Prognostic value and targeted inhibition of survivin expression in esophageal adenocarcinoma and cancer-adjacent squamous epithelium.
BACKGROUND
Survivin is an inhibitor of apoptosis and its over expression is associated with poor prognosis in several malignancies. While several studies have analyzed survivin expression in esophageal squamous cell carcinoma, few have focused on esophageal adenocarcinoma (EAC) and/or cancer-adjacent squamous epithelium (CASE). The purpose of this study was 1) to determine the degree of survivin up regulation in samples of EAC and CASE, 2) to evaluate if survivin expression in EAC and CASE correlates with recurrence and/or death, and 3) to examine the effect of survivin inhibition on apoptosis in EAC cells.


METHODS
Fresh frozen samples of EAC and CASE from the same patient were used for qRT-PCR and Western blot analysis, and formalin-fixed, paraffin-embedded tissue was used for immunohistochemistry. EAC cell lines, OE19 and OE33, were transfected with small interfering RNAs (siRNAs) to knockdown survivin expression. This was confirmed by qRT-PCR for survivin expression and Western blot analysis of cleaved PARP, cleaved caspase 3 and survivin. Survivin expression data was correlated with clinical outcome.


RESULTS
Survivin expression was significantly higher in EAC tumor samples compared to the CASE from the same patient. Patients with high expression of survivin in EAC tumor had an increased risk of death. Survivin expression was also noted in CASE and correlated with increased risk of distant recurrence. Cell line evaluation demonstrated that inhibition of survivin resulted in an increase in apoptosis.


CONCLUSIONS
Higher expression of survivin in tumor tissue was associated with increased risk of death; while survivin expression in CASE was a superior predictor of recurrence. Inhibition of survivin in EAC cell lines further showed increased apoptosis, supporting the potential benefits of therapeutic strategies targeted to this marker.
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Usha
U
Malhotra
Ali H
AH
Zaidi
Juliann E
JE
Kosovec
Pashtoon M
PM
Kasi
Yoshihiro
Y
Komatsu
Christina L
CL
Rotoloni
Jon M
JM
Davison
Clint
C
R
Irvin
Toshitaka
T
Hoppo
Katie S
KS
Nason
Lori A
LA
Kelly
Michael K
MK
Gibson
Blair A
BA
Jobe
D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D016019:Survival Analysis; D000077022:Survivin; D016707:Tissue Fixation; D059016:Tumor Microenvironment / Q000235:genetics*
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3