Annexin A1 is associated with gastric cancer survival and promotes gastric cancer cell invasiveness through the formyl peptide receptor/extracellular signal-regulated kinase/integrin beta-1-binding protein 1 pathway.
BACKGROUND
Annexin A1 (AnxA1) has been well-known as a glucocorticoid-regulated anti-inflammatory protein, and it is implicated in tumorigenesis in a tumor type-specific pattern. However, the role of AnxA1 in gastric cancer (GC) is indeterminate, and the underlying mechanism is not clear. The purpose of this study was to evaluate the prognostic significance and associated mechanism of AnxA1 in GC.


METHODS
Immunohistochemical staining was employed to analyze 118 GC patients. Both AnxA1 gain-of-function and loss-of-function approaches were performed in GC cells. Western blotting and reverse-transcription polymerase chain reaction were used for assessment of the AnxA1 regulation mechanism in GC cells. An intraperitoneal inoculation model in severe combined immunodeficient mice was used for an in vivo assay.


RESULTS
High AnxA1 expression was significantly associated with peritoneal metastasis (P = .009) and serosal invasion (P = .044). Cox multivariate analysis showed that high AnxA1 expression was an independent risk factor for poor overall survival in GC patients (P = .037). AnxA1 expression positively correlated with invasiveness of human GC cells both in vitro and in vivo. AnxA1 could regulate the GC cell invasion through the formyl peptide receptor (FPR)/extracellular signal-regulated kinase/integrin beta-1-binding protein pathway, and all 3 FPRs (FPR1 through FPR3) were involved in the regulation process.


CONCLUSIONS
High AnxA1 expression was associated with more serosal invasion, more peritoneal metastasis, and poorer overall survival in GC patients. The current study demonstrated a novel mechanism involving FPRs, extracellular signal-regulated kinases 1 and 2, and integrin beta-1-binding protein 1 by which AnxA1 regulated GC cell invasion.
Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan.
Tsu-Yao
TY
Cheng
Ming-Shiang
MS
Wu
Jaw-Town
JT
Lin
Ming-Tsan
MT
Lin
Chia-Tung
CT
Shun
Hsin-Yi
HY
Huang
Kuo-Tai
KT
Hua
Min-Liang
ML
Kuo
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000818:Animals; D017305:Annexin A1 / Q000032:analysis / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D044042:Receptors, Formyl Peptide / Q000502:physiology*; D013274:Stomach Neoplasms / Q000401:mortality* / Q000473:pathology*
D048868:Adaptor Proteins, Signal Transducing; D017305:Annexin A1; C108257:ITGB1BP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D044042:Receptors, Formyl Peptide; D048049:Extracellular Signal-Regulated MAP Kinases