Expression and signi ! cance of FOXM 1 in human cervical cancer : A tissue microarray study

Objective: !is study was designed to investigate the expression and signi"cance of the Forkhead Box M1 (FOXM1) transcription factor in human cervical cancer. Methods: !e expression of FOXM1 protein was assessed in tissue microarrays containing 102 cervical cancer tissues by the Streptavidin–Peroxidase (SP) immunohistochemitry technique. !e relationship between FOXM1 protein and clinico-pathological features (pathological stages, pathological types, TNM stage) was analyzed. Results: FOXM1 protein was located in the cytoplasma and/or nucleus. !e overall expression of FOXM1 in the cytoplasm and nucleus was not associated with T stages (P=0.217) or lymph node status (P=0.313). !e nuclear expression of FOXM1 protein was not associated with T stage (P=0.508) or lymph node status (P=0.345). Elevated translocation and activity of FOXM1 were discovered with a secondary analysis that showed that the di#erences of the nuclear expression of FOXM1, among di#erent pathological stages, were statistically signi"cant (P<0.05). !e nuclear expression of FOXM1 in low di#erential cervical cancer tissues was signi"cantly higher than in high di#erential cervical cancer tissues (P<0.05). Conclusion: !e overexpression of FOXM1 protein in cervical cancer maybe associated with the progression of cervical cancer, and could be a potentially novel tumor marker useful for diagnosis and therapy of cervical cancer. ORIGINAL RESEARCH © 2011 CIM Clin Inv E1 Correspondence to: Dr. Hong Chen, Department of Gynecology and Obstetrics, Zhongnan Hospital of Wuhan University No. 169 Donghu Road, Wuhan, 430071, China E-mail: chen.hong888@126.com Clin Invest Med 2011; 34 (1): E1-E7. Although the 5-year relative survival rate of cervical cancer has improved, as a potentially preventable disease, cervical cancer is still the seventh in frequency overall and the second most common cancer among women worldwide [1, 2]. It has been evidenced that human papillomavirus (HPV) is one of the most important risk factors and maybe the most essential etiological agent in cervical cancer [3]. Recent studies have demonstrated that HPV alone is insu$cient in cervical cancer development. !e average of women with invasive cervical cancer is approximately 50 years of age, whereas the mean age of women with detectable HPV is much earlier than 28 years, which suggests in most cases a long precancerous state exist that allows the accumulation of secondary genetic changes [4, 5]. !erefore, there are must be other factors involving in the development of cellular genetic changes or in the activation of signal transduction pathways in the progress of carcinogenesis and tumor progression. Cancer is o%en de"ned as a disease of cell proliferation, and the majority of cancer studies have focused on examining functional consequences of activating and/or inactivating mutations in critical genes and signaling pathways regulating cell proliferation and/or cell death [6]. Forkhead box (FOX) is such a critical gene and FOX protein family is a growing group of transcription factors that plays important roles in cellular proliferation, di#erentiation and organ morphogenesis [7]. FOXM1, an essential member of FOX family, is broadly expressed in actively dividing cells and is crucial for cell cycledependent gene expression in the process of the cell cycle. As more and more studies have uncovered the mechanism by which FOXM1 controls the transcriptional network of genes that are essential for cell division and exit from mitosis, it has been proposed that FOXM1 may also mediate cellular transformation into cancer cells [8, 9]; however, little is known about FOXM1 expression in human cervical cancer and its clinical implications. In the present study, the expression and signi"cance of FOXM1 protein were examined by immunohistochemistry in a tissue micro-array composed of human cervical cancer tissues.

[1]  Raza Ali,et al.  RETRACTED ARTICLE: FoxM1 down-regulation leads to inhibition of proliferation, migration and invasion of breast cancer cells through the modulation of extra-cellular matrix degrading factors , 2010, Breast Cancer Research and Treatment.

[2]  Yan Li,et al.  The expression and significance of P-glycoprotein, lung resistance protein and multidrug resistance-associated protein in gastric cancer , 2009, Journal of experimental & clinical cancer research : CR.

[3]  J. Asara,et al.  A Conserved Phosphorylation Site within the Forkhead Domain of FoxM1B Is Required for Its Activation by Cyclin-CDK1* , 2009, The Journal of Biological Chemistry.

