Abstract
BackgroundA functional role of microRNAs (miRNAs or miRs) in neoplasia and metastasis is becoming clear, and the miR-200 family has received much attention for potentially regulating tumor progression. The miRNAs of this family have been shown to suppress epithelial-mesenchymal transition, and their down-regulation in some tumors promotes invasion and metastasis. Interestingly, while miR-200 is down-regulated in some cancers, it is up-regulated in others.Principal FindingsWe show that levels of miR-200 are increased in melanoma cell lines compared to normal melanocytes and that miR-200 family members play a role in determining modes of tumor cell migration. Individual tumor cells can invade in either elongated, “mesenchymal-type” or rounded, “amoeboid-like” modes and these two modes of invasion are inter-convertible [1]. In melanoma cell lines, expression of miR-200 members does not suppress invasion but rather leads to a switch between modes of invasion. MicroRNA-200c results in a higher proportion of cells adopting the rounded, amoeboid-like mode of invasion, while miR-200a results in a protrusion-associated elongated mode of invasion. Functional target identification studies suggest that the morphological effects of miR-200c may be mediated by reduced expression of MARCKS, which has been linked to formation of cell protrusions. In contrast miR-200a reduces actomyosin contractility, a feature of rounded morphology.SignificanceOverall our findings call into question the general role of miR-200 in suppressing invasion and metastasis, and highlight novel distinguishing characteristics of individual miR-200 family members.
Highlights
Melanoma is a highly aggressive human cancer refractory to most treatments
In order to examine expression of miR-200 members in melanoma, we examined expression of miR200a and -200c using quantitative PCR in a panel of melanoma cell lines compared to normal human melanocytes using miR-30b* as a control as we found its levels were relatively invariant across the melanocytes and melanoma cell line panel (Fig. S1)
For these studies the cells were plated on a thick deformable layer of collagen-I because this substrate mimics aspects of a true 3D matrix and represents a more physiologic environment for studies of melanoma cell migration [1]
Summary
Melanoma is a highly aggressive human cancer refractory to most treatments. Progression from benign hyperplastic melanocytes to more aggressive disease occurs when tumor cells begin to break down and invade through the basement membrane, and subsequently migrate into the collagen-rich dermis [2]. It has become clear that cancer cells have multiple modes of cell migration during tissue invasion: collective, individual elongated or ‘‘mesenchymal-type,’’ and individual rounded or ‘‘amoeboidtype’’ [1,3,4] The latter two modes of individual cell migration are determined in large part by the balance of Rho and Rac small GTPase signalling. There is negative feedback between these two signalling pathways, with Rho-kinase inhibiting the mesenchymal mode and Rac inhibiting the rounded form of migration [1] This interplay allows for dynamic signalling and survival pathway dependence, and plasticity or switching between different morphologies allows cancer cells to invade using distinct pathways to adapt to different environments [4]. While miR-200 is down-regulated in some cancers, it is up-regulated in others
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