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

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.

• Authors: Amy Loercher, Tin Lap Lee, Justin L Ricker, April Howard, Joel Geoghegen, Zhong Chen, John B Sunwoo, Raquel Sitcheran, Eric Y Chuang, James B Mitchell, Albert S Baldwin Jr, Carter Van Waes
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 18 Pg. 6511-23 (Sep 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15374962 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CTNNB1 protein, mouse
• Cytoskeletal Proteins
• I-kappa B Proteins
• Inhibitor of Apoptosis Proteins
• NF-kappa B
• Proteins
• RNA, Messenger
• Trans-Activators
• Tumor Suppressor Protein p53
• beta Catenin
• Cyclin D1
• Doxycycline

Topics

• Animals
• Base Sequence
• Carcinoma, Squamous Cell (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Survival (genetics)
• Cell Transformation, Neoplastic (genetics)
• Cyclin D1 (biosynthesis, genetics)
• Cytoskeletal Proteins (biosynthesis, genetics)
• Doxycycline (pharmacology)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• I-kappa B Proteins (genetics)
• Inhibitor of Apoptosis Proteins
• Keratinocytes (metabolism, physiology)
• Mice
• Mice, Inbred BALB C
• NF-kappa B (antagonists & inhibitors, genetics)
• Neovascularization, Pathologic (genetics, pathology)
• Oligonucleotide Array Sequence Analysis
• Promoter Regions, Genetic (drug effects)
• Protein Biosynthesis
• Proteins (genetics)
• RNA, Messenger (biosynthesis, genetics)
• Sequence Homology, Nucleic Acid
• Skin Neoplasms (genetics, metabolism, pathology)
• Trans-Activators (biosynthesis, genetics)
• Tumor Suppressor Protein p53 (biosynthesis, genetics)
• beta Catenin