Original ResearchFull Report: Basic and Translational—Alimentary TractLoss of NFKB1 Results in Expression of Tumor Necrosis Factor and Activation of Signal Transducer and Activator of Transcription 1 to Promote Gastric Tumorigenesis in Mice
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Mice
All animal experiments complied with and were approved by The Walter and Eliza Hall Institute of Medical Research Animals Ethics Committee. Nfkb1–/– mice were crossed with Il6–/–, Il11Rα–/–, Il22–/–, Tnf–/–, or STAT1–/– mice (see Supplementary Materials for original sources). The resulting intercrossed mice were used to generate Nfkb1–/–Il6–/–, Nfkb1–/–Il11Rα–/–, Nfkb1–/–Il22–/–, Nfkb1–/–Tnf–/–, and Nfkb1–/–STAT1–/– mice. Genotyping was performed by polymerase chain reaction using published
The Absence of Signal Transducer and Activator of Transcription 1 Affords Nfkb1–/– Mice With Long-Term Protection From Gastric Cancer
We previously reported that the loss of STAT1 prevented gastric pathology in Nfkb1–/– mice, whereas loss of 1 allele of Stat3 (complete loss of STAT3 causes embryonic lethality) had no effect.7 However, Nfkb1–/–Stat1–/– compound mutant animals were only followed for 1 year. To determine whether STAT1 loss only delayed disease progression or was sufficient to abrogate IGC development in Nfkb1–/– mice, we aged a cohort of Nfkb1–/–Stat1–/– mice to timepoints at which we would expect invasive GC
Discussion
Cytokine/cytokine receptor signaling is a key component in the overall regulation of the immune system. Accordingly, its dysregulation has been linked to many chronic inflammatory diseases, autoimmune disorders, and cancer.45,46 Pertinently, chronic inflammation has been identified as a key initiator of the development of IGC.3,45 Even though activation of the NF-κB family of transcription factors has been linked to the control of cytokine and chemokine production in several
Acknowledgments
The authors thank Professors Emad El-Omar and John Silke for discussions and critical reading of this manuscript, G. Siciliano and K. Hughes for animal care, B. Helbert for genotyping, E. Tsui and her team for preparation of histologic sections, and C. McLean for secretarial assistance.
CRediT Authorship Contributions
Jun Ting Low, PhD (Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Writing – original draft: Lead); Michael Christie, PhD, Medical degree (Data curation: Supporting; Formal analysis: Supporting;
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Conflicts of interest The authors disclose no conflicts.
Funding This work was supported by a Cancer Council Victoria Grant-in-Aid project grant 1161400 (to Lorraine A. O’Reilly, Andreas Strasser, Tracy Putoczki, and Matthias Ernst) a Cancer Australia and Cancer Council New South Wales project grant 1047672 (to Lorraine A. O’Reilly, Tracy Putoczki, Andreas Strasser, and Matthias Ernst) and, a Cancer Council NSW (Box Rallies) RG 20-13 (to Lorraine A. O'Reilly, Tracy Putoczki, Michael Christie, Matthias Ernst). Additional support included fellowships and grants from the National Health and Medical Research Council, Canberra, program 1016701 (Andreas Strasser), fellowship; 1020363 (Andreas Strasser) and project grants; 1046010 (Andreas Strasser); 1008614, 1080498 (Tracy Putoczki); The Walter and Eliza Hall Institute of Medical Research Dyson Bequest Centenary Fellowship (Tracy Putoczki), Victorian Cancer Agency Fellowship MCRF16009 (Tracy Putoczki), Worldwide Cancer Research project grant 14-1197 (Tracy Putoczki), Australian Postgraduate Award (Jun Ting Low), Top-Up Scholarship, Cancer Therapeutics CRC (Australia; Jun Ting Low) and an NHMRC infrastructure grant, Independent Research Institutes Infrastructure Support Scheme grant 361646, the Victorian State Government (Operational Infrastructure Support Program grant), the Leukemia and Lymphoma Society (grant 7413 and 7001-13) and the Juvenile Diabetes Research Foundation/National Health and Medical Research Council 466658 (Andreas Strasser).
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Authors share co-senior authorship.