋亡通过激活JAK2-STAT3通路增强VEGFA表达，促进CC的肿瘤增殖和侵袭能力。贝伐单抗诱导CC细胞发生坏死性凋亡，可能导致治疗耐药。贝伐单抗与坏死性凋亡抑制剂联合使用可减弱VEGFA表达，提示一种新的治疗策略。此外，坏死性凋亡激活与T细胞相关的信号通路，促进Jurkat T细胞的浸润和激活。CC中的肿瘤抑制基因CD3D被确定为关键标志物，其表达可通过Jurkat T细胞中的JAK2-STAT3通路被坏死性凋亡上调。用坏死性凋亡诱导的Jurkat细胞的上清液处理CC细胞可导致肿瘤细胞增殖和侵袭减少。本研究揭示了CC中坏死性凋亡、肿瘤进展和免疫反应之间的复杂相互作用。这些发现提出了一种利用坏死性凋亡进行治疗干预的细致方法，强调了将坏死性凋亡抑制剂与现有疗法联合使用以改善CC治疗效果的潜力。
