Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the lack of expression of activated Smad2.
OBJECTIVE
Transforming growth factor beta (TGF-beta) regulates cell growth and differentiation, in normal squamous epithelium, via specific TGF-beta receptors and intracellular signaling molecules (Smads). We have previously observed that TGF-beta type II receptor (TbetaR-II) expression decreases in squamous cell carcinomas as tumors become less differentiated and more biologically aggressive. However, a small fraction of tumors remain TbetaR-II positive. In this article, we examine the integrity of the other members of the TGF-beta-signaling machinery, the Smad proteins.


METHODS
Thirteen archived head and neck squamous cell carcinomas were selected from the files of the Pathology Department of the H. Lee Moffitt Cancer Center. Protein immunoexpression was quantitated by image analysis in the context of histopathological parameters. Mutation analysis of the MADR2/Smad2 gene was also performed.


RESULTS
In both TbetaR-II-positive and TbetaR-II-negative tumors, expression of the non-TGF-beta-specific Smads (4, 6, and 7) was variable, whereas expression of the pathway-specific Smad2 was lost in 38% of the tumors. Expression of the activated, phosphorylated form of this molecule, Smad2-P, was lost in approximately 70% of the tumors. No abnormal mRNA expression and no mutations in the MADR2/Smad2 gene were observed.


CONCLUSIONS
These results suggest that multiple defects in TGF-beta signaling, both at the receptor and postreceptor level, may play a role in the oncogenesis of head and neck squamous cell carcinoma.
Muro-Cacho
C A
CA
Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 33612, USA. antoniaT@moffitt.usf.edu
Rosario-Ortiz
K
K
Livingston
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S
Muñoz-Antonia
T
T
D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein; D051905:Smad6 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497802:SMAD6 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051905:Smad6 Protein; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta