Cytoplasmic Ape1 expression elevated by p53 aberration may predict survival and relapse in resected non-small cell lung cancer.
BACKGROUND
Subcellular localization of apurinic/apyrimidinic endonuclease-1/redox factor-1 (Ape1) has been demonstrated to promote lung tumor malignancy via NF-κB activation. We hypothesized that increased cytoplasmic Ape1 expression might cause NF-κB activation by p53 aberration, and result in poor outcome in non-small cell lung cancer (NSCLC).


METHODS
Herein, knockdown of E6 or p53 and overexpression of E6 were performed in various lung cancer cells to test whether cytoplasmic Ape1 expression could be elevated by p53 aberration. To examine whether cytoplasmic Ape1 could be associated with patients' outcome, 125 lung tumors from patients with NSCLC were collected to determine Ape1 protein and mRNA expression by immunohistochemistry and real-time RT-PCR.


RESULTS
Our data showed that cytoplasmic Ape1 decreased in E6-knockdown TL-1 cells and increased in E6-overexpressed TL-4 and p53-knockdown H520 cells; and cell invasion capability was dependent on the presence of cytoplasmic Ape1. Increases in cytoplasmic Ape1 by p53 aberration may be through activation of Ape1 transcription and S-nitrosation of Ape1 protein. Kaplan-Meier and Cox models showed that patients with high cytoplasmic Ape1 had shorter cancer-specific survival (CSS) and relapse-free survival (RFS) periods than did those with low cytoplasmic Ape1.


CONCLUSIONS
We suggest that cytoplasmic Ape1 expression elevated by p53 aberration may be used to predict poor survival and relapse in patients with NSCLC.
Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, ROC.
Heng-Hsiung
HH
Wu
Ya-Chiung
YC
Chu
Lee
L
Wang
Lung-Hung
LH
Tsai
Ming-Ching
MC
Lee
Chi-Yi
CY
Chen
Shwn-Huey
SH
Shieh
Ya-Wen
YW
Cheng
Huei
H
Lee
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D003593:Cytoplasm / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase