title: EPAC1 overexpression is a prognostic marker and its inhibition shows promising therapeutic potential for gastric cancer.
abstract: cAMP signaling controls a variety of cellular functions. In addition to the well-known signal transducer cAMP-dependent protein kinase, a more recently discovered transducer is the exchange protein directly activated by cAMP (EPAC). EPAC responses are mediated by small G proteins, which regulate biologic functions such as cell adhesion, migration and proliferation. Recently, the clinical importance of EPAC1 has received increased attention. This study investigated the correlations between the expression of EPAC1 and various clinicopathologic parameters as well as the survival of the patients with gastric cancer (GC). The patient cohort in this study consisted of 141 cases of GC that presented from 1999 through 2011; documented clinicopathologic parameters and clinical outcomes were available for all cases. Immunoblotting, immunohistochemistry and quantitative real-time PCR were used to examine EPAC1 expression in gastric cells and tissues. siRNA technology was used to study the effect of EPAC1 knockdown on cell proliferation and invasion. An increase in EPAC1 expression was found in GC cells and tissues. The overexpression of EPAC1 was associated with the depth of invasion (P=0.0021), stage (P=0.0429), and vascular invasion (P=0.0049) and was correlated with poor disease-free survival (P=0.0029) and overall survival (P=0.0024). A univariate Cox regression analysis showed that the overexpression of EPAC1 was a prognostic marker for GC (P=0.038). Furthermore, cell studies indicated that the knockdown of EPAC1 in GC cells suppressed cell proliferation and invasion. The overexpression of EPAC1 can be used as a marker to predict the outcome of patients with GC, and EPAC1 represents a potential therapeutic modality for treating GC.
authors.affiliation: Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan, R.O.C.
authors.forename: Ding-Ping
authors.initials: DP
authors.lastname: Sun
authors.affiliation: Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, R.O.C.
authors.forename: Chia-Lang
authors.initials: CL
authors.lastname: Fang
authors.affiliation: Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan, R.O.C.
authors.forename: Han-Kun
authors.initials: HK
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Chi Mei Medical Center, Tainan, Taiwan, R.O.C.
authors.forename: Kuo-Shan
authors.initials: KS
authors.lastname: Wen
authors.affiliation: Department of Cosmeceutics, China Medical University, Taichung, Taiwan, R.O.C.
authors.forename: You-Cheng
authors.initials: YC
authors.lastname: Hseu
authors.affiliation: Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan, R.O.C.
authors.forename: Shih-Ting
authors.initials: ST
authors.lastname: Hung
authors.affiliation: The Superintendent's Office, Chi Mei Hospital Chiali, Tainan, Taiwan, R.O.C.
authors.forename: Yih-Huei
authors.initials: YH
authors.lastname: Uen
authors.affiliation: Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan, R.O.C.
authors.forename: Kai-Yuan
authors.initials: KY
authors.lastname: Lin
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D000242:Cyclic AMP / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D000242:Cyclic AMP