Abstract 1396: The role of NFκB/IKK2 pathway in the pathogenesis of lung cancer

The nuclear factor [[Unable to Display Character: ƙ]]B (NF-[[Unable to Display Character: ƙ]]B) comprises a family of transcription factors involved in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. The dimeric NFκB transcription factors are inhibited in quiescent cells through stable association with inhibitor IκBs. Recent literature suggests aberrant or constitutive NF-[[Unable to Display Character: ƙ]]B activation in many human malignancies, including lung cancer. Hence, we aim to decipher the role of NF-[[Unable to Display Character: ƙ]]B on tumour progression and metastasis employing a non-metastatic tumour animal model, SPC-CRaf-BXB. We generated SPC-CRaf BXB mice, where constitutively active C-Raf is expressed in alveolar type II cells. These mice develop tumour nodules within 3-5 months. Further, we cross breed these mice with SPC- rtTA/Tet-O IKK2-CA (inducible constitutively active IKK2 under SPC promoter) or SPC-rtTA/Tet-O-IKK2-DN (dominant negative IKK2 under SPC promoter) to generate triple transgenic mice (SPC-C-Raf BxB/SPC rtTA/Tet-O IKK2 CA or SPC-C-Raf BxB/SPC rtTA/Tet-O-IKK2-DN). At different time intervals of induction (one month, two months and 10-12 months), these mice were sacrificed and analysed for histomorphological changes. Immunohistochemical staining showed NFκB localization within the cell and its translocation to the nucleus, which was confirmed by protein expression levels in cytoplasm and nucleus. Modification of NF-[[Unable to Display Character: ƙ]]B levels in mice showed tumours and significant histological changes such as alveolar enlargement and emphysema like structures. Similarly, Lewis lung carcinoma 1 (LLC1) cells injected to SPC-rtTA/TetO-IKK2-CA and SPC-rtTA/TetO-IKK2- DN transgenic mice showed tumour reduction and tumour microenvironmental changes as seen with CD3, F4/80 and CD11b staining. Screening 10 different human cancer cell lines, for the NFκB pathway members revealed variation in expression levels of NFκB in different cancer types. Based on their expression, selected cell lines (A549, H23 and H226), were stably transfected with NF-[[Unable to Display Character: ƙ]]B pathway-modifying constructs to study the functional significance of inducible constitutively active or dominant negative IKK2.Cells transfected with NF-[[Unable to Display Character: ƙ]]B pathway-modifying constructs, like pEGZ-IKK2-CA and pEGZ-IKK2-DN, showed changes regarding their proliferation and migration abilities. Cells with an activated NFκB pathway were less apoptotic and more proliferative, suggesting contribution of the NFκB signalling pathway to lung cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1396. doi:1538-7445.AM2012-1396