miR-155通过HBP1靶向调控Wnt/β-catenin信号通路促进CD肠道纤维化

Stricture caused by intestinalfibrosis is a serious problem in the clinical practice in crohn's disease, as there is no effective diagnostic and therapeutic method. Studies show that miR-155 participate in the fibrosis process. HBP1 is nuclear factor inhibitor of promoting cell proliferation gene. Recent studies have found that HBP1 have negative regulatory role to Wnt signaling pathways, and Wnt/beta-catenin signaling pathway is thought to play a pivotal role in organ fibrosis. Our previous studies have shown that HBP1 is target genes of miR-155, miR-155 can down-regulated HBP1 expression and miR-155 is up-regulated in intestinal tissue samples of patients with stenosis CD. So we assume that: miR-155 up-regulate in intestinal tissue with stenosis CD, which combined with HBP1 to inhibit HBP1 expression, and the Wnt/beta-catenin signaling pathway signal was increased, thereby promoting the intestinal fibrosis. To confirm this hypothesis, we will clarify miR-155 regulates Wnt/beta-catenin signaling pathway signal by inhibiting HBP1 including both in vitro and vivo tests to regulate intestinal fibrosis. It will provide a new theoretical basis for the molecular mechanism of regulation of intestinal fibrosis by miRNAs.

肠道纤维化所致肠腔狭窄是克罗恩病（CD）临床工作中的棘手问题，目前缺乏有效诊治措施。有研究显示miR-155参与了纤维化疾病过程。HBP1是一些促细胞增殖基因的转录抑制因子，近期的研究发现，HBP1对于Wnt信号通路有负向调控作用，而Wnt/β-catenin信号通路目前认为在器官纤维化形成中起着关键作用。我们前期研究显示HBP1是miR-155的靶基因，miR-155可下调HBP1的表达，miR-155在狭窄型CD患者肠道组织标本中表达上调。因此我们假设：在狭窄型CD患者肠道组织中miR-155表达上调，与HBP1结合抑制HBP1表达，继而上调Wnt/β-catenin信号通路信号，从而促进肠道纤维化。本研究拟结合体内、外实验，进一步证实miR-155可通过抑制HBP1，调控Wnt/β-catenin信号通路，参与CD肠道纤维化，为miRNAs调控肠道纤维化的分子机制提供新的理论依据。

克罗恩病是炎症性肠病的主要疾病之一，肠纤维化是克罗恩病常见的并发症，但其确切机制尚不清楚。既往研究发现miR-155与纤维化疾病有关，但miR-155是否参与到了克罗恩病导致的肠纤维化病变及其可能作用机制仍不清楚。通过本课题的研究，我们明确了miR-155在调节肠纤维化中的作用。肠狭窄克罗恩病患者较非狭窄型克罗恩病患者肠粘膜miR-155水平显著上调。过表达miR-155显著加重了TNBS诱导的小鼠结肠炎相关的肠纤维化。在机制层面上，我们发现Wnt/β-catenin信号通路的负调节因子HBP1是miR-155的直接靶点。此外，体内外实验证明miR-155/HBP1轴通过激活Wnt/β-catenin信号通路诱导肠纤维化。本课题研究结论为miR-155通过直接靶向HBP1激活Wnt/β-catenin信号通路，最终诱导克罗恩病相关的肠纤维化。