Zhao Qun, Guo Jian, Cheng Xinran, Liao Yingying, Bi Yun, Gong Yingxia, Zhang Xudong, Guo Yang, Wang Xianhui, Yu Wei, Jin Shu, Tan Yan, Yu Xianjun
Laboratory of Inflammation and Molecular Pharmacology, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences & Biomedical Research Institute, Hubei University of Medicine, Shiyan, China.
Department of Gastroenterology, Renming Hospital, Hubei University of Medicine, Shiyan, China.
Front Oncol. 2021 Apr 30;11:664927. doi: 10.3389/fonc.2021.664927. eCollection 2021.
Receptor-interacting protein 3 (RIPK3), a member of the family of serine/threonine protein kinases, emerged as a critical regulator of necroptosis. Downregulated expression of RIPK3 is correlated with poor prognosis in multiple tumor types. Here, we show that RIPK3 is involved in the progression of spontaneous intestinal tumorigenesis. As a clinical correlate, reduced expression of RIPK3 is positively associated with histological grade, lymphatic metastasis and poor prognosis in CRC patients. RIPK3-deficient ( ) mice exhibit increased tumor formation in spontaneous intestinal tumorigenesis. tumors promote hyperactivation of IL-6/STAT3 signaling, which exacerbates proliferation and inhibits apoptosis. Blocking IL-6 signaling suppressed tumor formation and reduced STAT3 activation in mice. Thus, our results reveal that RIPK3 is a tumor suppressor in spontaneous intestinal tumorigenesis, and implicate targeting the IL-6/STAT3 signaling axis as a potential therapeutic strategy for intestinal tumor patients with reduced RIPK3.
受体相互作用蛋白3（RIPK3）是丝氨酸/苏氨酸蛋白激酶家族的一员，是坏死性凋亡的关键调节因子。RIPK3表达下调与多种肿瘤类型的不良预后相关。在此，我们表明RIPK3参与自发性肠道肿瘤发生的进程。作为临床关联，RIPK3表达降低与结直肠癌患者的组织学分级、淋巴转移及不良预后呈正相关。RIPK3基因敲除小鼠在自发性肠道肿瘤发生中表现出肿瘤形成增加。RIPK3基因敲除肿瘤促进IL-6/STAT3信号通路的过度激活，这加剧了增殖并抑制了凋亡。阻断IL-6信号通路可抑制RIPK3基因敲除小鼠的肿瘤形成并降低STAT3激活。因此，我们的结果揭示RIPK3是自发性肠道肿瘤发生中的一种肿瘤抑制因子，并表明靶向IL-6/STAT3信号轴作为RIPK3降低的肠道肿瘤患者的一种潜在治疗策略。
