The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer.
The proliferation-specific Forkhead Box m1 (Foxm1 or Foxm1b) transcription factor (previously called HFH-11B, Trident, Win, or MPP2) regulates expression of cell cycle genes essential for progression into DNA replication and mitosis. Expression of Foxm1 is found in a variety of distinct human cancers including hepatocellular carcinomas, intrahepatic cholangiocarcinomas, basal cell carcinomas, ductal breast carcinomas, and anaplastic astrocytomas and glioblastomas. In this study, we show that human Foxm1 protein is abundantly expressed in highly proliferative human non-small cell lung cancers (NSCLC) as well as in mouse lung tumors induced by urethane. To determine the role of Foxm1 during the development of mouse lung tumors, we used IFN-inducible Mx-Cre recombinase transgene to delete mouse Foxm1 fl/fl-targeted allele before inducing lung tumors with urethane. We show that Mx-Cre Foxm1-/- mice exhibit diminished proliferation of lung tumor cells causing a significant reduction in number and size of lung adenomas. Transient transfection experiments with A549 lung adenocarcinoma cells show that depletion of Foxm1 levels by short interfering RNA caused diminished DNA replication and mitosis and reduced anchorage-independent growth of cell colonies on soft agar. Foxm1-depleted A549 cells exhibit reduced expression of cell cycle-promoting cyclin A2 and cyclin B1 genes. These data show that Foxm1 stimulates the proliferation of tumor cells during progression of NSCLC.
Kim
Il-Man
IM
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Ackerson
Timothy
T
Ramakrishna
Sneha
S
Tretiakova
Maria
M
Wang
I-Ching
IC
Kalin
Tanya V
TV
Major
Michael L
ML
Gusarova
Galina A
GA
Yoder
Helena M
HM
Costa
Robert H
RH
Kalinichenko
Vladimir V
VV
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D048708:Cell Growth Processes / Q000502:physiology; D019925:Cyclin A / Q000096:biosynthesis / Q000235:genetics; D056751:Cyclin A2; D019926:Cyclin B / Q000096:biosynthesis / Q000235:genetics; D056744:Cyclin B1; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000096:biosynthesis; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008938:Mitosis; D034741:RNA, Small Interfering / Q000235:genetics; D014520:Urethane
C503721:CCNA2 protein, human; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019925:Cyclin A; D056751:Cyclin A2; D019926:Cyclin B; D056744:Cyclin B1; D004273:DNA, Neoplasm; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D034741:RNA, Small Interfering; D014520:Urethane