Affiliation:
1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Beijing China
2. Peking University International Cancer Institute Peking University Beijing China
3. Research Unit of Molecular Cancer Research Chinese Academy of Medical Sciences Beijing China
4. Soochow University Cancer Institute Suzhou China
5. Institute of Cancer Research Shenzhen Bay Laboratory Shenzhen China
Abstract
AbstractEsophageal squamous cell carcinoma (ESCC) is a frequently seen esophageal tumor type in China. Activation of signaling proteins and relevant molecular mechanisms in ESCC are partially explored, impairing the antitumor efficiency of targeted therapy in ESCC treatment. Tumor‐associated macrophages (TAMs)‐released C‐C motif chemokine 22 (CCL22) can activate intratumoral focal adhesion kinase (FAK), thus promoting the progression of ESCC. Here, we demonstrated that highly secreted CCL22 by TAMs (CCL22‐positive TAMs) induced ESCC cell stemness and invasion through facilitating transcriptional activity of intratumoral glioma‐associated oncogene 1 (Gli1), a downstream effector for Hedgehog (HH) pathway. Mechanistically, FAK‐activated protein kinase B (AKT) mediated Gli1 phosphorylation at its Ser112/Thr115/Ser116 sites and released Gli1 from suppressor of fused homolog, the endogenous inhibitor of Gli1 to activate downstream stemness‐associated factors, such as SRY‐box transcription factor 2 (SOX2), Nanog homeobox (Nanog), or POU class 5 homeobox (OCT4). Furthermore, inhibition of FAK activity by VS‐4718, the FAK inhibitor, enhanced antitumor effect of GDC‐0449, the HH inhibitor, both in xenografted models and in vitro assays. Clinically, CCL22/Gli1 axis is used to evaluate ESCC prognosis. Overall, our study establishes the communication of FAK with HH pathway and offers the novel mechanism related to Gli1 activation independent of Smoothened as well as the rationale for the anti‐ESCC combination treatment.
Funder
National Natural Science Foundation of China
Subject
Cell Biology,Biochemistry (medical),Genetics (clinical),Computer Science Applications,Drug Discovery,Genetics,Oncology,Immunology and Allergy
Cited by
3 articles.
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