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(FGF-2) Overexpression Is a Risk Factor for Esophageal Cancer

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(FGF-2) Overexpression Is a Risk Factor for Esophageal Cancer Human Cancer Biology Basic Fibroblast Growth Factor (FGF-2) Overexpression Is a Risk Factor for Esophageal Cancer Recurrence and Reduced Survival, which Is Ameliorated by Coexpression oftheFGF-2AntisenseGene Christie Barclay,1Audrey W. Li,1Laurette Geldenhuys,2 Mark Baguma-Nibasheka,1Geoffrey A. Porter,3 Paul J.Veugelers,4 Paul R. Murphy,1and Alan G. Casson2,3 Abstract Purpose:The basic fibroblast growth factor (FGF-2) gene is bidirectionally transcribed to gener- ate overlapping sense and antisense (FGF-AS) mRNAs. FGF-AS has been implicated in the post- transcriptional regulation ofFGF-2 expression. The aim ofthis study was to characterize FGF-2 and FGF-AS in esophageal cancer and to correlate their expression with clinicopathologicfindings and outcome. Experimental Design: Reverse transcription-PCR was used to study FGF-2 and FGF-AS mRNA expression (normalized to glyceraldehyde-3-phosphate dehydrogenase) in 48 esophageal can- cers relative to matched histologically normal esophageal epithelia (internal control). We used Cox proportional hazards analysis to calculate hazard ratios for recurrence and survival of patients with underexpression relative to the overexpression ofFGF-2 and/or FGF-AS. Results: Overexpression ofFGF-2 mRNA, by comparison with tumors underexpressing FGF-2, was associated with significantly increased risk for tumor recurrence (hazard ratio, 3.80; 95% confidence interval, 1.64-8.76) and reduced overall survival (hazard ratio, 2.11;95% confidence interval, 1.0-4.58).When the effects of FGF-2 and FGF-AS were considered simultaneously, the association ofFGF-2 mRNA overexpression with recurrence and mortality was even more pronounced, whereas FGF-AS mRNA overexpression was associated with reduced risk for recurrence and improved survival. Conclusions: Overexpression ofFGF-2 mRNA is associated with tumor recurrence and reduced survival after surgical resection of esophageal cancer and that these risks are reduced in tumors coexpressing the FGF-AS mRNA. These data support the hypothesis that FGF-AS is a novel tumor suppressor that modulates the effect of FGF-2 expression and may have potential clinical application to the development ofnovel therapeutic strategies. Cancer of the esophagus, one of the ten most frequent Although the incidence of esophageal squamous cell carcinoma malignancies worldwide, is a relatively uncommon tumor in has remained steady, incidence rates for adenocarcinomas of North America (1). However, over the past three decades, there the lower esophagus and esophagogastric junction have has been a marked change in the epidemiology of this disease. increased in excess of any other human solid tumor (2, 3). Furthermore, despite recent advances in multimodality therapy, the prognosis for patients with invasive esophageal malignancy Authors’ Affiliations: Departments of 1Physiology and Biophysics, 2Pathology, remains generally poor (4). Substantial progress in the and 3Surgery, Faculty ofMedicine, Dalhousie University, Halifax, Nova Scotia, treatment of esophageal malignancy requires a clearer under- Canada and 4Department ofPublic Health Sciences, University ofAlberta, standing of esophageal tumor biology and the incorporation Edmonton, Alberta, Canada of molecular biomarkers into clinically relevant treatment Received 4/7/05; revised 7/22/05; accepted 8/4/05. Grant support: Cancer Research Society, Inc., Canadian Institutes for Health strategies. Research, Cancer Research Training Program Award from the Dalhousie Cancer Basic fibroblast growth factor (FGF-2) is the prototypic Research Program (C. Barclay), Nova Scotia Health Research Foundation (M. member of a family of related genes encoding heparin-binding Baguma-Nibasheka), and Dalhousie University Faculty ofMedicine Clinical proteins with growth, antiapoptotic, and differentiation pro- Research scholarships (G.A. Porter and A.G. Casson). moting activity (5). FGF-2 is expressed in esophageal squamous The costs ofpublication ofthis article were defrayed in part by the payment ofpage charges. This article must therefore be hereby marked advertisement in accordance cell carcinoma cell lines (6) and is elevated in esophageal with 18 U.S.C. Section 1734 solely to indicate this fact. adenocarcinoma (7), suggesting an autocrine or paracrine role Requests for reprints: Alan G. Casson, Division ofThoracic Surgery, Queen in esophageal tumorigenesis. The FGF-2 gene maps to Elizabeth II Health Science Centre, Victoria Building 7S-013, 1278 Tower Road, chromosome 4q26. This region is a site of frequent gain or Halifax, Nova Scotia, Canada B3H 2Y9. Phone: 902-473-2281; Fax: 902-473- 4426; E-mail: [email protected]. loss in esophageal adenocarcinoma