Lou Yunwei, Song Miaomiao, Han Meijuan, Zhong Jiateng, Tian Xueqin, Ren Yahan, Song Yaru, Duan Liangwei, Zhao Peiqing, Song Xiangfeng, Zhang Wen, Chen Youhai H, Wang Hui
Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China.
Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China.
Cancer Immunol Res. 2022 Mar 1;10(3):354-367. doi: 10.1158/2326-6066.CIR-21-0666.
Although increasing evidence links the gut microbiota with the development of colorectal cancer, the molecular mechanisms for microbiota regulation of tumorigenesis are not fully understood. Here, we found that a member of the TNFα-induced protein 8 (TNFAIP8) family called TIPE2 (TNFAIP8-like 2) was significantly upregulated in murine intestinal tumors and in human colorectal cancer, and colorectal cancer with high expression of Tipe2 mRNA associated with reduced survival time of patients. Consistent with these findings, TIPE2 deficiency significantly inhibited the development of colorectal cancer in mice treated with azoxymethane/dextran sodium sulfate and in Apcmin/+ mice. TIPE2 deficiency attenuated the severity of colitis by successfully resolving and restricting colonic inflammation and protected colonic myeloid cells from death during colitis. Transplantation of TIPE2-deficient bone marrow into wild-type mice successfully dampened the latter's tumorigenic phenotype, indicating a hematopoietic-specific role for TIPE2. Mechanistically, restricting the expansion of Enterobacteriaceae/Escherichia coli (E. coli) decreased intestinal inflammation and reduced the incidence of colonic tumors. Collectively, these data suggest that hematopoietic TIPE2 regulates intestinal antitumor immunity by regulation of gut microbiota. TIPE2 may represent a new therapeutic target for treating colorectal cancer.
尽管越来越多的证据表明肠道微生物群与结直肠癌的发生有关，但微生物群调节肿瘤发生的分子机制尚未完全了解。在此，我们发现肿瘤坏死因子α诱导蛋白8（TNFAIP8）家族的一个成员，称为TIPE2（TNFAIP8样2），在小鼠肠道肿瘤和人类结直肠癌中显著上调，并且Tipe2 mRNA高表达的结直肠癌与患者生存时间缩短相关。与这些发现一致，TIPE2缺陷显著抑制了用氧化偶氮甲烷/葡聚糖硫酸钠处理的小鼠和Apcmin/+小鼠中结直肠癌的发展。TIPE2缺陷通过成功解决和限制结肠炎症减轻了结肠炎的严重程度，并在结肠炎期间保护结肠髓样细胞免于死亡。将TIPE2缺陷的骨髓移植到野生型小鼠中成功抑制了后者的致瘤表型，表明TIPE2具有造血特异性作用。从机制上讲，限制肠杆菌科/大肠杆菌（E. coli）的扩张可减轻肠道炎症并降低结肠肿瘤的发生率。总体而言，这些数据表明造血TIPE2通过调节肠道微生物群来调节肠道抗肿瘤免疫。TIPE2可能代表了治疗结直肠癌的一个新的治疗靶点。