[4]  J. Whitsett,et al.  Deletion of Forkhead Box M1 Transcription Factor from Respiratory Epithelial Cells Inhibits Pulmonary Tumorigenesis , 2009, PloS one.

[5]  F. Fang,et al.  Expression of FLJ10540 is correlated with aggressiveness of oral cavity squamous cell carcinoma by stimulating cell migration and invasion through increased FOXM1 and MMP-2 activity , 2009, Oncogene.

[6]  J. Hartman,et al.  FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer. , 2009, International journal of oncology.

[7]  A. Gartel,et al.  A novel mode of FoxM1 regulation: Positive auto-regulatory loop , 2009, Cell cycle.

[8]  J. S. Rao,et al.  Inhibition of matrix metalloproteinase‐2 enhances radiosensitivity by abrogating radiation‐induced FoxM1‐mediated G2/M arrest in A549 lung cancer cells , 2009, International journal of cancer.

[9]  D. Tan,et al.  Critical role and regulation of transcription factor FoxM1 in human gastric cancer angiogenesis and progression. , 2009, Cancer research.

[10]  S. Teo,et al.  FOXM1 Upregulation Is an Early Event in Human Squamous Cell Carcinoma and it Is Enhanced by Nicotine during Malignant Transformation , 2009, PloS one.

[11]  Sonja Loges,et al.  Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. , 2009, Cancer cell.

[12]  M. Barbacid,et al.  Cell cycle, CDKs and cancer: a changing paradigm , 2009, Nature Reviews Cancer.

[13]  P. Christopoulos,et al.  Human papilloma virus molecular profile and mechanisms of cancerogenesis: a review. , 2009, European journal of gynaecological oncology.

[14]  Raymond Sawaya,et al.  FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells. , 2008, Cancer research.

[15]  Mark J. Murphy,et al.  C‐Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia , 2008, Hepatology.

[16]  Hao Li,et al.  Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression , 2008, Nature Cell Biology.

[17]  A. Tyner,et al.  FoxM1 Regulates Transcription of JNK1 to Promote the G1/S Transition and Tumor Cell Invasiveness* , 2008, Journal of Biological Chemistry.

[18]  H. Wang,et al.  TIS21 negatively regulates hepatocarcinogenesis by disruption of cyclin B1–Forkhead box M1 regulation loop , 2008, Hepatology.

[19]  M. Mabruk The mystery of human papillomaviruses in carcinogenesis , 2008, Expert review of molecular diagnostics.

[20]  Arndt Hartmann,et al.  Tight correlation between expression of the Forkhead transcription factor FOXM1 and HER2 in human breast cancer , 2008, BMC Cancer.

[21]  Satoki Nakamura,et al.  Elevated FoxM1 Expression Promotes Cell Cycle Progression by Induction of KIS Expression and Contributes to the Development of Leukemia Cells. , 2007 .

[22]  E. Lam,et al.  The emerging roles of forkhead box (Fox) proteins in cancer , 2007, Nature Reviews Cancer.

[23]  Zhiwei Wang,et al.  Down-regulation of Forkhead Box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells. , 2007, Cancer research.

[24]  Satoki Nakamura,et al.  Analysis of FoxM1 Expression and Regulation of Cell Cycle, and Anti-Leukemic Effectss by FoxM1 Knockdown on Leukemia Cells Transfected with siRNA FoxM1. , 2006 .

[25]  R. Costa,et al.  Chk2 Mediates Stabilization of the FoxM1 Transcription Factor To Stimulate Expression of DNA Repair Genes , 2006, Molecular and Cellular Biology.

[26]  I. Wierstra,et al.  FOXM1c transactivates the human c‐myc promoter directly via the two TATA boxes P1 and P2 , 2006, The FEBS journal.

[27]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[28]  R. Costa FoxM1 dances with mitosis , 2005, Nature Cell Biology.

[29]  Hans Clevers,et al.  FoxM1 is required for execution of the mitotic programme and chromosome stability , 2005, Nature Cell Biology.

[30]  J. Wolf,et al.  The Molecular Biology of Cervical Cancer , 2001, Cancer investigation.

[31]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.