Aerosol delivery of lentivirus-mediated O-glycosylation mutant osteopontin suppresses lung tumorigenesis in K-ras               (LA1) mice.
BACKGROUND
Osteopontin (OPN) is a secreted glycophosphoprotein that has been implicated in the regulation of cancer development. The function of OPN is primarily regulated through post-translational modification such as glycosylation. As yet, however, the relationship between OPN glycosylation and lung cancer development has not been investigated. In this study, we addressed this issue by studying the effect of a triple mutant (TM) of OPN, which is mutated at three O-glycosylation sites, on lung cancer development in K-ras                   (LA1) mice, a murine model for human non-small cell lung cancer.


METHODS
Aerosolized lentivirus-based OPN TM was delivered into the lungs of K-ras                   (LA1) mice using a nose-only-inhalation chamber 3 times/wk for 4 wks. Subsequently, the effects of repeated delivery of OPN TM on lung tumorigenesis and its concomitant OPN-mediated signaling pathways were investigated.


RESULTS
Aerosol-delivered OPN TM inhibited lung tumorigenesis. In addition, the OPN-mediated Akt signaling pathway was inhibited. OPN TM also decreased NF-κB activity and the phosphorylation of 4E-BP1, while facilitating apoptosis in the lungs of K-ras                   (LA1) mice.


CONCLUSIONS
Our results show that aerosol delivery of OPN TM successfully suppresses lung cancer development in the K-ras                   (LA1) mouse model and, therefore, warrant its further investigation as a possible therapeutic strategy for non-small cell lung cancer.
Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
Arash
A
Minai-Tehrani
Seung-Hee
SH
Chang
Jung-Taek
JT
Kwon
Soon-Kyung
SK
Hwang
Ji-Eun
JE
Kim
Ji-Young
JY
Shin
Kyeong-Nam
KN
Yu
Sung-Jin
SJ
Park
Hu-Lin
HL
Jiang
Ji-Hye
JH
Kim
Seong-Ho
SH
Hong
Bitna
B
Kang
Duyeoul
D
Kim
Chan-Hee
CH
Chae
Kee-Ho
KH
Lee
George R
GR
Beck
Myung-Haing
MH
Cho
D048868:Adaptor Proteins, Signal Transducing; D000336:Aerosols / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006031:Glycosylation; D016086:Lentivirus / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D009154:Mutation; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D047368:Tumor Burden / Q000235:genetics; D000097763:Polypeptide N-acetylgalactosaminyltransferase
D048868:Adaptor Proteins, Signal Transducing; D000336:Aerosols; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D017350:N-Acetylgalactosaminyltransferases; D016328:NF-kappa B; D053495:Osteopontin; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D000097763:Polypeptide N-acetylgalactosaminyltransferase; C499527:Eif4ebp1 protein, mouse; C514862:Akt1 protein, mouse; C495971:Hras protein, mouse