The transcription factor HOXB7 regulates ERK kinase activity and thereby stimulates the motility and invasiveness of pancreatic cancer cells.

HOX genes encode transcription factors that function as sequence-specific transcription factors that are involved in cellular proliferation, differentiation, and death. The aim of this study was to investigate the role of a HOX family protein, HOXB7, in the motility and invasiveness of pancreatic cancer cells. We previously identified a HOXB7 transcript that is one of a number of transcripts that are preferentially translated in membrane protrusions in pancreatic cancer cells. Immunocytochemistry showed that HOXB7 was localized to the cell protrusions of migrating pancreatic cancer cells. Knockdown of HOXB7 by transfection with HOXB7-specific siRNA decreased these protrusions and inhibited the motility and invasiveness of the cells. Transfection of a HOXB7-rescue construct into the HOXB7-knockdown cells restored peripheral actin structures in cell protrusions and abrogated the HOXB7 knockdown-induced decrease in cell protrusions. It is generally accepted that the Rho family of GTPases regulate the organization of actin filaments and contribute to the formation of cell protrusions. The levels of the active Rho GTPases were not influenced by HOXB7 in the cells; however, HOXB7 knockdown decreased the level of phosphorylated ERK1/2. This inactivation of ERK1/2 decreased cell protrusions, thereby inhibiting the invasiveness of pancreatic cancer cells. Further investigation showed that HOXB7/ERK1/2 signaling selectively stimulated JNK and HSP27 phosphorylation and thereby increased the motility and invasiveness of pancreatic cancer cells. These results suggested that HOXB7 stimulates ERK1/2 phosphorylation and provided evidence that HOXB7, besides its role in transcriptional regulation, also promotes cell motility and invasiveness.