Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells

Background: The RaI guanine nucleotide-exchange factors (RaIGEFs) serve as key effectors for Ras oncogene transformation of immortalized human cells. RaIGEFs are activators of the highly related RaIA and RaIB small GTPases, although only the former has been found to promote Ras-mediated growth transformation of human cells. In the present study, we determined whether RaIA and RaIB also had divergent roles in promoting the aberrant growth of pancreatic cancers, which are characterized by the highest occurrence of Ras mutations. Results: We now show that inhibition of RaIA but not RaIB expression universally reduced the transformed and tumorigenic growth in a panel of ten genetically diverse human pancreatic cancer cell lines. Despite the apparent unimportant role of RaIB in tumorigenic growth, it was nevertheless critical for invasion in seven of nine pancreatic cancer cell lines and for metastasis as assessed by tail-vein injection of three different tumorigenic cell lines tested. Moreover, both RaIA and RaIB were more commonly activated in pancreatic tumor tissue than other Ras effector pathways. Conclusions: RaIA function is critical to tumor initiation, whereas RaIB function is more important for tumor metastasis in the tested cell lines and thus argues for critical, but distinct, roles of RaI proteins during the dynamic progression of Ras-driven pancreatic cancers.