Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma

Bellovin, David I.; Simpson, Kaylene J.; Danilov, Tatyana A.; Maynard, Elizabeth; Rimm, David L.; Oettgen, Peter; Mercurio, Arthur M.

doi:10.1038/sj.onc.1209682

Cited by 120 publications

(108 citation statements)

References 27 publications

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“…A similar result was reported in breast carcinoma SUM-159 cell line, which revealed a compensatory relationship between RhoA and RhoC (27). As two Rho isoforms, RhoA and RhoC, share high sequence similarity, it is possible that they share similar feedback regulation or signaling pathway, which resulted in this compensation (28).…”

Section: Discussionsupporting

confidence: 64%

Inhibition of Invasion and Metastasis of Hepatocellular Carcinoma Cells via Targeting RhoC In vitro and In vivo

Wang

Wu²,

Fěng³

et al. 2008

Clinical Cancer Research

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Purpose: Hepatocellular carcinoma (HCC) is one of the most deadly human cancers because of its high incidence of metastasis. Our previous work identified a strong correlation between increased expression of RhoC and HCC metastasis. Here, we investigate to define the role of RhoC in HCC metastasis. Furthermore, we sought to determine whether inhibition of the expression of RhoC might block the metastasis of HCC in vivo. Experimental Design: A stable retroviral small interfering RNA approach was employed to selectively knockdown the expression of RhoC in vitro and in vivo. Invasion and migration assay, MTT and fluorescence-activated cell sorting analysis, Rho activity assay, and immunofluorescence staining were carried out to characterize RhoC in vitro. An anti-RhoC retroviral gene delivery BALB/c nude mice model was established to investigate whether knockdown of the expression of RhoC might inhibit the metastasis of HCC in vivo. Results: We confirmed the correlation of RhoC expression and metastatic potentials of HCC cell lines.We also showed that suppression of RhoC expression resulted in inhibition of invasion and migration without an apparent effect on cell survival and proliferation in HCCLM3 cells. Furthermore, a similar effect of RhoC on autotaxin-induced invasion of HCCLM3 cells was also observed. Significantly, we successfully adopted an HCC metastatic mouse model that allowed us to show that knockdown of the RhoC expression resulted in inhibition of metastasis of HCC in vivo for the first time. Conclusions: Our results show a critical role of RhoC in metastasis of HCC, implicating RhoC as a potential therapeutic target to block HCC metastasis.Hepatocellular carcinoma (HCC) is one of the most common malignancies in Asia and Africa, especially in China (1, 2). During the past decade, the long-term survival remains unsatisfactory because of a high incidence of recurrence and metastasis after the hepatic resection, with a 5-year actuarial recurrence rate of 75% to 100% reported in the literature (3). Thus, the inhibition of invasion and metastasis is of great importance in the HCC therapies.Available information indicates that invasion and metastasis is to a large extent attributable to the ability of cell migration (4, 5). Rho-GTPases, members of Ras superfamily of small GTPases, shuttle between inactive GDP-bound and active GTPbound form and exhibit intrinsic GTPase activities. Activation of the Rho protein leads to the assembly of the actin-myosin contractile filaments into focal adhesion complexes that lead to cell polarity and facilitate motility (6). Recently, RhoC has attracted interest because its increased expression has been linked to increased invasion in breast, melanoma, pancreatic, colon, bladder, hepatocellular, non-small cell lung carcinoma, and primary gastric tumor or cell lines (7 -13). Our previous study revealed that RhoC was a prognostic marker with HCC and its expression was correlated with invasion and metastasis of HCC (14 -16). Interestingly, a recent study using RhoCdefic...

