Rnd3/RhoE Is down-regulated in hepatocellular carcinoma and controls cellular invasion

Abstract

We performed a review of public microarray data that revealed a significant down-regulation of Rnd3 expression in hepatocellular carcinoma (HCC), as compared to nontumor liver. Rnd3/RhoE is an atypical RhoGTPase family member because it is always under its active GTP-bound conformation and not sensitive to classical regulators. Rnd3 down-regulation was validated by quantitative real-time polymerase chain reaction in 120 independent tumors. Moreover, Rnd3 down-expression was confirmed using immunohistochemistry on tumor sections and western blotting on human tumor and cell-line extracts. Rnd3 expression was significantly lower in invasive tumors with satellite nodules. Overexpression and silencing of Rnd3 in Hep3B cells led to decreased and increased three-dimensional cell motility, respectively. The short interfering RNA-mediated down-regulation of Rnd3 expression induced a loss of E-cadherin at cell-cell junctions that was linked to epithelial-mesenchymal transition through the up-regulation of the zinc finger E-box binding homeobox protein, ZEB2, and the down-regulation of miR-200b and miR-200c. Rnd3 knockdown mediated tumor hepatocyte invasion in a matrix-metalloproteinase-independent, and Rac1-dependent manner. Conclusion: Rnd3 down-regulation provides an invasive advantage to tumor hepatocytes, suggesting that RND3 might represent a metastasis suppressor gene in HCC. (HEPATOLOGY 2012;55:1766-1775 H epatocellular carcinoma (HCC) is the main primary malignancy of the liver worldwide. 1 Its overall poor prognosis is the result of high rates of postoperative recurrence and metastasis incidence. Intrahepatic metastases, especially venous metastases, are hallmark features of HCC progression. The escape of carcinoma cells from the tumor may be influenced by a permissive liver microenvironment and a gain of invasive abilities of tumor cells. Many data suggest that the latter involves dedifferentiation of epithelial cells, which occurs by loss of cell polarity and cell-cell contacts and the concomitant acquisition of migratory and invasive features, referred to as the epithelial-mesenchymal transition (EMT). 2 Although recent evidence suggest that hepatocellular EMT plays a pivotal role in the dissemination of malignant hepatocytes during HCC progression, the underlying molecular mechanisms remain to be characterized. 3,4 Ras homolog (Rho) GTPases, including RhoA, Rac1, and cell division cycle 42 (Cdc42), are the main regulators of the actin cytoskeleton and therefore general modulators of cellular processes important for tumor biology. Moreover, deregulated Rho GTPase signaling was reported to play an important role in the initiation

miR-200b and miR-200c as Prognostic Factors and Mediators of Gastric Cancer Cell Progression

“…Several studies support our results. For example, miR-200b and miR-200c are downregulated in hepatocellular carcinoma and can attenuate cellular invasion (38). miR-200b and miR-200c regulate epithelial-to-mesenchymal transition in bladder cancer cells and reverse resistance to epidermal growth factor receptor therapy by targeting ERRFI-1 (31).…”

Effect of Galium verum aqueous extract on growth, motility and gene expression in drug-sensitive and -resistant laryngeal carcinoma cell lines

“…The role of RND3/RhoE in cancer and metastasis is still unclear; controversial results concerning the expression have been published. While RND3 has been shown to be downregulated in hepatocellular carcinoma (43) or prostate carcinoma (44) it has been reported to be upregulated in nonsmall cell lung cancer (45) or colon carcinoma (46). In vitro RND3 expression has been associated with melanoma cell migration and invasive outgrowth (47).…”

RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition

“…5 In contrast, Rnd3/RhoE downregulation controls cellular invasion in hepatocellular carcinoma. 7 RhoGTPases have a dynamic role in EMT, 8 such as RhoA and RhoC in colon carcinoma 9 and amoeboid-mesenchymal transition, where Rac1 activation triggers a mesenchymal phenotype, 10 whereas RhoA regulates the highly contractile amoeboid migration via the ROCK-myosin II signaling axis. 11 The RhoB protein is distinguishable from its homologs RhoA and RhoC.…”