In both normal and neoplastic cells, the actin cytoskeleton drives cell motility, and many molecules regulating actin remodelling have been implicated in this process [1
]. Polymerization of actin filaments near the cell membrane leads to the formation of filopodia, in which microfilaments are parallel and linearly arrayed, or lamellipodia, in which microfilaments are branched; actin polymerization-mediated protrusion of the leading edge drives the movement of the cell [4
]. Shuttling RNAs to the leading edge of cells can ensure a ready supply of proteins that are needed when processes are quickly formed [5
]. Thus, β-actin mRNA, as well as mRNAs coding for proteins in the Arp2/3 complex that generate actin branching, is localized in minutes to the leading edge of fibroblasts induced to migrate [6
]. Disruption of β-actin mRNA localization was found to cause a loss of polarity coupled with a loss of migration in different cell types [8
cVICKZ1, a β-actin mRNA binding protein (also termed ZBP-1 [9
]), has been isolated from chick fibroblasts and is involved in intracellular localization of β-actin mRNA to the leading edge of migrating fibroblasts [10
]. In the last few years, it has become clear that cVICKZ1 is a member of a family of highly related RNA binding proteins expressed in different organisms and cell types. Strikingly, screens for RNAs and antigens overexpressed in various tumours have ‘fished out’ members of this family. Overexpression of one or more of these proteins has been reported in pancreatic carcinomas [13
], hepatocellular carcinomas [15
], and CRCs [16
] (reviewed in refs 9
). Recently, hVICKZ3 was shown to be a prognostic indicator for metastases in renal cell carcinoma [18
]. In contrast, the protein is either low or not detectable in most normal adult tissues [13
]. A possible function of these proteins in transformed cells has remained unclear.
In the process of analysing intracellular RNA localization in Xenopus
oocytes, we identified and characterized a VICKZ protein homologue, xVICKZ3 (also termed Vg1 RBP) [22
]. We found that in addition to its role in the oocyte, xVICKZ3 plays an essential role in cell migration during Xenopus
embryogenesis: xVICKZ3 localizes to the leading edge of explanted migratory neural crest cells, and reduction of xVICKZ3 expression inhibits normal migration during development [23
]. Not only neural crest, but also roof plate progenitor cells require xVICKZ3 in order to reach their proper destinations. Thus, xVICKZ3 is necessary for the migration of specific cell populations during embryogenesis.
We hypothesized that VICKZ proteins may also be playing a role in neoplastic cell migration. Using a pan-VICKZ antibody, we found that VICKZ proteins are highly expressed in certain types of cancer. An in-depth analysis of one of these types, CRC, revealed that VICKZ expression is tightly correlated with metastasis to lymph nodes, and VICKZ proteins appear to be useful prognostic indicators for CRC. To elucidate the biological function of these proteins in CRC, we examined their distribution and function in a human CRC cell line, SW480. VICKZ proteins localize to the leading edge of SW480 cells and are required for the dynamic cell surface morphology necessary for cell movement. These proteins appear to play an important role in CRC metastasis by trafficking RNAs required for migration to the leading edge of motile cells.