Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes

摘要

Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia. We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and is required for timely onset of Gli2-induced skin tumorigenesis in mice. The induction of Aire mRNA in keratinocytes depends on a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each factor is bound to a specific promoter region featuring an NF-kB consensus sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia. High levels of expression oiKRT17 (encoding K17) have been correlated with aggressive behavior and poor prognosis for several types of human tumors. Genetic loss of Krt17but not the related Krtl4 delays tumor onset in a GZ/2-transgenic mouse model of basaloid skin tumorigenesis, correlating with striking changes in the amplitude and character of inflammatory and immune responses. Moreover, K17 positively regulates several effectors of mitogenic signaling associated with oncogenic transformation (for example, Akt-PKB, mTOR7 and the Rac1 GTPase) and is necessary to sustain normal Akt-PKB activation in the context of Gill-mediated oncogenic transformation in Ewing sarcoma. Whether K17 influences additional types of tumors in a similar manner and which mechanisms account for its effect are unknown. Targeted expression of the early genes from human papillomavirus (HPV) type 16 (El to ￡7) to basal keratinocytes of the epidermiscauses tumors in adult mouse skin that resemble human skin squa-mous cell carcinoma. Tumors arise with complete penetrance between postnatal day (P) 60 and P120 in HPV16Ts/+ ear skin (FVB/N strain) (Supplementary Fig. la), with no apparent discordance between the sexes. Although normally restricted to ectodermal appendages and glabrous skin, expression of K17 is robustly upregulated in the interfollicular epidermis between P20 and P40 in HPV16TS/+ mice (Supplementary Fig. lb).