Int6 expression can predict survival in early-stage non-small cell lung cancer patients.
OBJECTIVE
The Int6 gene was originally identified as a common insertion site for the mouse mammary tumor virus in virally induced mouse mammary tumors. Recent studies indicate that Int6 is a multifaceted protein involved in the regulation of protein translation and degradation through binding with three complexes: the eukaryotic translation initiation factor 3, the proteasome regulatory lid, and the constitutive photomorphogenesis 9 signalosome. This study aimed to investigate the prognostic role of Int6 in a large series of stage I non-small cell lung cancers (NSCLC) patients with long-term follow-up.


METHODS
We determined the methylation status of Int6 DNA by methylation-specific PCR and the steady-state levels of Int6 RNA by quantitative real-time reverse transcription-PCR in 101 NSCLCs and matched normal lung tissues.


RESULTS
In 27% of the tumors, Int6 RNA levels were reduced relative to normal tissue. In 85% of the tumors with reduced Int6 expression, the transcription promoter and first exon were hypermethylated, whereas only 4% of the tumors with elevated Int6 RNA levels were hypermethylated (P <0.000001). Low levels of Int6 RNA were found a significant predictor of overall and disease-free survival (P=0.0004 and P=0.0020, respectively). A multivariate analysis confirmed that low Int6 expression was the only independent factor to predict poor prognosis, for both overall (P=0.0006) and disease-free (P=0.024) survival.


CONCLUSIONS
Our results suggest that Int6 expression, evaluated by quantitative real-time PCR, may represent a new prognostic factor in patients with stage I NSCLC.
Buttitta
Fiamma
F
Clinical Research Center, Center of Excellence on Aging, University Foundation, Chieti, Italy.
Martella
Carla
C
Barassi
Fabio
F
Felicioni
Lara
L
Salvatore
Simona
S
Rosini
Sandra
S
D'Antuono
Tommaso
T
Chella
Antonio
A
Mucilli
Felice
F
Sacco
Rocco
R
Mezzetti
Andrea
A
Cuccurullo
Franco
F
Callahan
Robert
R
Marchetti
Antonio
A
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D019175:DNA Methylation; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics*; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
D039621:Eukaryotic Initiation Factor-3; D012333:RNA, Messenger