2. Academic Validation
  3. Interplay between estrogen and Stat3/NF-κB-driven immunomodulation in lung cancer

Interplay between estrogen and Stat3/NF-κB-driven immunomodulation in lung cancer

  • Carcinogenesis. 2020 Nov 13;41(11):1529-1542. doi: 10.1093/carcin/bgaa064.
Shanshan Deng 1 2,  Marco Ramos-Castaneda 2,  Walter V Velasco 2,  Michael J Clowers 2 3,  Berenice A Gutierrez 2,  Oscar Noble 2,  Yiping Dong 4,  Melody Zarghooni 2,  Lucero Alvarado 5,  Mauricio S Caetano 2,  Shuanying Yang 1,  Edwin J Ostrin 5 6,  Carmen Behrens 7,  Ignacio I Wistuba 8,  Laura P Stabile 9,  Humam Kadara 3 8,  Stephanie S Watowich 3 10,  Seyed Javad Moghaddam 2 3
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 The University of Texas M.D. Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 4 Department of Oncology Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 5 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6 Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7 Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 9 Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 10 Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
PMID: 32603404 DOI: 10.1093/carcin/bgaa064
Abstract

K-Ras mutant lung adenocarcinoma (LUAD) is the most common type of lung Cancer, displays abysmal prognosis and is tightly linked to tumor-promoting inflammation, which is increasingly recognized as a target for therapeutic intervention. We have recently shown a gender-specific role for epithelial STAT3 signaling in the pathogenesis of K-Ras mutant LUAD. The absence of epithelial STAT3 in male K-Ras mutant mice (LR/Stat3Δ/Δ mice) promoted tumorigenesis and induced a nuclear factor-kappaB (NF-κB)-driven pro-tumor immune response while reducing tumorigenesis and enhancing anti-tumor immunity in female counterparts. In the present study, we manipulated estrogen and NF-κB signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3Δ/Δ females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-κB-driven immunosuppressive response, and reduced anti-tumor cytotoxicity, whereas estrogen replacement reversed these changes. On the other hand, exogenous estrogen in males successfully inhibited tumorigenesis, attenuated NF-κB-driven immunosuppression and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-κB activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3Δ/Δ males, but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-κB-driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-Ras mutant LUAD.

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  • HY-10172
    99.51%, IKKβ 抑制剂
    IKK
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