and its premalignant F 2005 American Association for Cancer Research. lesion, Barrett’s esophagus (8–10), suggesting a possible doi:10.1158/1078-0432.CCR-05-0771 structural basis for dysregulation of FGF-2 function. www.aacrjournals.org 7683 Clin Cancer Res 2005;11(21) November 1, 2005 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2005 American Association for Cancer Research. Human Cancer Biology Although the control of FGF-2 expression is poorly under- normal esophageal epithelium adjacent to the proximal resection stood, one intriguing possibility is regulation by an endoge- margin were snap frozen in liquid nitrogen and stored in our nous antisense RNA, FGF-AS (11). Like the majority of esophageal tumor bank at À80jC for subsequent molecular analysis. cis-antisense transcript pairs characterized to date, FGF-2 and All remaining esophageal tissues were processed according to standard FGF-AS are transcribed as 3V-to-3V overlaps; the sense and protocol by the Department of Pathology of the Faculty of Medicine of Dalhousie University (Halifax, Nova Scotia, Canada). Representative antisense RNAs are fully complementary over extensive regions sections were stained with H&E and examined by an independent V of their 3 untranslated regions and have been shown to form consultant histopathologist. Serial unstained formalin-fixed, paraffin- stable double-stranded RNA duplexes in vivo (12). The organi- embedded tissue sections were used for subsequent immunohisto- zation and sequence of the FGF-2 and FGF-AS genes has been chemical analysis. All tumors were staged according to the International highly conserved from amphibian to human, indicating a Union Against Cancer (UICC) classification based on pTNM subsets functional importance for this structural relationship (reviewed (24). Strict clinicopathologic criteria (25) were used to define primary in ref. 13). The inverse association of FGF-2 and FGF-AS mRNA esophageal adenocarcinomas (Siewert type I), thereby excluding expression observed in a variety of species supports the adenocarcinomas of the cardia (Siewert type II) or proximal (subcardia) hypothesis that FGF-2 may be regulated by interaction with the gastric tumors (Siewert type III). antisense RNA (14–18). We have shown recently that forced All participating patients gave full informed consent, and collection overexpression of the FGF-AS mRNA can effectively suppress and storage of resected esophageal tissues was in accordance with the 1998 Canadian Tri-Council Policy ‘‘Statement on Ethical Conduct for FGF-2 levels in stably transfected cells in vitro (11). In addition Research Involving Humans.’’ Approval to study banked esophageal to its putative role as a regulatory RNA, FGF-AS also encodes tissues was approved by the Health Sciences and Humanities Research the protein GFG/NUDT6, a member of the nudix family of Ethics Board at Dalhousie University (2002-539). nucleoside phosphohydrolases (19, 20). The nudix motif is Reverse transcription-PCR. Reverse transcription-PCR was used to characteristic of a diverse group of phosphohydrolase enzymes study FGF-2 and FGF-AS mRNA expression [normalized to glyceralde- active on nucleoside diphosphates linked to another moiety (x). hyde-3-phosphate dehydrogenase (GAPDH)] in tumors, relative to Several nudix motif proteins, including the human homologues matched histologically normal esophageal epithelia (internal control), of MutT and MutY, have been shown to play important roles in using techniques reported previously (11). RNA was extracted from prevention and repair of DNA transversion mutations (21). each esophageal tissue specimen using the TRIzol reagent (Life Although the physiologic function of GFG is unknown, we have Technologies, Burlington, Ontario, Canada) according to the manu- facturer’s instructions. Briefly, the tissue was homogenized in 1 mL shown recently that it can partially complement MutT function À TRIzol per 0.1 g tissue. The homogenate was centrifuged and RNA in in mutT Escherichia coli (20). the supernatant was purified using sequential washing with chloroform, The primary objective of this study was to evaluate the isopropanol, and 75% ethanol. The isolated RNA was resuspended expression of FGF-2 and FGF-AS mRNAs and their cognate using RNase-free water and stored at À80jC. Total RNA yield was proteins in a well-characterized series of surgically resected determined spectrophotometrically. Reverse transcription of 5 Ag RNA human esophageal tissues and cell lines and to correlate these was done using Moloney murine leukemia virus reverse transcriptase findings with clinicopathologic features and outcome. (Promega, Madison, WI) according to the manufacturer’s instructions. Amplification was done using EnzyPlus 2000 polymerase (EnzyPol Ltd., London, Ontario, Canada) in a 25 AL reaction composed of Materials and Methods
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