DataSheet_1_RIPK3 Suppresses the Progression of Spontaneous Intestinal Tumorigenesis.docx

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 (Ripk3-/-) mice exhibit increased tumor formation in Apcmin/+ spontaneous intestinal tumorigenesis. Apcmin/+Ripk3-/- 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 Apcmin/+Ripk3-/- 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）作为丝氨酸/苏氨酸蛋白激酶家族的一员，是细胞坏死性凋亡（necroptosis）的关键调控因子。RIPK3表达下调与多种肿瘤的不良预后显著相关。本研究发现，RIPK3参与自发性肠道肿瘤发生的进程。作为临床相关指标，结直肠癌（Colorectal Cancer, CRC）患者中RIPK3表达降低与组织学分级升高、淋巴转移及不良预后呈正相关。RIPK3基因敲除（Ripk3-/-）小鼠在Apcmin/+自发性肠道肿瘤模型中肿瘤形成能力显著增强。Apcmin/+Ripk3-/-小鼠的肿瘤可促进白细胞介素6（Interleukin 6, IL-6）/信号转导与转录激活因子3（Signal Transducer and Activator of Transcription 3, STAT3）信号通路的过度激活，进而加剧细胞增殖并抑制细胞凋亡。阻断IL-6信号通路可抑制Apcmin/+Ripk3-/-小鼠的肿瘤形成，并降低STAT3的激活水平。综上，本研究结果证实RIPK3是自发性肠道肿瘤发生过程中的抑癌基因，并提示靶向IL-6/STAT3信号轴可作为RIPK3表达降低的肠道肿瘤患者的潜在治疗策略。