FoxM1 is up-regulated in gastric cancer and its inhibition leads to cellular senescence, partially dependent on p27 kip1.
The FoxM1 transcription factor, a master regulator of mitotic gene expression, promotes the pathogenesis of several malignancies. However, little is known about its expression and function in gastric cancer. In the present study we determined whether FoxM1 is over-expressed in gastric cancer, and whether it is required to maintain an immortal phenotype of gastric cancer cells. The over-expression of FoxM1 was observed in 37/42 tumour specimens from patients with gastric cancer. When FoxM1 in gastric cancer cells was knocked-down, impaired clonogenicity and cellular senescence occurred independently of p53 and p16 status. FoxM1 depletion led to the down-regulation of its target genes c-MYC and Skp2, coupled with the accumulation of the CDK inhibitor p27(kip1). Importantly, the FoxM1 inhibition-mediated cellular senescence and clonogenic defect was attenuated by the abolition of p27(kip1) induction. Telomerase reverse transcriptase, the key component of telomerase essential for cellular immortalization, was also inhibited in the FoxM1-depleted cells. Taken together, the FoxM1 gene is aberrantly activated in gastric cancer and its inhibition triggers p53- and p16-independent senescence of cancer cells by regulating the expression of p27(kip1) and other targets. These findings provide mechanistic insights into the role of FoxM1 in the pathogenesis of gastric cancer, which may have diagnostic and therapeutic implications in gastric cancer.
Zeng
Jiping
J
Department of Medicine, Division of Haematology, Karolinska University Hospital, Solna, and Karolinska Institutet, Stockholm, Sweden.
Wang
Lixiang
L
Li
Qiao
Q
Li
Wenjuan
W
Björkholm
Magnus
M
Jia
Jihui
J
Xu
Dawei
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000032:analysis / Q000235:genetics; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000032:analysis
D015415:Biomarkers; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; C509186:TERT protein, human; D019098:Telomerase; D001616:beta-Galactosidase