Chronic pancreatitis results in the formation of pancreatic intraepithelial neoplasia (PanIN) and poses a risk of developing pancreatic cancer. Our previous study demonstrated that Krüppel-like factor 5 (KLF5) is necessary for forming acinar-to-ductal metaplasia (ADM) in acute pancreatitis. Here, we investigated the role of KLF5 in response to chronic injury in the pancreas. Human tissues originating from chronic pancreatitis patients showed increased levels of epithelial KLF5. An inducible genetic model combining the deletion ofKlf5and the activation ofKrasG12Dmutant expression in pancreatic acinar cells together with chemically induced chronic pancreatitis was used. The chronic injury resulted in increased levels of KLF5 in both control andKrasG12Dmutant mice. Furthermore, it led to numerous ADM and PanIN lesions and extensive fibrosis in the KRAS mutant mice. In contrast, pancreata withKlf5loss (with or withoutKrasG12D) failed to develop ADM, PanIN, or significant fibrosis. Furthermore, the deletion ofKlf5reduced the expression level of cytokines and fibrotic components such asIl1b,Il6,Tnf,Tgfb1,Timp1, andMmp9. Notably, using ChIP-PCR, we showed that KLF5 binds directly to the promoters ofIl1b,Il6, andTgfb1genes. In summary, the inactivation ofKlf5inhibits ADM and PanIN formation and the development of pancreatic fibrosis.
慢性胰腺炎可导致胰腺上皮内瘤变（PanIN）的形成，并增加胰腺癌的发病风险。我们先前的研究表明，Krüppel样因子5（KLF5）在急性胰腺炎中腺泡-导管化生（ADM）的形成过程中是必需的。本研究旨在探讨KLF5在胰腺慢性损伤应答中的作用。来自慢性胰腺炎患者的人体组织显示上皮细胞中KLF5水平升高。我们采用了一种诱导性遗传模型，该模型结合了胰腺腺泡细胞中Klf5基因的缺失与KrasG12D突变表达的激活，并辅以化学诱导的慢性胰腺炎。慢性损伤导致对照组和KrasG12D突变小鼠中KLF5水平均有所上升。此外，在KRAS突变小鼠中，慢性损伤引发了大量ADM和PanIN病变以及广泛的纤维化。相比之下，缺失Klf5（无论是否伴有KrasG12D突变）的胰腺未能形成ADM、PanIN或明显的纤维化。进一步研究发现，Klf5的缺失降低了细胞因子及纤维化相关成分如Il1b、Il6、Tnf、Tgfb1、Timp1和Mmp9的表达水平。值得注意的是，通过染色质免疫沉淀-聚合酶链反应（ChIP-PCR）技术，我们证实KLF5可直接结合Il1b、Il6和Tgfb1基因的启动子区域。综上所述，Klf5的失活能够抑制ADM和PanIN的形成以及胰腺纤维化的发展。
Krüppel-like Factor 5 Plays an Important Role in the Pathogenesis of Chronic Pancreatitis
肿瘤(癌症)患者之家