Hong, Hea Nam; Won, You Jin; Shim, Ju Hee; Kim, Hyun Ji; Han, Seung Hee; Kim, Byung Sik; Kim, Hee Sung
Journal of cancer research and clinical oncology
2018Sep ; 144 ( 9 ) :1649-1663.
PMID : 29948146
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Hong, Hea Nam - Department of Anatomy, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
Won, You Jin - Department of Anatomy, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
Shim, Ju Hee - Department of Anatomy, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
Kim, Hyun Ji - Department of Anatomy, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
Han, Seung Hee - Department of Anatomy, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
Kim, Byung Sik - Department of Gastric Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
Kim, Hee Sung - Department of Gastric Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea. vangogh420@amc.seoul.kr.
ABSTRACT
PURPOSE: Under physiologic conditions, the binding of erythropoietin-producing hepatocellular (Eph) A2 receptor and its ligand ephrinA1 results in decreased EphA2 level and tumor suppression. However, EphA2 and ephrinA1 are highly expressed in human cancers including gastric adenocarcinoma. In this study, we tested our hypothesis that cancer-associated fibroblasts (CAFs) promote gastric tumorigenesis through EphA2 signaling in a ligand-independent manner.
METHODS: Expression of EphA2 protein in primary tumor tissues of 91 patients who underwent curative surgery for gastric adenocarcinoma was evaluated by immunohistochemistry and western blotting. Conditioned medium of cancer-associated fibroblasts (CAF-CM) was used to evaluate the tumorigenic effect of CAFs on gastric cancer cell lines. Epithelial-mesenchymal transition (EMT), cell proliferation, migration, and invasion were assessed. EphrinA1-Fc ligand was used to determine the suppressor role of EphA2 receptor-ligand binding.
RESULTS: CAF-CM-induced EMT and promoted cancer cell motility even without cell-cell interaction. Treatment with a selective EphA2 inhibitor (ALW-II-41-27) or EphA2-targeted siRNA markedly reduced CAF-CM-induced gastric tumorigenesis. EphrinA1-Fc ligand treatment showing ligand-dependent tumor suppression diminished the EphA2 expression and EMT progression. In contrast, ephrinA1-targeted siRNA did not significantly affect CAF-CM-mediated increases in EphA2 expression and EMT progression. Treatment with VEGF showed effects like CAF-CM in terms of EphA2 activation and EMT progression. CONCLUSION: CAFs may contribute to gastric tumorigenesis by activating EphA2 signaling pathway in a ligand-independent manner. Our results suggest that ligand-independent activation of EphA2 was triggered by VEGF released from CAF-CM. Our result may partially explain why ligand-dependent tumor suppressor roles of EphA2 are not evident in gastric cancer despite the prominent level of ephrinA1.
keyword
Cancer-associated fibroblasts; EphA2; EphrinA1; EphrinA1-Fc; Gastric cancer; Ligand-independent manner
MESH
Cancer-Associated Fibroblasts/*metabolism/*pathology, Carcinogenesis/*metabolism/*pathology, Cell Line, Tumor, Ephrin-A2/*metabolism, Epithelial-Mesenchymal Transition/physiology, Female, Humans, Ligands, Male, Middle Aged, RNA, Small Interfering/metabolism, Signal Transduction/physiology, Stomach/metabolism/pathology, Stomach Neoplasms/*metabolism/*pathology
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