B lymphocyte-induced maturation protein 1 (Blimp1) is a master regulator of B cell differentiation, and controls migration of primordial germ cells. Recently we observed aberrant Blimp1 expression in
breast cancer cells resulting from an NF-κB RelB to Ras signaling pathway. In order to address the question of whether the unexpected expression of Blimp1 is seen in other epithelial-derived
tumors, we selected
lung cancers as they are frequently driven by Ras signaling. Blimp1 was detected in all five
lung cancer cell lines examined and shown to promote
lung cancer cell migration and invasion. Interrogation of microarray datasets demonstrated elevated BLIMP1
RNA expression in
lung adenocarcinoma,
pancreatic ductal carcinomas, head and neck
tumors as well as in
glioblastomas. Involvement of Ras and its downstream
kinase c-Raf was confirmed using mutant and
siRNA strategies. We next addressed the issue of mechanism of Blimp1 activation in
lung cancer. Using knockdown and ectopic expression, the role of the Activator
Protein (AP)-1 family of
transcription factors was demonstrated. Further,
chromatin immunoprecipitation assays confirmed binding to identified
AP-1 elements in the BLIMP1 promoter of ectopically expressed c-Jun and of endogenous
AP-1 subunits following serum stimulation. The propeptide domain of
lysyl oxidase (LOX-PP) was identified as a
tumor suppressor, with ability to reduce Ras signaling in
lung cancer cells. LOX-PP reduced expression of Blimp1 by binding to c-Raf and inhibiting activation of
AP-1, thereby attenuating the migratory phenotype of
lung cancer cells. Thus, Blimp1 is a mediator of Ras/Raf/AP-1 signaling that promotes cell migration, and is repressed by LOX-PP in
lung cancer.