Abstract
Simple SummaryWhilst mutations in genes encoding RHO GTPase proteins are rare in different type of cancers, altered expression of several RHO GTPases has been reported in a variety of human malignancies. As key regulators of gene expression, lncRNAs coordinate a wide range of molecular processes, including post-translational regulation through miRNA sponging. The purpose of the present study was to address the current state of knowledge about the lncRNAs involved in the regulation of the expression of the RHO GTPases including RHOA, RHOB, RHOC, RAC1, and CDC42, with a specific focus on the regulatory mechanism of lncRNAs as the molecular sponges of miRNAs. Considering the critical roles of lncRNAs in malignancies, lncRNA-based therapeutics are representing promising approaches in cancer treatment through novel technologies. In this regard, well-characterized examples of lncRNAs associated with tumorigenicity present experimental frameworks for future studies in this rapidly evolving field.RHO GTPases are critical signal transducers that regulate cell adhesion, polarity, and migration through multiple signaling pathways. While all these cellular processes are crucial for the maintenance of normal cell homeostasis, disturbances in RHO GTPase-associated signaling pathways contribute to different human diseases, including many malignancies. Several members of the RHO GTPase family are frequently upregulated in human tumors. Abnormal gene regulation confirms the pivotal role of lncRNAs as critical gene regulators, and thus, they could potentially act as oncogenes or tumor suppressors. lncRNAs most likely act as sponges for miRNAs, which are known to be dysregulated in various cancers. In this regard, the significant role of miRNAs targeting RHO GTPases supports the view that the aberrant expression of lncRNAs may reciprocally change the intensity of RHO GTPase-associated signaling pathways. In this review article, we summarize recent advances in lncRNA research, with a specific focus on their sponge effects on RHO GTPase-targeting miRNAs to crucially mediate gene expression in different cancer cell types and tissues. We will focus in particular on five members of the RHO GTPase family, including RHOA, RHOB, RHOC, RAC1, and CDC42, to illustrate the role of lncRNAs in cancer progression. A deeper understanding of the widespread dysregulation of lncRNAs is of fundamental importance for confirmation of their contribution to RHO GTPase-dependent carcinogenesis.
Highlights
RHO family proteins are GDP/GTP-binding proteins of the RAS superfamily that transduce extracellular signals into intracellular responses
Recognition of Testis developmental related gene 1 (TDRG1) and prostate cancer gene 3 (PCA3) as the two positive regulators of RHOC with the everincreasing number of other RHO GTPase-specific long noncoding RNAs (lncRNAs) strongly indicates their potential contribution with the entire process of RHO GTPase-driven carcinogenesis (Figure 2)
It was revealed that the X-inactive–specific transcript (XIST)-miR-137-RAC1 pathway regulatory axis could be a therapeutic target in the treatment of glioma [214]. These data suggest that dysregulation of network corresponding RAC1, miRNAs, and oncogenic lncRNAs needs to be carefully examined to increase our understanding about potential oncogenic drivers associated with the RHOC-related tumorigenesis (Figure 2)
Summary
RHO family proteins are GDP/GTP-binding proteins of the RAS superfamily that transduce extracellular signals into intracellular responses. Activated RHO GTPases bind to their downstream effectors and thereby regulate diverse cellular processes (Figure 1), including the reorganization of the actin cytoskeleton and thereby cell adhesion, polarity, and migration [17,18] They are associated with the control of various biological processes, such as cell trafficking, wound healing, immune response, embryonal development, and neuronal plasticity [19,20]. While most studies on RHO GTPase-associated tumorigenesis have narrowly focused on cytoskeletalrelated biological processes and canonical pathways, the contribution of noncanonical mechanisms has been observed [16] These mechanisms include the regulation of autocrine and paracrine loops critical for remodeling of the tumor microenvironment and tumor growth [25], nucleolar functions connected with either efficient ribogenesis or the suppression of nucleolar stress in cancer cells [26,27,28], the regulation of both the centrosome and chromosome stability [27,29], the regulation of the YAP/TAZ pathway [30], and the recruitment of pathways to avoid antitumoral immune responses [31].
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