Nuclear factor-kappaB is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma. Academic Article uri icon

abstract

  • 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.

published proceedings

  • Cancer Res

author list (cited authors)

  • Loercher, A., Lee, T. L., Ricker, J. L., Howard, A., Geoghegen, J., Chen, Z., ... Van Waes, C.

citation count

  • 145

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

publication date

  • September 2004