Loss of RhoB Expression Promotes Migration and Invasion of Human Bronchial Cells Via Activation of AKT1

Abstract

Lung cancer is the leading cause of cancer-related death worldwide, mainly due to its highly metastatic properties. Previously, we reported an inverse correlation between RhoB expression and the progression of the lung cancer, occurring between preinvasive and invasive tumors. Herein, we mimicked the loss of RhoB observed throughout lung oncogenesis with RNA interference in nontumoral bronchial cell lines and analyzed the consequences on both cell transformation and invasion. Down-regulation of RhoB did not modify the cell growth properties but did promote migration and invasiveness. Furthermore, RhoB depletion was accompanied by modifications of actin and cell adhesion. The specific activation of the Akt1 isoform and Rac1 was found to be critical for this RhoB-mediated regulation of migration. Lastly, we showed that RhoB down-regulation consecutive to KRasV12 cell transformation is critical for cell motility but not for cell proliferation. We propose that RhoB loss during lung cancer progression relates to the acquisition of invasiveness mediated by the phosphatidylinositol 3-kinase (PI3K)/AKT and Rac1 pathways rather than to tumor initiation. [Cancer Res 2009;69(15):6092-9]

RETRACTED: The Pseudogene DUXAP8 Promotes Non-small-cell Lung Cancer Cell Proliferation and Invasion by Epigenetically Silencing EGR1 and RHOB

“…Moreover, RhoB loss could induce Rac1-dependent mesenchymal cell invasion in lung cells through the control of PP2A activity, 29 and promote the invasion of human bronchial cells via the activation of AKT1. 42 Furthermore, Mazieres et al 43 also reported that the loss of RhoB expression was induced via epigenetic regulation by histone deacetylation in lung cancer, whereas we found that LSD1 recruited by DUXAP8-mediated histone demethylation also contributed to RHOB loss of expression in NSCLC cells. Interestingly, rescue experiments demonstrated that the pseudogene DUXAP8 exerts oncogenic function in a manner partly dependent on the repression of RHOB and EGR1 expression in NSCLC cells.…”

A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration

“…Our results showed that miR-21 activates Akt1/mTORC1-mediated cyclin D1 translation by inhibiting Rhob. While Rhob has been shown to inhibit Akt1 (22,23), to our knowledge, it was not previously known that this effect of Rhob results in inhibition of cyclin D1 translation.…”

“…Although Rhob had not been implicated in the regulation of cyclin D1 expression, several lines of evidence suggested this possibility. First, Rhob inhibits activating phosphorylation of Akt1 (22,23). Then, activated Akt1 regulates cyclin D1 expression through mTORC1 (24,25).…”

RhoB regulates uPAR signalling

“…RhoB has previously been implicated in regulating cell adhesion in other cell types. For example, macrophages and fibroblasts from RhoB-null mice have defective adhesion and spreading (Liu et al, 2001;Wheeler and Ridley, 2007), and RhoB depletion inhibits adhesion of human lung epithelial cells (Bousquet et al, 2009). In macrophages, RhoB has been postulated to affect adhesion by affecting surface levels of b-integrins (Wheeler and Ridley, 2007).…”

“…RhoB is often considered a tumour suppressor because its expression is downregulated in some cancers, and this has been linked to its role in stimulating apoptosis (Huang and Prendergast, 2006;Vega and Ridley, 2008;Bousquet et al, 2009). By contrast, RhoB can either stimulate or inhibit cancer migration or invasion depending on the cellular context.…”