Putative tumor-suppressive function of Kruppel-like factor 4 in primary lung carcinoma.
OBJECTIVE
Krüppel-like factor 4 (KLF4) is a zinc-finger protein that plays important roles in stem cells and the development of gastric cancers. However, the role of KLF4 in primary lung cancer is unknown. The purpose of this study is to determine possible roles of KLF4 in lung cancer.


METHODS
The KLF4 expression in primary lung cancer tissues and case-matched normal lung tissues were determined by protein and mRNA analyses. The effects of KLF4 on cell proliferation, clonogenic formation, and cell cycle progression were determined in cultured lung cancer cells or bronchial epithelial cells after enforced KLF4 overexpression or small interfering RNA knockdown. The in vivo antitumor activity of KLF4 was evaluated by using stably transfected lung cancer cells and by adenovector-mediated gene delivery. The effect of KLF4 in regulating p21 and cyclin D1 was also evaluated.


RESULTS
KLF4 protein and mRNA levels were dramatically decreased in most primary lung tumors compared with in case-matched normal lung tissues. Enforced expression of KLF4 resulted in marked inhibition of cell growth and clonogenic formation. The tumor-suppressive effect of KLF4 was associated with its role in up-regulating p21 and down-regulating cyclin D1, leading to cell cycle arrest at the G(1)-S checkpoint. Knockdown of KLF4 promoted cell growth in immortalized human bronchial epithelial cells. The enforced expression of KLF4 gene to lung cancer cells by ex vivo transfection or adenovector-mediated gene transfer suppressed tumor growth in vivo.


CONCLUSIONS
Our results suggest that KLF4 plays an important role in suppressing the growth of lung carcinoma.
Hu
Wenxian
W
Sir Run Run Shaw Hospital, Zhejiang University, Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, People's Republic of China.
Hofstetter
Wayne L
WL
Li
Hong
H
Zhou
Yanbin
Y
He
Yong
Y
Pataer
Abujiang
A
Wang
Li
L
Xie
Keping
K
Swisher
Stephen G
SG
Fang
Bingliang
B
D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured
D050759:Cyclin-Dependent Kinase Inhibitor p21; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D019938:Cyclin D1