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The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia
Open accessAbstract
Pancreatic cancer is an almost uniformly lethal disease, characterized by late diagnosis, early metastasis, resistance to chemotherapy, and early mutation of the Kras oncogene. Here we show that the receptor for advanced glycation endproducts (RAGE) is required for the activation of interleukin 6 (IL-6)–mediated mitochondrial signal transducers and activators of transcription 3 (STAT3) signaling in pancreatic carcinogenesis. RAGE expression correlates with elevated levels of autophagy in pancreatic cancer in vivo and in vitro, and this heightened state of autophagy is required for IL-6–induced STAT3 activation. To further explore the intersection of RAGE, autophagy, and pancreatic carcinogenesis, we created a transgenic murine model, backcrossing RAGE-null mice to a spontaneous mouse model of pancreatic cancer, Pdx1-Cre : Kras G12D/+ (KC). Targeted ablation of Rage in KC mice delayed neoplasia development, decreased levels of autophagy, and inhibited mitochondrial STAT3 activity and subsequent ATP production. Our results suggest a critical role for RAGE expression in the earliest stages of pancreatic carcinogenesis, potentially acting as the “autophagic switch,” regulating mitochondrial STAT3 signaling.
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“RAGE is highly upregulated in metastatic and aggressive breast, ovarian, and pancreatic cancer, acting as a promotor of the progression of premalignant precursors to invasive carcinoma88,89.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [88]
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Metadata
- Authors
- Kang, R., Loux, T., Tang, D., Schapiro, N. E., Vernon, P., Livesey, K. M., Krasinskas, A., Lotze, M. T., & Zeh, H. J.
- Affiliations
- UPMC Hillman Cancer Center (US)
- University of Pittsburgh Medical Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-04-16
- Volume
- 109
- Issue
- 18
- Pages
- 7031-7036
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3345001
- OpenAlex
- W2017280299
- Cited by
- 163
- References
- 34
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 7 · 2023: 8 · 2022: 10 · 2021: 14 · 2020: 11 · 2019: 14 · 2018: 13 · 2017: 8 · 2016: 10 · 2015: 12 · 2014: 17 · 2013: 18 · 2012: 8
- FWCI
- 11.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000005)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- receptor for advanced glycation end products, RAGE, pancreatic carcinogenesis, pancreatic neoplasia, autophagy, STAT3 signaling, interleukin-6, mitochondrial signaling, KRAS G12D, Pdx1-Cre, ATP production
- MeSH terms
- Receptor for Advanced Glycation End Products, Adenosine Triphosphate, Animals, Autophagy, Humans, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Mitochondria, Pancreatic Neoplasms, Phosphorylation, Receptors, Immunologic, Signal Transduction, Interleukin-6, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, STAT3 Transcription Factor, Mice, Mice, 129 Strain, Tumor Microenvironment
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