TY - JOUR
T1 - Dysregulation of PI3K and Hippo signaling pathways synergistically induces chronic pancreatitis via CTGF upregulation
AU - Tamura, Takeshi
AU - Kodama, Takahiro
AU - Sato, Katsuhiko
AU - Murai, Kazuhiro
AU - Yoshioka, Teppei
AU - Shigekawa, Minoru
AU - Yamada, Ryoko
AU - Hikita, Hayato
AU - Sakamori, Ryotaro
AU - Akita, Hirofumi
AU - Eguchi, Hidetoshi
AU - Johnson, Randy L.
AU - Yokoi, Hideki
AU - Mukoyama, Masashi
AU - Tatsumi, Tomohide
AU - Takehara, Tetsuo
N1 - Funding Information:
This work was partially supported by a Grant-in-Aid for Scientific Research (to T Takehara) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. This work was supported by the Cancer Prevention Research Institute of Texas under grant RP180530 (to RLJ) and the Japan Agency for Medical Research and Development (AMED) under grant JP20fk0210074 (to TK). The authors thank FibroGen for providing the anti-CTGF neutralizing antibody FG-3154.
Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/7
Y1 - 2021/7
N2 - The role of PI3K and Hippo signaling in chronic pancreatitis (CP) pathogenesis is unclear. Therefore, we assessed the involvement of these pathways in CP by examining the PI3K and Hippo signaling components PTEN and SAV1, respectively. We observed significant decreases in pancreatic PTEN and SAV1 levels in 2 murine CP models: repeated cerulein injection and pancreatic ductal ligation. Additionally, pancreas-specific deletion of Pten and Sav1 (DKO) induced CP in mice. Pancreatic connective tissue growth factor (CTGF) was markedly upregulated in both CP models and DKO mice, and pancreatic CCAAT/ enhancer-binding protein-α (CEBPA) expression was downregulated in the CP models. Interestingly, in pancreatic acinar cells (PACs), CEBPA knockdown reduced PTEN and SAV1 and increased CTGF levels in vitro. Furthermore, CEBPA knockdown in PACs induced acinar-to-ductal metaplasia and activation of cocultured macrophages and pancreatic stellate cells. These results were mitigated by CTGF inhibition. CP in DKO mice was also ameliorated by Ctgf gene deletion, and cerulein-induced CP was alleviated by antibody-mediated CTGF neutralization. Finally, we observed significantly decreased PTEN, SAV1, and CEBPA and increased CTGF levels in human CP tissues compared with nonpancreatitis tissues. Taken together, our results indicate that dysregulation of PI3K and Hippo signaling induces CP via CTGF upregulation.
AB - The role of PI3K and Hippo signaling in chronic pancreatitis (CP) pathogenesis is unclear. Therefore, we assessed the involvement of these pathways in CP by examining the PI3K and Hippo signaling components PTEN and SAV1, respectively. We observed significant decreases in pancreatic PTEN and SAV1 levels in 2 murine CP models: repeated cerulein injection and pancreatic ductal ligation. Additionally, pancreas-specific deletion of Pten and Sav1 (DKO) induced CP in mice. Pancreatic connective tissue growth factor (CTGF) was markedly upregulated in both CP models and DKO mice, and pancreatic CCAAT/ enhancer-binding protein-α (CEBPA) expression was downregulated in the CP models. Interestingly, in pancreatic acinar cells (PACs), CEBPA knockdown reduced PTEN and SAV1 and increased CTGF levels in vitro. Furthermore, CEBPA knockdown in PACs induced acinar-to-ductal metaplasia and activation of cocultured macrophages and pancreatic stellate cells. These results were mitigated by CTGF inhibition. CP in DKO mice was also ameliorated by Ctgf gene deletion, and cerulein-induced CP was alleviated by antibody-mediated CTGF neutralization. Finally, we observed significantly decreased PTEN, SAV1, and CEBPA and increased CTGF levels in human CP tissues compared with nonpancreatitis tissues. Taken together, our results indicate that dysregulation of PI3K and Hippo signaling induces CP via CTGF upregulation.
UR - http://www.scopus.com/inward/record.url?scp=85109019573&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85109019573&partnerID=8YFLogxK
U2 - 10.1172/JCI143414
DO - 10.1172/JCI143414
M3 - Article
C2 - 34032634
AN - SCOPUS:85109019573
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 13
M1 - e143414
ER -