Trefoil factor 1 inhibits epithelial-mesenchymal transition of pancreatic intraepithelial neoplasm
Junpei Yamaguchi, … , Atsushi Enomoto, Masato Nagino
Junpei Yamaguchi, … , Atsushi Enomoto, Masato Nagino
Published May 29, 2018
Citation Information: J Clin Invest. 2018;128(8):3619-3629. https://doi.org/10.1172/JCI97755.
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Research Article Gastroenterology Oncology

Trefoil factor 1 inhibits epithelial-mesenchymal transition of pancreatic intraepithelial neoplasm

Abstract

The tumor-suppressive role of trefoil factor family (TFF) members in gastric carcinogenesis has been suggested, but their significance and mechanisms in other digestive diseases remain elusive. To clarify the role of TFF1 in pancreatic carcinogenesis, we performed IHC on human samples, transfected siRNA against TFF1 into pancreatic cancer cell lines, and employed mouse models in which PanIN development and loss of TFF1 occur simultaneously. In human samples, the expression of TFF1 was specifically observed in pancreatic intraepithelial neoplasm (PanIN), but was frequently lost in the invasive component of pancreatic ductal adenocarcinoma (PDAC). When the expression of TFF1 was suppressed in vitro, pancreatic cancer cell lines showed enhanced invasive ability and features of epithelial-mesenchymal transition (EMT), including upregulated Snail expression. TFF1 expression was also observed in PanIN lesions of Pdx-1 Cre; LSL-KRASG12D (KC) mice, a model of pancreatic cancer, and loss of TFF1 in these mice resulted in the expansion of PanIN lesions, an EMT phenotype in PanIN cells, and an accumulation of cancer-associated fibroblasts (CAFs), eventually resulting in the development of invasive adenocarcinoma. This study indicates that the acquisition of TFF1 expression is an early event in pancreatic carcinogenesis and that TFF1 might act as a tumor suppressor to prevent EMT and the invasive transformation of PanIN.

Authors

Junpei Yamaguchi, Yukihiro Yokoyama, Toshio Kokuryo, Tomoki Ebata, Atsushi Enomoto, Masato Nagino

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Figure 5

Loss of TFF1 results in the expansion of PanIN lesions in KC mice.

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Loss of TFF1 results in the expansion of PanIN lesions in KC mice. (A) I...
(A) IHC revealed abundant TFF1 expression in PanIN cells in KC mice, while no expression was observed in PanIN cells in KC/TFF1–/– mice. In the low-magnification image, PanIN lesions were observed more extensively in KC/TFF1–/– than in KC mice. Scale bars: 50 μm (left and middle panels); 100 μm (right panels ). (B) PanIN lesions infiltrated into the ductal epithelium in KC/TFF1–/–, but not KC, mice. PanIN cells without TFF1 expression were likely derived from acinar cells (white arrow), infiltrating into the pancreatic ducts (black arrow) and eventually spreading along pancreatic ducts and replacing normal ductal epithelial cells with tumor cells (black arrowheads) with strong Snail expression. Asterisks indicate ductal lumen. Scale bars: 50 μm. (C) Quantitative analysis of PanIN-occupied areas. *P < 0.01, ANOVA. (D) Quantitative analysis of ducts infiltrated by PanIN lesions revealed more frequent infiltration in KC/TFF1–/– mice. *P < 0.01, ANOVA. Data are presented as mean ± SD.