TLR7 and TLR8 expression increases tumor cell proliferation and promotes chemoresistance in human pancreatic cancer

Grimmig,Tanja; Matthes,Niels; Hoeland,Katharina; Tripathi,Sudipta; Chandraker,Anil; Grimm,Martin; Moench,Romana; Moll,Eva-Maria; Friess,Helmut; Tsaur,Igor; Blaheta,Roman  A.; Germer,Cristoph  T.; Waaga-Gasser,Ana   Maria; Gasser,Martin

doi:10.3892/ijo.2015.3069

TLR7 and TLR8 expression increases tumor cell proliferation and promotes chemoresistance in human pancreatic cancer

Authors:
- Tanja Grimmig
- Niels Matthes
- Katharina Hoeland
- Sudipta Tripathi
- Anil Chandraker
- Martin Grimm
- Romana Moench
- Eva-Maria Moll
- Helmut Friess
- Igor Tsaur
- Roman A. Blaheta
- Cristoph T. Germer
- Ana Maria Waaga-Gasser
- Martin Gasser
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Affiliations: Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg, Germany, Department of Surgery I, University of Wuerzburg, Wuerzburg, Germany, Brigham and Women's Hospital, Transplant Research Center, Harvard Medical School, Boston, MA, USA, Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Tuebingen, Germany, Department of Surgery, University of Munich, Klinikum rechts der Isar, Munich, Germany, Department of Urology, University of Frankfurt, Frankfurt am Main, Germany
Published online on: July 2, 2015 https://doi.org/10.3892/ijo.2015.3069
Pages: 857-866
Copyright: © Grimmig et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Chronic inflammation as an important epigenetic and environmental factor for putative tumorigenesis and tumor progression may be associated with specific activation of Toll-like receptors (TLR). Recently, carcinogenesis has been suggested to be dependent on TLR7 signaling. In the present study, we determined the role of both TLR7 and TLR8 expression and signaling in tumor cell proliferation and chemoresistance in pancreatic cancer. Expression of TLR7/TLR8 in UICC stage I-IV pancreatic cancer, chronic pancreatitis, normal pancreatic tissue and human pancreatic (PANC1) cancer cell line was examined. For in vitro/in vivo studies TLR7/TLR8 overexpressing PANC1 cell lines were generated and analyzed for effects of (un-)stimulated TLR expression on tumor cell proliferation and chemoresistance. TLR expression was increased in pancreatic cancer, with stage-dependent upregulation in advanced tumors, compared to earlier stages and chronic pancreatitis. Stimulation of TLR7/TLR8 overexpressing PANC1 cells resulted in elevated NF-κB and COX-2 expression, increased cancer cell proliferation and reduced chemosensitivity. More importantly, TLR7/TLR8 expression increased tumor growth in vivo. Our data demonstrate a stage-dependent upregulation of both TLR7 and TLR8 expression in pancreatic cancer. Functional analysis in human pancreatic cancer cells point to a significant role of both TLRs in chronic inflammation-mediated TLR7/TLR8 signaling leading to tumor cell proliferation and chemoresistance.

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