SummaryThe endoplasmic reticulum (ER) is an organelle specialized for the folding and assembly of secretory and transmembrane proteins. ER homeostasis is often perturbed in tumor cells because of dramatic changes in the microenvironment of solid tumors, thereby leading to the activation of an adaptive mechanism named the unfolded protein response (UPR). The activation of the UPR sensor IRE1a has been described to play an important role in tumor progression. However, the molecular events associated with this phenotype remain poorly characterized. In the present study, we examined the effects of IRE1a signaling on the adaptation of glioma cells to their microenvironment. We show that the characteristics of U87 cell migration are modified under conditions where IRE1a activity is impaired (DN_IRE1). This is linked to increased stress fiber formation and enhanced RhoA activity. Gene expression profiling also revealed that loss of functional IRE1a signaling mostly resulted in the upregulation of genes encoding extracellular matrix proteins. Among these genes, Sparc, whose mRNA is a direct target of IRE1a endoribonuclease activity, was in part responsible for the phenotypic changes associated with IRE1a inactivation. Hence, our data demonstrate that IRE1a is a key regulator of SPARC expression in vitro in a glioma model. Our results also further support the crucial contribution of IRE1a to tumor growth, infiltration and invasion and extend the paradigm of secretome control in tumor microenvironment conditioning.
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
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