ABSTRACT: 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 Gαi1/3. In contrast, overexpression of Gαi1/3 could enhance IL-11-induced signaling. The binding of Gαi1/3 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, shGαi1/3 inhibited cell growth, proliferation, and migration as well as blocked the tumor-promoting ability of IL-11. However, overexpression of Gαi1/3 enhanced the IL-11-induced cell growth, proliferation, and migration. ShGαi1/3 also inhibited the proliferation of LUAD cells in vivo. Overall, the findings of this study demonstrate the Gαi1 and Gαi3 are critical for IL-11 signal transduction. Moreover, we reveal that Gαi1 and Gαi3 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.
