Abstract 897: CHOP-deficiency promotes chronic inflammation-induced pancreatic fibrosis
Authors: Taki Katsunobu , Ohmuraya Masaki , Hashimoto Daisuke , Arima Kota , Takeyama Hideaki , Kaida Takayoshi , Higashi Takaaki , Nitta Hidetoshi , Hayashi Hiromitsu , Chikamoto Akira , Beppu Toru , Araki Kimi , Baba Hideo 
Published: August 2015

Background and Aims: Endoplasmic reticulum (ER) stress is involved in the pathogenesis of various diseases, including neurodegenerative disease, diabetes mellitus, atherosclerosis, heart disease, and pancreatic disease. CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), also known as growth arrest- and DNA damage-inducible gene 153 (GADD153) is a transcriptional regulator induced by ER stress and a key factor in the ER stress-mediated apoptosis pathway. Chronic inflammation in the pancreas causes progressive pancreatic fibrosis that eventually leads to pancreatic ductal adenocarcinoma. The aim of our study is to prove the role of the ER stress-CHOP pathway in chronic pancreatitis. Methods: We generated gene engineered chronic pancreatitis model (Spink3 SPINK1/-) mice, and crossed them with CHOP-deficient (Chop-/-) mice. We assessed the pancreatic fibrosis by hematoxylin eosin and Sirius red staining, and performed Western blotting to measure alpha smooth muscle actin (α-SMA), which is a maker of the activated pancreatic stellate cells, transforming growth factor beta 1 (TGF-β, Desmin, amylase, and trypsinogen, which are makers of exocrine function, in wild-type (Chop+/+) and CHOP-deficient chronic pancreatitis model (Chop-/-; Spink3SPINK1/-) mice at 3-weeks-old. Results: There were no significant differences between the pancreases of Chop+/+ and Chop-/- mice. The body weight of Chop-/-; Spink3 SPINK1/- mice was not so different from that of Spink3 SPINK1/- mice at 2-weeks-old, but the body weight of Chop-/-; Spink3 SPINK1/- mice was lighter than that of Spink3 SPINK1/- mice at 4-weeks-old (p&lt;0.001). However, there was no significant difference between the survival of Spink3 SPINK1/- mice than that of Chop-/-; Spink3 SPINK1/- mice. mRNA levels for inflammatory cytokines, such as TNFα, IL-6 and IL-1β increased in Chop-/-; Spink3 SPINK1/- mice than in Spink3 SPINK1/- mice at 2-weeks-old. We found the progression of pancreatic fibrosis and the activated pancreatic stellate cells in Chop-/-; Spink3 SPINK1/- mice compared with Spink3 SPINK1/- mice at 3-weeks-old. In addition, the expression levels of α-SMA, TGF-β and Desmin increased in Chop-/-; Spink3 SPINK1/- mice at 3-weeks-old. Apoptotic cells decreased in Chop-/-; Spink3 SPINK1/- mice compared with Chop-/-; Spink3 SPINK1/- mice at 3-weeks-old. Conclusions: These results indicated that the ER stress-CHOP pathway may have an essential role in the suppression of pancreatic fibrosis through the inactivation of pancreatic stellate cells in chronic pancreatitis. Therefore, anti-inflammatory treatment against chronic pancreatitis through the ER stress-CHOP pathway may reduce the risk of pancreatic cancer.

Citation Format: Katsunobu Taki, Masaki Ohmuraya, Daisuke Hashimoto, Kota Arima, Hideaki Takeyama, Takayoshi Kaida, Takaaki Higashi, Hidetoshi Nitta, Hiromitsu Hayashi, Akira Chikamoto, Toru Beppu, Kimi Araki, Hideo Baba. CHOP-deficiency promotes chronic inflammation-induced pancreatic fibrosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 897. doi:10.1158/1538-7445.AM2015-897