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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Research Article Gastroenterology

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 7

CP tissues exhibit lower PTEN and SAV1 levels and higher CTGF levels than nonpancreatitis tissues from humans.

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CP tissues exhibit lower PTEN and SAV1 levels and higher CTGF levels tha...
(A and B) Representative images of H&E, Sirius red, and SOX9 staining of pancreatic tissue from the head or tail side of PDAC tumors from pancreatic cancer patients (A) and quantification of the Sirius red–positive area (B, left) and SOX9 staining intensity (B, right). (C and D) Representative images of CEBPA, PTEN, SAV1, p-AKT, nuclear YAP, and CTGF staining of pancreatic tissue from the head or tail side of PDAC tumors from pancreatic cancer patients (C) and the relative staining intensity of CEBPA, PTEN, SAV1, p-AKT, nuclear YAP, and CTGF (D). (E) The relative intensity of CEBPA, PTEN, SAV1, p-AKT, nuclear YAP, and CTGF staining of pancreatic tissue from the normal pancreatic regions obtained from pancreatic neuroendocrine tumor patients or from the chronic pancreatic regions obtained from CP patients. All data are presented as the means ± SDs of results for 6 samples 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).