IRAK1 promotes gastric cancer progression by activating the PI3K/AKT/mTOR pathway and inducing the M2 polarization of tumor-associated macrophages.

[BACKGROUND] Interleukin-1 receptor-associated kinase 1 (IRAK1), an active serine/threonine kinase, is an indispensable mediator of inflammatory responses and innate immunity. Emerging evidence has highlighted the oncogenic role of IRAK1 in tumors. However, the role of IRAK1 in gastric cancer (GC) progression remains unclear.

[METHODS] IRAK1 expression levels in patients with GC at Peking Union Medical College Hospital were assessed by Western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. To elucidate the role of IRAK1 in GC pathogenesis, we established GC cells with clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) mediated IRAK1 knockout and lentiviral vector-mediated IRAK1 overexpression and subsequently conducted in vitro and in vivo experiments. Additionally, we assessed the effect of IRAK1 expression levels in GC cells on the M2 polarization of tumor-associated macrophages (TAMs) via a Transwell coculture system. Functional assays were subsequently carried out to determine whether IRAK1 regulates the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of GC cells through the induction of TAM M2 polarization and to clarify the associated regulatory mechanisms.

[RESULTS] IRAK1 expression was progressively increased during GC progression. Clinicopathological feature analysis revealed that high IRAK1 expression predicted poor survival outcomes. In vitro and in vivo experiments revealed that IRAK1 was highly expressed in GC cells and facilitated the proliferation, migration, invasion, and EMT of GC cells via the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. More interestingly, IRAK1 affected the malignant biological behavior of GC cells by inducing M2-like polarization of macrophages. Mechanistically, coculturing M0 macrophages with IRAK1 -knockout GC cells suppressed interleukin (IL)-8 secretion, thereby inhibiting Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway activation in TAMs. Inactivation of the JAK2/STAT3 pathway suppressed the M2 polarization of TAMs, ultimately inhibiting GC progression.

[CONCLUSIONS] IRAK1 influences the malignant biological behavior of GC cells by activating the PI3K/AKT/mTOR pathway and inducing the M2-like polarization of macrophages via the IL-8/JAK2/STAT3 pathway in TAMs. Our findings provide a novel diagnostic biomarker and a promising therapeutic strategy for GC.