Independent and tissue-specific prognostic impact of miR-126 in nonsmall cell lung cancer: coexpression with vascular endothelial growth factor-A predicts poor survival.
BACKGROUND
Angiogenesis is pivotal in tumor development. Vascular endothelial growth factor-A (VEGF-A) is considered one of the most important angiogenic factors, but lately several microRNAs (miRs) have been associated with vascular development. miR-126 has been related to tumor angiogenesis and in the regulation of VEGF-A. The authors aimed to investigate the prognostic impact of miR-126 and its co-expression with VEGF-A in nonsmall cell lung cancer (NSCLC) patients.


METHODS
Tumor tissue samples from 335 resected stage I to IIIA NSCLC patients were obtained and tissue microarrays (TMAs) were constructed with 4 cores from each tumor specimen. VEGF-A expression was evaluated by immunohistochemistry, and in situ hybridization was used to evaluate the expression of miR-126.


RESULTS
In the total material, miR-126 was a significant negative prognostic factor in both univariate (P = .005) and multivariate analyses (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2-2.8, P = .01). Stratified by histology, miR-126 was only significant in squamous cell carcinomas (univariate: P < .001; multivariate: HR 3.1, CI 95% 1.7-5.6, P<.001). Stratified by lymph node status, miR-126 was significant only in the lymph node-positive subgroup (univariate: P<.001; multivariate: HR 4.1, CI 95% 2.0-8.4, P < .001). High miR-126 expression correlated significantly with high VEGF-A expression (P = .037). The co-expression of miR-126 and VEGF-A had a significant prognostic impact (P = .002), with 5-year survival rates of 68%, 51%, and 42% for low/low (n = 150), mixed combinations (n = 129), and high/high (n = 35) expression, respectively.


CONCLUSIONS
miR-126 is a strong and independent negative prognostic factor in NSCLC, and its prognostic impact appears related primarily to histology and nodal status.
Department of Oncology, University Hospital of North Norway, Tromso, Norway. tom.donnem@uit.no
Tom
T
Donnem
Kenneth
K
Lonvik
Katrine
K
Eklo
Thomas
T
Berg
Sveinung W
SW
Sorbye
Khalid
K
Al-Shibli
Samer
S
Al-Saad
Sigve
S
Andersen
Helge
H
Stenvold
Roy M
RM
Bremnes
Lill-Tove
LT
Busund
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000401:mortality; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009928:Organ Specificity; D011379:Prognosis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D042461:Vascular Endothelial Growth Factor A