Dysregulation of PI3K and Hippo signaling pathways synergistically induces chronic pancreatitis via CTGF upregulation
Takeshi Tamura, … , Tomohide Tatsumi, Tetsuo Takehara
Takeshi Tamura, … , Tomohide Tatsumi, Tetsuo Takehara
Published May 25, 2021
Citation Information: J Clin Invest. 2021;131(13):e143414. https://doi.org/10.1172/JCI143414.
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Dysregulation of PI3K and Hippo signaling pathways synergistically induces chronic pancreatitis via CTGF upregulation

Abstract

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.

Authors

Takeshi Tamura, Takahiro Kodama, Katsuhiko Sato, Kazuhiro Murai, Teppei Yoshioka, Minoru Shigekawa, Ryoko Yamada, Hayato Hikita, Ryotaro Sakamori, Hirofumi Akita, Hidetoshi Eguchi, Randy L. Johnson, Hideki Yokoi, Masashi Mukoyama, Tomohide Tatsumi, Tetsuo Takehara

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Figure 1

Expression of PTEN and SAV1 is downregulated in the pancreatic tissues of mice in 2 models of CP.

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Expression of PTEN and SAV1 is downregulated in the pancreatic tissues o...
(A and B) Representative images of H&E, Sirius red, and SOX9 staining of pancreatic tissue in mice after repeated cerulein or vehicle (control) injection (A) and in mice subjected to pancreatic duct ligation (PDL) surgery or sham surgery (B). (C and D) Cd68, Tnfa, Il1b, Ccl2, Tgfb1, Col1a1, and Col1a2 mRNA levels in pancreatic tissue in mice after repeated cerulein injection (C) and in mice subjected to PDL surgery (D). (E and F) Pten and Sav1 mRNA levels in pancreatic tissue in mice after repeated cerulein injection (E) and in mice subjected to PDL surgery (F). (G and H) Representative images of PTEN and SAV1 staining of pancreatic tissue in mice after repeated cerulein injection (G, left), with quantification of the PTEN and SAV1 staining intensity (G, right); and in mice subjected to PDL surgery (H, left), with quantification of PTEN and SAV1 staining intensity (H, right). (I and J) Protein levels of AKT, p-AKT, YAP, p-YAP, and ACTB in the pancreata of mice after repeated cerulein injection (I) and in mice subjected to PDL surgery (J). (K) Ctgf mRNA levels in pancreatic tissue in mice after repeated cerulein injection (left) and in mice subjected to PDL surgery (right). Blots run in parallel contemporaneously or run at different times with loading control for each gel are shown. All data are presented as the means ± SDs of results for 3 mice per group. Student’s t test was used to evaluate differences between 2 groups. *P < 0.05 and **P < 0.005. Scale bars: 100 μm and 50 μm (insets).