Nuclear factor-kappaB is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma.
- Additional Document Info
- View All
We reported previously that transcription factor nuclear factor (NF)-kappaB is constitutively activated in human and murine squamous cell carcinomas (SCCs). The role of NF-kappaB in the cumulative changes in gene expression with transformation and progression of the murine SCC Pam 212 and after switching off NF-kappaB by a dominant negative inhibitor kappaB mutant (IkappaBalphaM) was explored by profiling with a 15,000-element cDNA micoarrray. Remarkably, NF-kappaB modulated the expression of >60% of the 308 genes differentially expressed between normal keratinocytes and metastatic SCCs. NF-kappaB directly or indirectly modulated expression of programs of genes functionally linked to proliferation, apoptosis, adhesion, and angiogenesis. Among these, changes in expression of cyclin D1, inhibitor of apoptosis-1, mutant Trp53, and beta-catenin detected with modulation of NF-kappaB by microarray were confirmed by Western and Northern blot. NF-kappaB DNA binding motifs were detected in the promoter of approximately 63% of genes showing increased expression and 33% of the genes showing decreased expression. The ACTACAG motif implicated in the NF-kappaB-dependent down-regulation of mRNA expression of MyoD and Sox9 was detected in the coding portion of about 15% of genes showing increased or decreased expression. Inactivation of NF-kappaB inhibited malignant phenotypic features including proliferation, cell survival, migration, angiogenesis, and tumorigenesis. These results provide evidence that NF-kappaB is an important modulator of gene expression programs that contribute to the malignant phenotype of SCC.
author list (cited authors)
Loercher, A., Lee, T. L., Ricker, J. L., Howard, A., Geoghegen, J., Chen, Z., ... Van Waes, C.
complete list of authors
Loercher, Amy||Lee, Tin Lap||Ricker, Justin L||Howard, April||Geoghegen, Joel||Chen, Zhong||Sunwoo, John B||Sitcheran, Raquel||Chuang, Eric Y||Mitchell, James B||Baldwin, Albert S||Van Waes, Carter