Abstract
The small Rho GTPases regulate important cellular processes that affect cancer metastasis, such as cell survival and proliferation, actin dynamics, adhesion, migration, invasion and transcriptional activation. The Rho GTPases function as molecular switches cycling between an active GTP-bound and inactive guanosine diphosphate (GDP)-bound conformation. It is known that Rho GTPase activities are mainly regulated by guanine nucleotide exchange factors (RhoGEFs), GTPase-activating proteins (RhoGAPs), GDP dissociation inhibitors (RhoGDIs) and guanine nucleotide exchange modifiers (GEMs). These Rho GTPase regulators are often dysregulated in cancer; however, the underlying mechanisms are not well understood. MicroRNAs (miRNAs), a large family of small non-coding RNAs that negatively regulate protein-coding gene expression, have been shown to play important roles in cancer metastasis. Recent studies showed that miRNAs are capable of directly targeting RhoGAPs, RhoGEFs, and RhoGDIs, and regulate the activities of Rho GTPases. This not only provides new evidence for the critical role of miRNA dysregulation in cancer metastasis, it also reveals novel mechanisms for Rho GTPase regulation. This review summarizes recent exciting findings showing that miRNAs play important roles in regulating Rho GTPase regulators (RhoGEFs, RhoGAPs, RhoGDIs), thus affecting Rho GTPase activities and cancer metastasis. The potential opportunities and challenges for targeting miRNAs and Rho GTPase regulators in treating cancer metastasis are also discussed. A comprehensive list of the currently validated miRNA-targeting of small Rho GTPase regulators is presented as a reference resource.
Highlights
Cancer progression is highlighted by changes in cancer cells that promote aggressiveness allowing cells to acquire a greater metastatic potential
It is well established that the activities of small Rho GTPases are tightly regulated mainly by the following four groups of regulators: guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), guanosine diphosphate (GDP) dissociation inhibitors (GDIs) and guanine nucleotide exchange modifiers (GEMs) [4–7]
We focused on recent exciting findings showing that miRNAs play important roles in regulating Rho GTPase regulators (RhoGEFs, Rho GTPase-activating proteins (RhoGAPs), Rho GTPase GDP dissociation inhibitors (RhoGDIs)), eventually affecting small Rho GTPase activities and cancer metastasis
Summary
Cancer progression is highlighted by changes in cancer cells that promote aggressiveness allowing cells to acquire a greater metastatic potential. Once cancer cells in the primary tumor gain the ability to invade the surrounding tissue, motile cells pass through the basement membrane and the extracellular matrix (ECM) penetrating into the lymphatic or vascular circulation. These motile cells travel through the circulatory system until they arrest at a different locations, extravasate through the vascular basement membrane and the ECM into the new environment where they gain epithelial characteristics and form a secondary or metastatic lesion. Rho GTPase regulators has only recently become a focused topic in cancer metastasis studies. We focused on recent exciting findings showing that miRNAs play important roles in regulating Rho GTPase regulators (RhoGEFs, RhoGAPs, RhoGDIs), eventually affecting small Rho GTPase activities and cancer metastasis.
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