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Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein.

ABSTRACT: We previously showed that an inflammation-related, molecule leucine-rich alpha-2 glycoprotein (LRG) enhances the transforming growth factor (TGF)-?1-induced phosphorylation of Smad proteins and is elevated in patients with pancreatic ductal adenocarcinoma (PDAC). As TGF-?/Smad signaling is considered to play a key role in epithelial-mesenchymal transition (EMT), we attempted to clarify the mechanism underlying LRG-related EMT in relation to metastasis in PDAC. We cultured LRG-overexpressing PDAC cells (Panc1/LRG) and evaluated the morphology, EMT-related molecules and TGF-?/Smad signaling pathway in these cells. We also assessed the LRG levels in plasma and resected specimens from patients with PDAC. Inflammatory cytokines induced LRG production in PDAC cells. A spindle-like shape was visualized more frequently than other shapes in Panc1/LRG with TGF-?1 exposure. The expression of E-cadherin in Panc1/LRG was decreased with TGF-?1 exposure. Invasion increased with TGF-?1 stimulation of Panc1/LRG. The phosphorylation of smad2 in Panc1/LRG was increased in comparison with parental Panc1 under TGF-?1 stimulation. In the plasma LRG-high group, the recurrence rate tended to be higher and the recurrence-free survival (RFS) tended to be worse in comparison with the plasma LRG-low group. LRG enhanced EMT induced by TGF-? signaling, thus indicating that LRG has a significant effect on the metastasis of PDAC.

SUBMITTER: Otsuru T

PROVIDER: S-EPMC6398893 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein.

Otsuru Toru T Kobayashi Shogo S Wada Hiroshi H Takahashi Tsuyoshi T Gotoh Kunihito K Iwagami Yoshifumi Y Yamada Daisaku D Noda Takehiro T Asaoka Tadafumi T Serada Satoshi S Fujimoto Minoru M Eguchi Hidetoshi H Mori Masaki M Doki Yuichiro Y Naka Testuji T

Cancer science 20190204 3

We previously showed that an inflammation-related, molecule leucine-rich alpha-2 glycoprotein (LRG) enhances the transforming growth factor (TGF)-β1-induced phosphorylation of Smad proteins and is elevated in patients with pancreatic ductal adenocarcinoma (PDAC). As TGF-β/Smad signaling is considered to play a key role in epithelial-mesenchymal transition (EMT), we attempted to clarify the mechanism underlying LRG-related EMT in relation to metastasis in PDAC. We cultured LRG-overexpressing PDAC ...[more]

PMID: 30575211

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Project description:This study aimed to determine the association between umbilical cord leucine-rich alpha-2 glycoprotein (LRG) and fetal infection and investigate the underlying mechanism of LRG elevation in fetuses. We retrospectively reviewed the medical records of patients who delivered at Osaka University Hospital between 2012 and 2017 and selected those with histologically confirmed chorioamnionitis (CAM), which is a common pregnancy complication that may cause neonatal infection. The participants were divided into two groups: CAM with fetal infection (CAM-f[+] group, n = 14) and CAM without fetal infection (CAM-f[-] group, n = 31). Fetal infection was defined by the histological evidence of funisitis. We also selected 50 cases without clinical signs of CAM to serve as the control. LRG concentrations in sera obtained from the umbilical cord were unaffected by gestational age at delivery, neonatal birth weight, nor the presence of noninfectious obstetric complications (all, p > 0.05). Meanwhile, the LRG levels (median, Interquartile range [IQR]) were significantly higher in the CAM-f(+) group (10.37 [5.21-13.7] μg/ml) than in the CAM-f(-) (3.61 [2.71-4.65] μg/ml) or control group (3.39 [2.81-3.93] μg/ml; p < 0.01). The area under the receiver operating characteristic (ROC) curve of LRG for recognizing fetal infection was 0.92 (optimal cutoff, 5.08 μg/ml; sensitivity, 86%; specificity, 88%). In a mouse CAM model established by lipopolysaccharide administration, the fetal LRG protein in sera and LRG mRNA in the liver were significantly higher than those in phosphate-buffered saline (PBS)-administered control mice (p < 0.01). In vitro experiments using a fetal liver-derived cell line (WRL68) showed that the expression of LRG mRNA was significantly increased after interleukin (IL)-6, IL-1β, and tumor necrosis factor- alpha (TNF-α) stimulation (p < 0.01); the induction was considerably stronger following IL-6 and TNF-α stimulation (p < 0.01). In conclusion, LRG is an effective biomarker of fetal infection, and fetal hepatocytes stimulated with inflammatory cytokines may be the primary source of LRG production in utero.

Dataset Information

Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein.

Publications

Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein.

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