The data presented here supports a role for the miR-200 family in AG-013736 melanoma cell invasion as both miR-200a and miR-200c are up-regulated in melanoma lines and drive different modes of invasion into a physiologic collagen-I matrix. Two miR-200 seed classes have been identified for the two subfamilies, miR-200bc/429 and miR-200a/141, based on one non-identical base within the seed region, and distinctive target predictions for these subfamilies are produced by algorithms such as TargetScan which take into account conservation of microRNA-target UTR complementarity across species. However, many reports have shown the different members of the miR-200 family have similar effects on epithelial-mesenchymal transition. Recently functional differences between these subclasses of miR-200 have been identified, and our findings demonstrate that miRs from different subfamilies have dramatically different effects on cellular morphology in 3D collagen invasion assays. Thus variation in the expression of miR-200 family members in melanoma could lead to plasticity of cell morphology and of mode of migration, conferring on tumor cells the capacity to cope with different milieus in the tumor microenvironment. Previous work shows that the rounded mode of cell movement is favoured at the edge of tumors while within the tumor, tumor cells move in an elongated fashion. The ability of miR-200 to regulate morphological plasticity may be important after dissemination from the tumor as it has been shown that miR200c levels are different in melanoma samples located at primary versus distant metastatic sites. We show that expression of miR-200c in melanoma cells drives the rounded-amoeboid form of cell migration and MARCKS down-regulation. MARCKS is a peripheral membrane protein whose translocation to the cytosol is mediated by PKC-dependent phosphorylation. The PKC-MARCKS axis has been shown to promote dendritic spine formation in hippocampal neurons and formation of protrusive adhesions in the highly motile Wm1617 melanoma line. We show MARCKS knockdown – using transfection of siRNA or of miR-200c – inhibits protrusion formation and results in rounded “amoeboid” morphology. These results with knockdown of MARCKS parallel our previous observations with inhibiting signalling by Rac or its effector WAVE2; inhibition of Rac-driven protrusions results in a round morphology and conversion to the rounded “amoeboid” mode of migration. Thus there seems to be a very tight coupling between inhibiting protrusion formation and adoption of the rounded “amoeboid” mode of migration. Interestingly MARCKS is inactivated in small intestinal adenocarcinoma and decreased MARCKS levels are observed in transformed cell lines. Moreover, over-expression of MARCKS in cancer cells results in decreased proliferation while knockdown has been shown to increase migration. We also show that invasion is not inhibited by miR-200 family members in a physiologic 3D matrix environment, which is in contrast to observations of others using rigid transwell migration chambers.