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Section: Discussionsupporting

confidence: 64%

Inhibition of Invasion and Metastasis of Hepatocellular Carcinoma Cells via Targeting RhoC In vitro and In vivo

Wang

Wu²,

Fěng³

et al. 2008

Clinical Cancer Research

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“…The authors also observed that inhibition of RhoA gene expression increased the invasive capacity of the MCF-7 cells. Analogous effects were observed in colon cancer (6). Taken together, the findings of previous studies and the present study, indicate that knockdown of the RhoC gene may inhibit the TGF-β1-induced invasiveness of SiHa cells.…”

Section: Discussionsupporting

confidence: 71%

“…In addition, EMT is characterized by alterations in the expression of a series of biomarkers, in particular, reduced E-cadherin and increased Vimentin expression levels. Ras homolog gene family, member C guanosine triphosphatase (RhoC GTPase) is an important member of the Rho-GTPase family, which regulates actin cytoskeleton reorganization during cellular motility, and actively participates in the EMT process (4)(5)(6). However, the role of RhoC in the process of EMT has remained to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

RhoC is essential in TGF-β1 induced epithelial-mesenchymal transition in cervical cancer cells

Qian

Cai

et al. 2015

Oncology Letters

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Abstract. Epithelial-mesenchymal transition (EMT) is a critical process in the promotion of epithelial tumor progression and metastasis. The present study aimed to investigate the role of Ras homolog gene family, member C (RhoC) guanosine triphosphatase (GTPase) in transforming growth factor (TGF)-β1 induced EMT. EMT occurred in human cervical carcinoma SiHa cells following TGF-β1 stimulation for 4 days, as demonstrated by the appearance of mesenchymal morphology, reorganization of the actin cytoskeleton, reduced E-cadherin expression and increased Vimentin expression, which was associated with increased RhoC expression and activity. However, EMT was not observed in cells that were pretreated with RhoC siRNA prior to TGF-β1 stimulation. Downregulation of RhoC 4 days following TGF-β1 stimulation was not able to reverse the existing EMT. In addition, TGF-β1 promoted the invasion of the control SiHa cells but not that of the cells in which RhoC was downregulated. In conclusion, RhoC expression is activated by TGF-β1, and sufficient RhoC expression levels are essential for TGF-β1-induced EMT.

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“…These GTPases have been implicated in the progression of tumors from a broad range of cellular origins, and analyses at both the RNA and protein level have correlated their increased expression with tumor progression. Several Rho GTPases have been shown to regulate diverse signal transduction pathways and are involved in a variety of biological processes, including cell morphology, motility, proliferation, and apoptosis [11][12][13] . It has been known that gastric carcinogenesis is a multistep process with morphological progression involving multiple genetic and epigenetic events.…”

Section: Discussionmentioning

confidence: 99%

RhoA and RhoC -siRNA inhibit the proliferation and invasiveness activity of human gastric carcinoma by Rho/PI3K/Akt pathway

Sun

Tong²,

He³

et al. 2007

WJG

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AIM:To evaluate the effects of adenovirus-mediated gene transfer of RhoA siRNA and RhoC siRNA on proliferation and invasion of SGC7901 cells by Rho/ PI3K/Akt pathway. METHODS:Plasmid of RhoA siRNA and RhoC siRNA were constructed and transfected into SGC7901 cells. siRNA and LY294002 (PI3K inhibitor) were designed as the control group. The mRNA and protein expressions of RhoA and RhoC were respectively detected with RT-PCR and western blotting. In order to find out the changes of proliferation and invasion power of SGC7901 cell lines, we analyzed the data by MTT, Boyden chamber and evaluated apoptosis of cell with flow cytometry. We treated BALB /C nude mice with RhoA and RhoC-siRNA, and tumor control rate (%) in nude mice was calculated. RESULTS:R h o A a n d R h o C s i R N A t ra n s fe c t i o n s specifically down-regulated the corresponding mRNA and protein levels in SGC7901 Cells.The experiment of permeated artificial basal membrane showed that the invasion power of SGC7901 cell lines are on the decline after treatment of Ad-RhoA and RhoC-siRNA (12.64 ± 3.27 vs 87.38 ± 17.38, P < 0.

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Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma

Cited by 120 publications

References 27 publications

Inhibition of Invasion and Metastasis of Hepatocellular Carcinoma Cells via Targeting RhoC In vitro and In vivo

Inhibition of Invasion and Metastasis of Hepatocellular Carcinoma Cells via Targeting RhoC In vitro and In vivo

RhoC is essential in TGF-β1 induced epithelial-mesenchymal transition in cervical cancer cells

RhoA and RhoC -siRNA inhibit the proliferation and invasiveness activity of human gastric carcinoma by Rho/PI3K/Akt pathway

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