Gai1 and Gai3 Mediate IL-11-Induced Signal Transduction and are Potential Therapeutic Targets for LUAD

Lung adenocarcinoma (LUAD) is the main histologic subtype of lung cancer, and its incidence is on the rise. However, since the vast majority of patients are already in advanced stages at the time of diagnosis, their 5-year survival rate is only 15%, so it is urgent to explore the mechanism of the development of LUAD and improve the survival time of patients. Interleukin-11 (IL-11), a member of the IL-6 cytokine family, has an influential role in the development and progression of a variety of tumors, but the specific molecular mechanisms that promote the malignant progression of LUAD are unknown. Here, we found that the IL-11-induced activation of Akt, Erk, and STAT3 could be inhibited by knocking out the expression of Gai1/3. In contrast, overexpression of Gai1/3 could enhance IL-11-induced signaling. The binding of Gai1/3 to GP130 mediates IL-11-induced downstream activation of Akt-mTOR, Erk, and STAT3, which requires recruitment of Grb2-associated binding protein 1 (Gab1). In LUAD cells, shGai1/3 inhibited cell growth, proliferation, and migration as well as blocked the tumor-promoting ability of IL-11. However, overexpression of Gai1/3 enhanced the IL-11-induced cell growth, proliferation, and migration. ShGai1/3 also inhibited the proliferation of LUAD cells in vivo. Overall, the findings of this study demonstrate the Gai1 and Gai3 are critical for IL-11 signal transduction. Moreover, we reveal that Gai1 and Gai3 are highly expressed and associated with poor overall survival in lung adenocarcinoma and may thus act as potential therapeutic targets in LUAD. These results provide a novel therapeutic strategy for LUAD patients with upregulated IL-11 expression. Overall design: To investigate the role of IL11 in lung adenocarcinoma, we constructed A549 cell lines transfected with lentiviruses expressing scr-shRNA and sh-IL11, respectively.