title: FoxM1 and its association with matrix metalloproteinases (MMP) signaling pathway in papillary thyroid carcinoma.
abstract: BACKGROUND
  Forkhead boxM1 (FoxM1) transcription factor has been shown to promote pathogenesis of several malignancies. FoxM1 has also been shown to be associated with matrix metalloproteinases (MMP) in various cancers. However, little is known about its function in papillary thyroid carcinoma (PTC).
  
  
  OBJECTIVE
  In this study, we investigated the role of FoxM1 in pathogenesis in a large series of PTC in a tissue microarray format followed by in vitro and in vivo studies using PTC cell lines and nude mice.
  
  
  METHODS
  Expression of FoxM1 and its associated proteins were investigated in Middle Eastern PTC samples by immunohistochemistry. Apoptosis was measured by flow cytometry and immunoblotting. Invasion and migration studies were performed using 8-μm Transwell plates.
  
  
  RESULTS
  FoxM1 was overexpressed in 28.4% of PTC and significantly associated with activated matrix metalloproteinase-9 (MMP-9) (P = 0.0004), X-linked inhibitor of apoptosis protein (XIAP) (P = 0.0024), and B-cell lymphoma-extra large (Bcl-XL) (P = 0.0014) expression. Treatment of PTC cell lines with thiostrepton, an inhibitor of FoxM1, resulted in inhibition of cell viability via induction of apoptosis. In addition, thiostrepton treatment of PTC cells or expression of FoxM1-specific small interfering RNA down-regulated expression of FoxM1 accompanied with decreased MMP-2 and MMP-9 expression. Furthermore, inhibition of FoxM1 attenuated migration and invasion of PTC cells. Interestingly, overexpression of FoxM1 rescued the effects of thiostrepton in PTC cell lines. Finally, treatment of PTC cell line xenografts with thiostrepton resulted in growth inhibition of tumors in nude mice via down-regulation of FoxM1 and MMP-9 and MMP-2.
  
  
  CONCLUSIONS
  Altogether, this is the first study showing that FoxM1 and its associated signaling pathway play a critical role in the pathogenesis of PTC and may be a potential target for therapeutic intervention for treatment of these cancers.
authors: Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, MBC#98-16, P.O. Box 3354, Riyadh 11211, Saudi Arabia.
authors: Maqbool
authors: M
authors: Ahmed
authors: Shahab
authors: S
authors: Uddin
authors: Azhar R
authors: AR
authors: Hussain
authors: Aisha
authors: A
authors: Alyan
authors: Zeenath
authors: Z
authors: Jehan
authors: Fouad
authors: F
authors: Al-Dayel
authors: Abdulrehman
authors: A
authors: Al-Nuaim
authors: Saif
authors: S
authors: Al-Sobhi
authors: Tarek
authors: T
authors: Amin
authors: Prashant
authors: P
authors: Bavi
authors: Khawla S
authors: KS
authors: Al-Kuraya
mesh_terms: D000818:Animals; D002277:Carcinoma; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046888:Tissue Array Analysis; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D020782:Matrix Metalloproteinases