Abstract
Abstract Introduction Interleukin-11 (IL-11) belongs to the IL6-family of cytokines, which are related to tumor development and progression in several types of cancer. These cytokines activate downstream pathways such as JAK/STAT, PI3K/AKT and RAS/ERK, triggered by their common receptor subunit, GP130. We have recently described that IL-11 is overexpressed in bronchoalveolar lavage fluid from patients with lung adenocarcinoma compared to non-cancer or other histological subtype's patients, thereby being useful as a diagnostic biomarker for this disease. So far, the role of IL-11 in lung cancer has been poorly studied. We aim to unravel the role of IL-11 in lung adenocarcinoma tumorigenesis, and its possible role as a prognostic biomarker. Material and Methods We have characterized a broad panel of human lung adenocarcinoma cell lines in terms of their expression levels of IL-11 and IL-11RA. We have studied the activation status of JAK/STAT, MEK/ERK and PI3K/AKT signaling pathways in these cell lines, after IL-11 stimulation. Additionally, several lung adenocarcinoma cell lines were alternatively transfected to overexpress IL-11RA or infected to silence IL-11 using CRISPR/Cas9 technology. We performed several different functional assays in these generated cell lines, such as growth curves, colony formation assays, soft-agar assays and xenografts models, in order to determine the tumorigenic effects of IL-11. Furthermore, we analyzed overall survival and progression-free survival of lung adenocarcinoma patients expressing high levels of IL-11 versus patients expressing low levels, using a public database. Results Different pathways are activated in adenocarcinoma cell lines after IL-11 stimulation. However, only the STAT1/3 pathway is differentially activated in IL-11RA-overexpressing cell lines subsequently stimulated with IL-11, or inhibited in IL-11-silenced cell lines. These molecular effects were translated into a slight increase or decrease in tumorigenic properties in the in vitro and in vivo assays when overexpressing IL-11RA and stimulating with rhIL-11 or when silencing IL-11, respectively. Furthermore, high levels of IL-11 correlated to poorer Overall-Survival and Progression-Free-Survival in patients with lung adenocarcinoma. Conclusions 1. IL-11 activates STAT1/3 pathways in lung adenocarcinoma. 2. IL-11 exerts oncogenic effects in vitro and in vivo. 3. High levels of IL-11 correlate with poorer outcomes in lung adenocarcinoma patients. Citation Format: Laura Ojeda Márquez, Patricia Yagüe Sanz, Sonia Molina Pinelo, Amancio Carnero Moya, Alejandro Sweet-Cordero, Luis Paz-Ares Rodríguez, Irene Ferrer Sánchez. IL-11, a novel diagnostic biomarker for lung adenocarcinoma, is involved in lung cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 543.
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