Abstract
IL13 signaling through its receptor IL13Rα2 plays a critical role in colon cancer invasion and liver metastasis, but the mechanistic features of this process are obscure. In this study, we identified a scaffold protein, FAM120A (C9ORF10), as a signaling partner in this process. FAM120A was overexpressed in human colon cancer cell lines and 55% of human colon cancer specimens. IL13Rα2-FAM120A coimmunoprecipitation experiments revealed further signaling network associations that could regulate the activity of IL13Rα2, including FAK, SRC, PI3K, G-protein-coupled receptors, and TRAIL receptors. In addition, FAM120A associated with kinesins and motor proteins involved in cargo movement along microtubules. IL13Rα2-triggered activation of the FAK and PI3K/AKT/mTOR pathways was mediated by FAM120A, which also recruited PI3K and functioned as a scaffold protein to enable phosphorylation and activation of PI3K by Src family kinases. FAM120A silencing abolished IL13-induced cell migration, invasion, and survival. Finally, antibody blockade of IL13Rα2 or FAM120A silencing precluded liver colonization in nude mice or metastasis. In conclusion, we identified FAM120A in the IL13/IL13Rα2 signaling pathway as a key mediator of invasion and liver metastasis in colon cancer.
Highlights
Interleukin 13 (IL13) has been associated to different pathologic conditions
We described the overexpression of IL13 receptor subunit a-2 (IL13Ra2) in 66% of tumor samples from patients with colon cancer, which was associated to late stages of progression and poor outcome of patients with colorectal cancer [2]
IL13Ra2 is overexpressed in a variety of human tumor types, such as colon, glioblastoma, renal cell carcinoma, pancreatic, melanoma, head and neck, mesothelioma, and ovarian, where it has been proposed as biomarker and potential therapeutic target [2,3,4,5,6,7,8,9,10]
Summary
Interleukin 13 (IL13) has been associated to different pathologic conditions (asthma, autoimmune diseases, ulcerative colitis, and others; ref. 1). We described the overexpression of IL13Ra2 in 66% of tumor samples from patients with colon cancer, which was associated to late stages of progression (metastasis in lymph nodes or liver) and poor outcome of patients with colorectal cancer [2]. IL13Ra2 is overexpressed in a variety of human tumor types, such as colon, glioblastoma, renal cell carcinoma, pancreatic, melanoma, head and neck, mesothelioma, and ovarian, where it has been proposed as biomarker and potential therapeutic target [2,3,4,5,6,7,8,9,10]. A similar situation occurs for head and neck squamous cell carcinoma [8] and ovarian cancer [9]
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