Expression of activated signal transducer and activator of transcription 3 predicts poor clinical outcome in gastric adenocarcinoma.
There are no known reliable biomarkers which can predict poor clinical outcome following curative resection of gastric adenocarcinoma. Given the importance of signal transducer and activator of transcription 3 (STAT3) activation in carcinogenesis, we attempted to determine whether STAT3 activation is prognostic of survival in curatively resected gastric cancer patients. We analyzed 311 surgically resected gastric cancer specimens for STAT3 activation and its downstream molecules such as matrix metalloproteinase (MMP)-9, MMP-10, cyclin D1, survivin, vascular endothelial growth factor (VEGF)-C, and VEGFR-3 using immunohistochemical studies and assessed their correlation with clinical outcome. Using immunohistochemistry, 303 specimens were interpretable for pSTAT3tyr705 expression. The pSTAT3 was detected in 79 (26.1%) of 303 gastric cancers. Of the downstream molecules tested, STAT3 activation was significantly associated with MMP-9 and MMP-10 expressions. On univariate analyses, 5-year disease-free survival (DFS) and overall survival (OS) for the tumors with STAT3 activation were considerably poorer than for those without STAT3 activation with statistical significance (5-year DFS 58.2% vs 68.3%; pSTAT3(-) vs pSTAT3(+); p = 0.0223; 5-year OS 59.5% vs 70.5%; pSTAT3(-) vs pSTAT3(+); p = 0.0128). On multivariate analyses, STAT3 activation was independently associated with inferior DFS (p = 0.049, hazard ratio [HR] = 1.445, 95% CI, 1.025, 2.120) along with AJCC stage IIIA or IIIB (p = 0.004, HR = 1.708, 95% CI, 1.178, 2.475). The STAT3 activation was also strongly correlated with inferior OS (p = 0.042, HR = 1.506, 95% CI, 1.025, 2.213). Based on our data, pSTAT3tyr705 may be a novel prognostic marker for poorer clinical outcome following curative resection and adjuvant therapy in gastric cancer. The clinical impact of a STAT3-targeted agent should be investigated in gastric cancer patients.
Lee
Jeeyun
J
Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Kang
Won Ki
WK
Park
Joon Oh
JO
Park
Se Hoon
SH
Park
Young Suk
YS
Lim
Ho Yeong
HY
Kim
Junga
J
Kong
Jeehyun
J
Choi
Min Gew
MG
Sohn
Tae Sung
TS
Noh
Jae Hyung
JH
Bae
Jae Moon
JM
Kim
Sung
S
Lim
Do Hoon
DH
Kim
Kyoung-Mee
KM
Park
Cheol Keun
CK
D000230:Adenocarcinoma / Q000401:mortality* / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D013274:Stomach Neoplasms / Q000401:mortality* / Q000473:pathology; D000077022:Survivin; D046888:Tissue Array Analysis; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D042582:Vascular Endothelial Growth Factor C; D019938:Cyclin D1; D040321:Vascular Endothelial Growth Factor Receptor-3; C511770:MMP10 protein, human; D053506:Matrix Metalloproteinase 10; D020780:Matrix Metalloproteinase 9