| First Author | Deng S | Year | 2020 |
| Journal | Carcinogenesis | Volume | 41 |
| Issue | 11 | Pages | 1529-1542 |
| PubMed ID | 32603404 | Mgi Jnum | J:299174 |
| Mgi Id | MGI:6478345 | Doi | 10.1093/carcin/bgaa064 |
| Citation | Deng S, et al. (2020) Interplay between estrogen and Stat3/NF-kappaB-driven immunomodulation in lung cancer. Carcinogenesis 41(11):1529-1542 |
| abstractText | 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/Stat3Delta/Delta mice) promoted tumorigenesis and induced a nuclear factor-kappaB (NF-kappaB)-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-kappaB signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3Delta/Delta females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-kappaB-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-kappaB-driven immunosuppression and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-kappaB activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3Delta/Delta males, but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-kappaB-driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-ras mutant LUAD. |
