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Open AccessArticle

Inflammation Associated Pancreatic Tumorigenesis: Upregulation of Succinate Dehydrogenase (Subunit B) Reduces Cell Growth of Pancreatic Ductal Epithelial Cells

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Institute for Experimental Cancer Research, University of Kiel and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, 24105 Kiel, Germany
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Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany
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Institute for Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
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Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
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Department of Hematology and Oncology, University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, 24105 Kiel, Germany
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Institute for Human Nutrition & Food Science, Department of Food Technology, University of Kiel, 24118 Kiel, Germany
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Institute of Immunology, University of Kiel and UKSH Campus Kiel, 24105 Kiel, Germany
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BAG für Pathologie und Molekularpathologie Stuttgart, 70176 Stuttgart, Germany
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Department of Pathology, UKSH Campus Kiel, 24105 Kiel, Germany
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Author to whom correspondence should be addressed.
Cancers 2020, 12(1), 42; https://doi.org/10.3390/cancers12010042
Received: 20 November 2019 / Revised: 12 December 2019 / Accepted: 19 December 2019 / Published: 21 December 2019
Pancreatic ductal adenocarcinoma (PDAC) is amongst the most fatal malignancies and its development is highly associated with inflammatory processes such as chronic pancreatitis (CP). Since the succinate dehydrogenase subunit B (SDHB) is regarded as tumor suppressor that is lost during cancer development, this study investigated the impact of M1-macrophages as part of the inflammatory microenvironment on the expression as well as function of SDHB in benign and premalignant pancreatic ductal epithelial cells (PDECs). Immunohistochemical analyses on pancreatic tissue sections from CP patients and control individuals revealed a stronger SDHB expression in ducts of CP tissues being associated with a greater abundance of macrophages compared to ducts in control tissues. Accordingly, indirect co-culture with M1-macrophages led to clearly elevated SDHB expression and SDH activity in benign H6c7-pBp and premalignant H6c7-kras PDECs. While siRNA-mediated SDHB knockdown in these cells did not affect glucose and lactate uptake after co-culture, SDHB knockdown significantly promoted PDEC growth which was associated with increased proliferation and decreased effector caspase activity particularly in co-cultured PDECs. Overall, these data indicate that SDHB expression and SDH activity are increased in PDECs when exposed to pro-inflammatory macrophages as a counterregulatory mechanism to prevent excessive PDEC growth triggered by the inflammatory environment. View Full-Text
Keywords: pancreatic cancer; SDHB; macrophages; inflammatory stroma; chronic pancreatitis pancreatic cancer; SDHB; macrophages; inflammatory stroma; chronic pancreatitis
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Rahn, S.; Dänzer Barbosa, P.; Möller, J.L.; Ammar, N.; Demetrowitsch, T.; Helm, O.; Wesch, D.; Sipos, B.; Röcken, C.; Schwarz, K.; Schäfer, H.; Sebens, S. Inflammation Associated Pancreatic Tumorigenesis: Upregulation of Succinate Dehydrogenase (Subunit B) Reduces Cell Growth of Pancreatic Ductal Epithelial Cells. Cancers 2020, 12, 42.

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