Mouse model resembling human lung cancer

Following our previous findings that IKKα reduction promotes carcinogen-induced skin carcinogenesis, somatic IKKα deletion induces spontaneous skin papillomas and squamous cell carcinomas (SCCs) in Ikkα-floxed mice, and overexpressed IKKα represses carcinogeninduced skin carcinogenesis [1-3], we recently reported that kinase-dead Ikkα knockin (IkkαKA/KA) mice develop spontaneous lung, forestomach, and skin SCCs, which are associated with IKKα downregulation and inflammation [4]. We further studied the pathogenesis of lung SCCs after stabilizing the skin condition by introducing the transgenic Lori.IKKα into the skin of IkkαKA/KA (L-IkkαKA/ KA) mice (Figure 1). The human Ikkα gene is located at 10q24.31, close to Pten (10q23). Many studies have suggested that alterations within the 10q22-10q26 region may be involved in human SCC development. IKKα downregulation and Ikkα mutations and deletions have been reported in various types of human SCCs. A point mutation-mediated IKKα deletion has been identified in a lethal human syndrome, in which multiple organs are malformed [5]. Chemical carcinogen treatment induces Ikkα mutations and deletions in mouse skin SCCs [1]. These findings underscore the importance of IKKα in the pathogenesis of these human diseases. Lung cancer is the leading cause of cancer mortality worldwide. Lung SCC, one of major types of lung cancers, is strongly associated with smoking that contains carcinogens. Smoking can also act as an inflammatory irritator. It is thought that SCCs, frequently found in the upper and central regions of the lungs, are derived from the basal cells (a type of squamous epithelial cell) of the pseudostratified epithelial layer of bronchi; whereas adenocarcinomas (ADCs) are derived from the epithelial cells of alveoli. Many molecular alterations, such as deregulated EGFR, PIK3CA, p53, Rb, and c-Myc, have been identified in human lung SCCs, but mice overexpressing or lacking these genes do not well recapitulate the development of lung SCCs, although a proportion of K-rasG12D;Lkb1-/mice develop mixed SCCs and ADCs in the lungs [4,6]. Biomarkers of increased p63, Trim29, and keratin 5 (K5) are used to distinguish human lung SCCs from ADCs. We also have demonstrated increased p63, Trim29, and K5 levels, deregulated RhoV, CDK1, IGF, ROS1, c-Myc, p53, Rb, and LKB1 expression, and