The forkhead box M1 transcription factor contributes to the development and growth of mouse colorectal cancer.
OBJECTIVE
In this study, we used Forkhead Box m1b (Foxm1b) transgenic mice and conditional Foxm1 knock-out mice to examine the role of Foxm1 in colon cancer development and proliferation.


METHODS
To induce mouse colorectal cancer, we used a single intraperitoneal injection of azoxymethane (AOM) followed by three 1-week cycles of 2.5% dextran sodium sulfate (DSS) water, each cycle separated by 2 weeks. For these colon tumor studies, we used either Rosa26-Foxm1b transgenic mice that ubiquitously expressed the human Foxm1b complementary DNA or mice in which the Foxm1 fl/fl targeted allele was deleted in colonic epithelial cells using the gut-specific Villin-Cre recombinase transgene (Villin-Cre). Colorectal tumor number and bromodeoxyuridine labeling were determined in Rosa26-Foxm1b mice, Villin-Cre Foxm1-/-, mice and wild-type mice after 12 weeks of AOM/DDS exposure. We also used Foxm1 small interfering RNA-depleted human DLD1 and mouse CT26 colon cancer cell lines to examine DNA replication and anchorage-independent growth.


RESULTS
After 12 weeks of treatment with AOM/DSS, Rosa26 Foxm1b transgenic mice showed an increase in the number and size of colorectal tumors compared with wild-type mice. Likewise, a significant reduction in the development and growth of colorectal tumors was found in Villin-Cre Foxm1-/- mice compared with Foxm1 fl/fl mice after AOM/DSS treatment, which was associated with decreased expression of cyclin A2, cyclin B1, survivin, and T-cell factor 4 genes. Moreover, Foxm1-depleted colon cancer cell lines showed reduced DNA replication and anchorage-independent growth.


CONCLUSIONS
These studies suggest that Foxm1 is critical for the proliferation and growth of colorectal cancer.
Yoshida
Yuichi
Y
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, USA. yyoshida@gh.med.osaka-u.ac.jp
Wang
I-Ching
IC
Yoder
Helena M
HM
Davidson
Nicholas O
NO
Costa
Robert H
RH
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000964:Antimetabolites, Antineoplastic; D001397:Azoxymethane / Q000633:toxicity; D014408:Biomarkers, Tumor / Q000235:genetics; D001973:Bromodeoxyuridine; D002273:Carcinogens / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019925:Cyclin A / Q000235:genetics; D056751:Cyclin A2; D019926:Cyclin B / Q000235:genetics; D056744:Cyclin B1; D016264:Dextran Sulfate / Q000633:toxicity; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D022661:RNA, Untranslated; D012097:Repressor Proteins; D000077022:Survivin; D051820:TCF Transcription Factors / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein
D000964:Antimetabolites, Antineoplastic; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; C117749:Birc5 protein, mouse; C503721:CCNA2 protein, human; C508184:CCNA2 protein, mouse; C534699:CCNB1 protein, human; D002273:Carcinogens; C534700:Ccnb1 protein, mouse; D019925:Cyclin A; D056751:Cyclin A2; D019926:Cyclin B; D056744:Cyclin B1; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; D012097:Repressor Proteins; D000077022:Survivin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D016264:Dextran Sulfate; D001973:Bromodeoxyuridine; D001397:Azoxymethane