PMID- 33941853 OWN - NLM STAT- MEDLINE DCOM- 20220114 LR - 20221027 IS - 1476-5594 (Electronic) IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 40 IP - 20 DP - 2021 May TI - EphA2-YES1-ANXA2 pathway promotes gastric cancer progression and metastasis. PG - 3610-3623 LID - 10.1038/s41388-021-01786-6 [doi] AB - Erythropoietin-producing hepatocellular receptor A2 (EphA2) is a key member of the receptor tyrosine kinase (RTK) family, while YES Proto-Oncogene 1 (YES1) is a non-receptor tyrosine kinase (nRTK) and annexin A2 (ANXA2) belongs to the calcium-dependent phospholipid-binding protein family annexins. Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells. Overexpression (OE) of YES1 increases, while knockdown (KD) of YES1 or ANXA2 decreases GC cell invasion and migration in vitro and tumor growth in mouse models. Reexpression of wildtype (WT) rather than mutant ANXA2 (Tyr24F) in ANXA2 knockdown (ANXA2-KD) GC cells restores YES1-induced cell invasion and migration, while neither WT nor mutant ANXA2 (Tyr24F) can restore cell invasion and migration in YES1-KD GC cells. In addition, the activation of EphA2-YES1-ANXA2 pathway is correlated with poor prognosis. Thus, our results establish EphA2-YES1-ANXA2 axis as a novel pathway that drives GC invasion and metastasis, targeting this pathway would be an efficient way for the treatment of GC. FAU - Mao, Linfeng AU - Mao L AUID- ORCID: 0000-0001-8113-1253 AD - Department of General Surgery, Xiangya Hospital, Central South University (CSU), Hunan, Changsha, China. AD - Department of Gastrointestinal Surgery, Xiangya Hospital, CSU, Hunan, Changsha, China. AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Yuan, Weijie AU - Yuan W AD - Department of General Surgery, Xiangya Hospital, Central South University (CSU), Hunan, Changsha, China. AD - Department of Gastrointestinal Surgery, Xiangya Hospital, CSU, Hunan, Changsha, China. AD - Department of Colorectal and Anus Surgery, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Cai, Kaimei AU - Cai K AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Lai, Chen AU - Lai C AD - Department of General Surgery, Xiangya Hospital, Central South University (CSU), Hunan, Changsha, China. AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. AD - Department of Colorectal and Anus Surgery, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Huang, Changhao AU - Huang C AD - Department of General Surgery, Xiangya Hospital, Central South University (CSU), Hunan, Changsha, China. AD - Department of Gastrointestinal Surgery, Xiangya Hospital, CSU, Hunan, Changsha, China. AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Xu, Yi AU - Xu Y AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Zhong, Shangwei AU - Zhong S AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Yang, Chen AU - Yang C AD - Department of General Surgery, Xiangya Hospital, Central South University (CSU), Hunan, Changsha, China. AD - Department of Gastrointestinal Surgery, Xiangya Hospital, CSU, Hunan, Changsha, China. AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Wang, Ran AU - Wang R AD - Department of General Surgery, Xiangya Hospital, Central South University (CSU), Hunan, Changsha, China. AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. AD - Department of Colorectal and Anus Surgery, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Zeng, Pengwei AU - Zeng P AD - Department of General Surgery, Xiangya Hospital, Central South University (CSU), Hunan, Changsha, China. AD - Department of Gastrointestinal Surgery, Xiangya Hospital, CSU, Hunan, Changsha, China. AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Huang, Heyuan AU - Huang H AD - Department of General Surgery, Xiangya Hospital, Central South University (CSU), Hunan, Changsha, China. AD - Department of Gastrointestinal Surgery, Xiangya Hospital, CSU, Hunan, Changsha, China. AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Chen, Zhikang AU - Chen Z AD - Department of General Surgery, Xiangya Hospital, Central South University (CSU), Hunan, Changsha, China. AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. AD - Department of Colorectal and Anus Surgery, Xiangya Hospital, CSU, Hunan, Changsha, China. AD - International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Xiangya Hospital, CSU, Hunan, Changsha, China. FAU - Chen, Zihua AU - Chen Z AUID- ORCID: 0000-0002-8467-7742 AD - Department of General Surgery, Xiangya Hospital, Central South University (CSU), Hunan, Changsha, China. zihuachenxy@126.com. AD - Department of Gastrointestinal Surgery, Xiangya Hospital, CSU, Hunan, Changsha, China. zihuachenxy@126.com. AD - The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, CSU, Hunan, Changsha, China. zihuachenxy@126.com. AD - International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Xiangya Hospital, CSU, Hunan, Changsha, China. zihuachenxy@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210503 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (ANXA2 protein, human) RN - 0 (Annexin A2) RN - 0 (EPHA2 protein, human) RN - EC 2.7.10.1 (Receptor, EphA2) RN - EC 2.7.10.2 (Proto-Oncogene Proteins c-yes) RN - EC 2.7.10.2 (YES1 protein, human) SB - IM EIN - Oncogene. 2022 Feb;41(8):1228-1230. PMID: 35046536 MH - Animals MH - Annexin A2/genetics/*metabolism MH - Cell Line, Tumor MH - Cell Proliferation MH - Humans MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Neoplasm Metastasis MH - Phosphorylation MH - Proto-Oncogene Proteins c-yes/genetics/*metabolism MH - Receptor, EphA2/genetics/*metabolism MH - Signal Transduction MH - Stomach Neoplasms/genetics/metabolism/*pathology MH - Survival Rate MH - Xenograft Model Antitumor Assays PMC - PMC8134040 COIS- The authors declare no competing interests. EDAT- 2021/05/05 06:00 MHDA- 2022/01/15 06:00 PMCR- 2021/05/03 CRDT- 2021/05/04 06:45 PHST- 2020/08/17 00:00 [received] PHST- 2021/04/12 00:00 [accepted] PHST- 2021/03/31 00:00 [revised] PHST- 2021/05/05 06:00 [pubmed] PHST- 2022/01/15 06:00 [medline] PHST- 2021/05/04 06:45 [entrez] PHST- 2021/05/03 00:00 [pmc-release] AID - 10.1038/s41388-021-01786-6 [pii] AID - 1786 [pii] AID - 10.1038/s41388-021-01786-6 [doi] PST - ppublish SO - Oncogene. 2021 May;40(20):3610-3623. doi: 10.1038/s41388-021-01786-6. Epub 2021 May 3.