α-Internexin: a novel biomarker for pancreatic neuroendocrine tumor aggressiveness.
OBJECTIVE
We aimed to test whether α-internexin could be a molecular biomarker of tumor aggressiveness and prognosis in pancreatic neuroendocrine tumors (PNETs).


METHODS
Using immunohistochemical staining and Western blot, we detected the expression of α-internexin in 350 tumors from 343 patients, of whom 257 were followed up. Methylation of α-internexin promoter was examined by bisulfite sequencing to identify the crucial region that determines gene expression. Methylation of gene promoter in tumors was quantitatively measured by denaturing high performance liquid chromatography (DHPLC). We correlated α-internexin expression with clinicopathological characteristics.


RESULTS
α-Internexin was expressed in 53% of 350 PNETs. The reduced expression of α-internexin was significantly associated with advanced stage (P < .0001), metastases (P < .0001), and recurrence (P = .003). α-Internexin expression was found in 57.1% of 212 surviving patients and in 17.1% of 35 deceased patients (P < .0001). Reduced expression of α-internexin was associated with shorter overall survival in PNET patients (log rank P < .0001) as well as in patients with noninsulinoma and nonfunctional (NF)-PNETs (log rank P = 0.0073 and P = 0.010, respectively). The crucial region of α-internexin promoter (-149 to +96 nucleotides [nt]) was identified, and the hypomethylation of this area in PNETs was significantly associated with gene expression (P = .015).


CONCLUSIONS
α-Internexin can be a useful prognostic biomarker for PNETs.
Departments of Gastroenterology (B.Li., M.M., X.-W.Q., H.-Y.W., C.-M.L., Y.-J.C.), Surgery (T.-P.Z., Y.-P.Z.), and Pathology (T.-H.L., Y.X., J.C.) and Key Laboratory of Endocrinology (Ministry of Health) (H.-D.X., Y.-J.C.), Department of Endocrinology, Peking Union Medical College Hospital, and Department of Biochemistry and Molecular Biology (Y.Z.), Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China; Department of Pathology (L.H.T.), Memorial Sloan-Kettering Cancer Center, New York, New York 10065; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) (Z.L., D.De.), Department of Etiology, Peking University Cancer Hospital/Institute, Beijing 100142, China; Departments of Endocrinology (R.Y.) and Pathology (D.Dh.), Cedars-Sinai Medical Center, University of California, Los Angeles, California 90048; Department of Gastroenterology (B.Lv.), the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China; and Department of Endocrinology (Y.-R.Z.), The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China.
Bei
B
Liu
Laura H
LH
Tang
Zhaojun
Z
Liu
Mei
M
Mei
Run
R
Yu
Deepti
D
Dhall
Xin-Wei
XW
Qiao
Tai-Ping
TP
Zhang
Yu-Pei
YP
Zhao
Tong-Hua
TH
Liu
Yu
Y
Xiao
Jie
J
Chen
Hong-Ding
HD
Xiang
Hai-Yan
HY
Wu
Chong-Mei
CM
Lu
Bin
B
Lv
Ya-Ru
YR
Zhou
Ye
Y
Zhang
Dajun
D
Deng
Yuan-Jia
YJ
Chen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic
D014408:Biomarkers, Tumor; D007381:Intermediate Filament Proteins; C046643:alpha-internexin