Liu Chao, Liu En-Dong, Meng Yun-Xiao, Dong Xiao-Ming, Bi Ya-Lan, Wu Huan-Wen, Jin Yan-Chao, Zhao Ke, Li Jian-Jie, Yu Miao, Zhan Yi-Qun, Chen Hui, Ge Chang-Hui, Yang Xiao-Ming, Li Chang-Yan
An Hui Medical University, Hefei, 230032, China.
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
Oncotarget. 2017 May 27;8(57):96774-96790. doi: 10.18632/oncotarget.18241. eCollection 2017 Nov 14.
Keratin 8 (CK8) is the major component of the intermediate filaments of simple or single-layered epithelia. Gene targeting mice model suggest that CK8 is involved in colonic active ion transport, colorectal hyperplasia and inflammation. In the present study, we found that CK8 is downregulated in the colon during DSS-induced colitis and AOM/DSS-induced colitis-associated colorectal cancer (CAC) development. In human patients with colon cancer, CK8 is downregulated. Using CK8 heterozygous knockout mice (CK8), we found that CK8 mice are highly susceptible to DSS-induced colitis and more prone to AOM/DSS-induced CAC than wild type (WT) mice. The colonic permeability is increased with DSS or AOM/DSS treatment, leading to alteration of gut microbiota in CK8 mice with CAC. Metagenomic analysis of fecal microbiota suggests and are increased in CK8 mice with CAC, while and are decreased. Antibiotic treatment decreases the incidence of colorectal cancer tumorigenesis and TLR4 inhibitor attenuates the susceptibility of CK8 mice to DSS-induced colitis. These data suggest CK8 protects mice from colitis and colitis-associated colorectal cancer by modulating colonic permeability and gut microbiota composition homeostasis.
角蛋白8（CK8）是单层上皮细胞中间丝的主要成分。基因敲除小鼠模型表明，CK8参与结肠活性离子转运、结直肠增生和炎症。在本研究中，我们发现，在葡聚糖硫酸钠（DSS）诱导的结肠炎和氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）诱导的结肠炎相关结直肠癌（CAC）发生过程中，结肠中CK8表达下调。在结肠癌人类患者中，CK8也下调。利用CK8杂合敲除小鼠（CK8），我们发现与野生型（WT）小鼠相比，CK8小鼠对DSS诱导的结肠炎高度敏感，更易发生AOM/DSS诱导的CAC。DSS或AOM/DSS处理后，CK8小鼠的结肠通透性增加，导致患CAC的CK8小鼠肠道微生物群发生改变。对粪便微生物群的宏基因组分析表明，患CAC的CK8小鼠中[具体物质1]和[具体物质2]增加，而[具体物质3]和[具体物质4]减少。抗生素治疗可降低结直肠癌肿瘤发生的发生率，Toll样受体4（TLR4）抑制剂可减轻CK8小鼠对DSS诱导的结肠炎的易感性。这些数据表明，CK8通过调节结肠通透性和肠道微生物群组成稳态来保护小鼠免受结肠炎和结肠炎相关结直肠癌的侵害。
