Minichromosome maintenance (MCM) protein 4 as a marker for proliferation and its clinical and clinicopathological significance in non-small cell lung cancer.
BACKGROUND
Minichromosome maintenance (MCM) proteins 2-7 form a complex essential for the initiation of DNA replication. In the process to screen expression changes related to growth suppression of non-small cell lung cancer (NSCLC) cells by a cJun dominant-negative mutant, we found that reduced expression of MCM4 was correlated with this growth suppression.


METHODS
We determined the relevance of MCM4 in proliferation of NSCLC by downregulating its expression with small-interfering RNA in three NSCLC cell lines. We then immunohistochemically analyzed MCM4 expression in 156 surgically resected NSCLCs to correlate clinicopathologic characteristics.


RESULTS
MCM4 downregulation reduced proliferation in two cell lines. MCM4 expression was higher in cancer cells than in adjacent normal bronchial epithelial cells (p<0.001). High MCM4 expression was correlated with male gender, heavy smoking, poorer differentiation and non-adenocarcinoma histology (p<0.001, respectively). High MCM4 expression was also correlated with proliferation markers, Ki-67 and cyclin E expression (p<0.001, respectively). MCM4 expression was not associated with survival.


CONCLUSIONS
MCM4 may play an essential role in the proliferation of some NSCLC cells. Taken together with higher expression in NSCLCs and its correlation with clinicopathologic characteristics such as non-adenocarcinoma histology, MCM4 may have potential as a therapeutic target in certain population with NSCLCs.
Kikuchi
Junko
J
First Department of Medicine, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan.
Kinoshita
Ichiro
I
Shimizu
Yasushi
Y
Kikuchi
Eiki
E
Takeda
Kayoko
K
Aburatani
Hiroyuki
H
Oizumi
Satoshi
S
Konishi
Jun
J
Kaga
Kichizo
K
Matsuno
Yoshihiro
Y
Birrer
Michael J
MJ
Nishimura
Masaharu
M
Dosaka-Akita
Hirotoshi
H
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D008297:Male; D064148:Minichromosome Maintenance Complex Component 4; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D012737:Sex Factors; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D048031:JNK Mitogen-Activated Protein Kinases; C099243:MCM4 protein, human; D064148:Minichromosome Maintenance Complex Component 4