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De novo expression of gastrokines in pancreatic precursor lesions impede the development of pancreatic cancer.
Steiner, Sabrina; Seleznik, Gitta M; Reding, Theresia; Stopic, Matea; Lenggenhager, Daniela; Ten Buren, Emiel; Eshmuminov, Dilmurodjon; Endhardt, Katharina; Hagedorn, Catherine; Heidenblut, Anna M; Bratus-Neuenschwander, Anna; Grossmann, Jonas; Trachsel, Christian; Jabbar, Karolina S; Hahn, Stephan A; Berg, Johannes Vom; Graf, Rolf; Gupta, Anurag.
Afiliación
  • Steiner S; Visceral & Transplantation Surgery, University Hospital Zürich, 8091, Zürich, Switzerland.
  • Seleznik GM; Visceral & Transplantation Surgery, University Hospital Zürich, 8091, Zürich, Switzerland.
  • Reding T; Visceral & Transplantation Surgery, University Hospital Zürich, 8091, Zürich, Switzerland.
  • Stopic M; Visceral & Transplantation Surgery, University Hospital Zürich, 8091, Zürich, Switzerland.
  • Lenggenhager D; Department of Pathology and Molecular Pathology, University Hospital Zürich and University of Zürich, 8091, Zürich, Switzerland.
  • Ten Buren E; Institute of Laboratory Animal Science, University of Zurich, 8952, Schlieren, Switzerland.
  • Eshmuminov D; Visceral & Transplantation Surgery, University Hospital Zürich, 8091, Zürich, Switzerland.
  • Endhardt K; Department of Pathology and Molecular Pathology, University Hospital Zürich and University of Zürich, 8091, Zürich, Switzerland.
  • Hagedorn C; Visceral & Transplantation Surgery, University Hospital Zürich, 8091, Zürich, Switzerland.
  • Heidenblut AM; Faculty of Medicine, Department of Molecular GI Oncology, Ruhr University of Bochum, 44780, Bochum, Germany.
  • Bratus-Neuenschwander A; Functional Genomics Center Zurich, University of Zurich, ETH, 8093, Zurich, Switzerland.
  • Grossmann J; Functional Genomics Center Zurich, University of Zurich, ETH, 8093, Zurich, Switzerland.
  • Trachsel C; Functional Genomics Center Zurich, University of Zurich, ETH, 8093, Zurich, Switzerland.
  • Jabbar KS; Department of Medical Biochemistry, University of Gothenburg, 405 30, Gothenburg, Sweden.
  • Hahn SA; Faculty of Medicine, Department of Molecular GI Oncology, Ruhr University of Bochum, 44780, Bochum, Germany.
  • Berg JV; Institute of Laboratory Animal Science, University of Zurich, 8952, Schlieren, Switzerland.
  • Graf R; Visceral & Transplantation Surgery, University Hospital Zürich, 8091, Zürich, Switzerland. Rolf.graf@usz.ch.
  • Gupta A; Visceral & Transplantation Surgery, University Hospital Zürich, 8091, Zürich, Switzerland. Anurag.Gupta@usz.ch.
Oncogene ; 41(10): 1507-1517, 2022 03.
Article en En | MEDLINE | ID: mdl-35082384
Molecular events occurring in stepwise progression from pre-malignant lesions (pancreatic intraepithelial neoplasia; PanIN) to the development of pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Thus, characterization of early PanIN lesions may reveal markers that can help in diagnosing PDAC at an early stage and allow understanding the pathology of the disease. We performed the molecular and histological assessment of patient-derived PanINs, tumor tissues and pancreas from mouse models with PDAC (KC mice that harbor K-RAS mutation in pancreatic tissue), where we noted marked upregulation of gastrokine (GKN) proteins. To further understand the role of gastrokine proteins in PDAC development, GKN-deficient KC mice were developed by intercrossing gastrokine-deficient mice with KC mice. Panc-02 (pancreatic cancer cells of mouse origin) were genetically modified to express GKN1 for further in vitro and in vivo analysis. Our results show that gastrokine proteins were absent in healthy pancreas and invasive cancer, while its expression was prominent in low-grade PanINs. We could detect these proteins in pancreatic juice and serum of KC mice. Furthermore, accelerated PanIN and tumor development were noted in gastrokine deficient KC mice. Loss of gastrokine 1 protein delayed apoptosis during carcinogenesis leading to the development of desmoplastic stroma while loss of gastrokine 2 increased the proliferation rate in precursor lesions. In summary, we identified gastrokine proteins in early pancreatic precursor lesions, where gastrokine proteins delay pancreatic carcinogenesis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma in Situ / Carcinoma Ductal Pancreático / Hormonas Peptídicas Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma in Situ / Carcinoma Ductal Pancreático / Hormonas Peptídicas Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido