title: Epidermal growth factor-like domain-containing protein 7 (EGFL7) enhances EGF receptor-AKT signaling, epithelial-mesenchymal transition, and metastasis of gastric cancer cells.
abstract: Epidermal growth factor-like domain-containing protein 7 (EGFL7) is upregulated in human epithelial tumors and so is a potential biomarker for malignancy. Indeed, previous studies have shown that high EGFL7 expression promotes infiltration and metastasis of gastric carcinoma. The epithelial-mesenchymal transition (EMT) initiates the metastatic cascade and endows cancer cells with invasive and migratory capacity; however, it is not known if EGFL7 promotes metastasis by triggering EMT. We found that EGFL7 was overexpressed in multiple human gastric cancer (GC) cell lines and that overexpression promoted cell invasion and migration as revealed by scratch wound and transwell migration assays. Conversely, shRNA-mediated EGFL7 knockdown reduced invasion and migration. Furthermore, EGFL7-overexpressing cells grew into larger tumors and were more likely to metastasize to the liver compared to underexpressing CG cells following subcutaneous injection in mice. EGFL7 overexpression protected GC cell lines against anoikis, providing a plausible mechanism for this enhanced metastatic capacity. In excised human gastric tumors, expression of EGFL7 was positively correlated with expression levels of the mesenchymal marker vimentin and the EMT-associated transcription repressor Snail, and negatively correlated with expression of the epithelial cell marker E-cadherin. In GC cell lines, EGFL7 knockdown reversed morphological signs of EMT and decreased both vimentin and Snail expression. In addition, EGFL7 overexpression promoted EGF receptor (EGFR) and protein kinase B (AKT) phospho-activation, effects markedly suppressed by the EGFR tyrosine kinase inhibitor AG1478. Moreover, AG1478 also reduced the elevated invasive and migratory capacity of GC cell lines overexpressing EGFL7. Collectively, these results strongly suggest that EGFL7 promotes metastasis by activating EMT through an EGFR-AKT-Snail signaling pathway. Disruption of EGFL7-EGFR-AKT-Snail signaling may a promising therapeutic strategy for gastric cancer.
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Bai-Hua
authors.initials: BH
authors.lastname: Luo
authors.affiliation: Center of Furong Judicial Authentication, the Second People's Hospital, Hunan, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xiong
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Jun-Pu
authors.initials: JP
authors.lastname: Wang
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Jing-He
authors.initials: JH
authors.lastname: Li
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Department of Pathology, Taishan Medical College, Taian, Shandong, China.
authors.forename: Qin-Lai
authors.initials: QL
authors.lastname: Liu
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Geng-Qiu
authors.initials: GQ
authors.lastname: Luo
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Yang
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Ni
authors.initials: N
authors.lastname: Xiao
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Rui-Jie
authors.initials: RJ
authors.lastname: Liu
authors.affiliation: Department of anesthesiology, Affiliated Tumor Hospital of Xiangya Medical College, Central South University, Changsha, Hunan, China.
authors.forename: Chang-Sheng
authors.initials: CS
authors.lastname: Dong
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Kuan-Song
authors.initials: KS
authors.lastname: Wang
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Ji-Fang
authors.initials: JF
authors.lastname: Wen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement; D066255:EGF Family of Proteins; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; C527877:EGFL7 protein, human; D016228:Endothelial Growth Factors; D011799:Quinazolines; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D020032:Tyrphostins; D014746:Vimentin; C101044:RTKI cpd; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt