The oncoprotein gankyrin promotes the development of colitis-associated cancer through activation of STAT3.
The oncoprotein gankyrin promotes the development of colitis-associated cancer through activation of STAT3.
复制标题
DOI：
10.18632/oncotarget.14983
复制
发表时间：
2017-04-11
期刊：
影响因子：
--
通讯作者：
Kudo M
中科院分区：
文献类型：
--
作者：
Sakurai T;Higashitsuji H;Kashida H;Watanabe T;Komeda Y;Nagai T;Hagiwara S;Kitano M;Nishida N;Abe T;Kiyonari H;Itoh K;Fujita J;Kudo M
虽然由于难治性炎症性肠病（IBD）引起的长期结肠炎症促进了结肠炎相关癌症（CAC）的发展，但导致CAC发展的分子机制在很大程度上仍然未知。在这项研究中，我们研究了Gankyrin在CAC发展中的作用，因为Gankyrin在散发性结直肠癌中过表达。我们分析了从344例IBD和CAC患者中获得的结肠组织的基因表达，发现Gankyrin在难治性IBD患者的结肠粘膜中的表达远高于缓解期IBD患者。结直肠癌患者结肠黏膜中Gankyrin在炎性细胞和肿瘤细胞中表达上调。利用标记的ganlyrin-cDNA的过表达研究确定了ganlyrin和含Src同源性2的蛋白酪氨酸磷酸酶-1（SHP-1）之间的物理相互作用。重要的是，甘丙素和SHP-1之间的相互作用导致炎症细胞中STAT 3活化的抑制和TNF-α和IL-17的增强。为了进一步阐明Gankyrin在CAC发展中的作用，我们建立了肠上皮细胞特异性Gankyrin消融（Vil-Cre; Gankyrin f/f）和骨髓和上皮细胞中Gankyrin缺失（Mx 1-Cre; Gankyrin f/f）的小鼠。骨髓细胞中Gankyrin缺乏，而不是在上皮细胞中，减少了有丝分裂原活化蛋白激酶的活性和干细胞标志物的表达，导致致瘤潜力减弱。这些发现为CAC的发病机制提供了重要的见解，并表明Gankyrin是开发针对CAC的治疗和预防策略的有前途的靶点。
Although long-standing colonic inflammation due to refractory inflammatory bowel disease (IBD) promotes the development of colitis-associated cancer (CAC), the molecular mechanisms accounting for the development of CAC remains largely unknown. In this study, we investigated the role of gankyrin in the development of CAC since gankyrin is overexpressed in sporadic colorectal cancers. We analyzed gene expression of colon tissues obtained from 344 patients with IBD and CAC and found that expression of gankyrin was much higher in colonic mucosa of patients with refractory IBD than in those with IBD in remission. Expression of gankyrin was upregulated in inflammatory cells as well as tumor cells in colonic mucosa of patients with CAC. Over-expressing studies utilizing tagged ganlyrin-cDNA identified physical interaction between ganlyrin and Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1). Importantly, the interaction between ganlyrin and SHP-1 leads to inhibition of STAT3 activation and to enhancement of TNF-α and IL-17 in inflammatory cells. To further address the role of gankyrin in the development of CAC, we created mice with intestinal epithelial cell-specific gankyrin ablation (Vil-Cre;Gankyrinf/f) and deletion of gankyrin in myeloid and epithelial cells (Mx1-Cre;Gankyrinf/f). Gankyrin deficiency in myeloid cells, but not in epithelial cells, reduced the activity of mitogen activated protein kinase and the expression of stem cell markers, leading to attenuated tumorigenic potential. These findings provide important insights into the pathogenesis of CAC and suggest that gankyrin is a promising target for developing therapeutic and preventive strategies against CAC.