Abstract 931: Role of IKKα in K-ras-driven lung carcinogenesis

Abstract

Abstract IKKα, one of subunits of the IKK complex, is required for the epidermal homeostasis. We previously demonstrated that keratin 5-specific deletion of IKKα induces spontaneous skin squamous cell carcinomas (SCCs) in mice. Interestingly, IKKα kinase dead knockin (IKKαK44A/K44A, KA) mice spontaneously develop lung SCCs which is associated with increased inflammation and IKKα reduction. Thus, IKKα downregulation is crucial for the SCC formation in skin and lung. Here, we attempted to verify whether IKKα inactivation plays a role in the development of lung adenocarcinomas (ADCs) as well. We have crossed between KA mice and K-rasG12D oncogenic mutant (Kras) mice. Then, these IKKαK44A/K44A;K-rasG12D (KA;Kras) mice were intratracheally treated with adenovirus carrying the cre recombinase gene to activate K-ras oncogene. At 4.5 months after intratracheal injection, the lung weight was significantly increased in KA;Kras compared to Kras mice. Moreover, the lungs of KA;Kras mice showed increased bronchial epithelial cells and Ki67-positive cells in the bronchial regions. At 7 months after treatment, lung tumors in KA;Kras mice were larger compared to tumors in Kras mice. Finally, KA;Kras mice had shorter life span due to breathing problems. KA;Kras mice started to die at around 20 weeks after injection, while KR mice started to die from around 30 weeks. To confirm whether IKKα reduction promotes K-ras-driven lung carcinogenesis, we generated IKKαf/f (FF) mice crossed with Kras (FF;Kras) mice. Similar to KA;Kras, FF;Kras mice showed significant increase of lung weight, hyperproliferative bronchial abnormalities, Ki-67-positive cells in the bronchial regions and the number of large tumors at 4 months following treatment compared with Kras only group. Taken together, these data suggest that IKKα downregulation promotes K-ras-driven lung tumorigenesis and plays an important role in lung ADCs as well as in SCCs. The underlying molecular mechanism needs to be further investigated. Citation Format: Na-Young Song, Jami Willette-Brown, Mahesh Dalta, Yinling Hu. Role of IKKα in K-ras-driven lung carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 931. doi:10.1158/1538-7445.AM2014-931