Knockdown of c-Met by adenovirus-delivered small interfering RNA inhibits hepatocellular carcinoma growth <i>in vitro</i> and <i>in vivo</i>

Zhang, Shengzhou; Pan, Feiyan; Xu, Jianfeng; Yuan, Jun; Guo, Shanshan; Dai, Gaole; Xue, Bin; Shen, Weishou; Cheng, Wen; Zhao, Donghong; Li, Chao Jun

doi:10.1158/1535-7163.mct-05-0106

Cited by 76 publications

(56 citation statements)

References 47 publications

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“…The expression of cyclin D1, which is a critical regulator of the G 1 -S transition, was markedly blocked by cabozantinib. These results are supported by the study of Zhang and colleagues, who showed that MET knockout induces significant G 1 arrest and a decrease of cyclin D1 in MHCC97L and MCC97H cells (16). Cabozantinib displayed a significant concentration-related antiproliferative effect on MHCC97L and MHCC97H cells at approximately 10 nmol/L, which was accompanied by a reduction of phosphorylation of MET and its downstream effectors STAT3, Akt, and Erk1/2.…”

Section: Discussionsupporting

confidence: 66%

“…Moreover, overexpression of MET has been reported in various types of human cancers, including HCC (13,14). Blocking MET expression by gene therapy reduces cell proliferation, colony formation, and migration in vitro and suppresses tumor growth, angiogenesis, and metastasis in vivo in multiple HCC cell lines (16)(17)(18). Interestingly, emerging evidence demonstrated that tumor vascular pruning caused by inhibition of the VEGF pathway led to the induction of hypoxia and subsequently triggered MET expression, which enhances tumor invasion and metastasis (10,11,19).…”

Section: Introductionmentioning

confidence: 99%

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Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

Xiang

Chen

Ren

et al. 2014

Clinical Cancer Research

203

159

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Purpose: MET signaling has been suggested a potential role in hepatocellular carcinoma (HCC) and associated with prometastasis during antiangiogenesis therapy. We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC. Antitumor effects of cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC cells as well as in vivo models.Experimental Design: Total MET and phosphorylated MET (p-MET) were measured in 29 resected HCC specimens, and correlated with response to sorafenib as postoperative adjuvant therapy. In the second set of experiments using cultured HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib were examined.Results: High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, leading to G 1 -phase arrest. Cabozantinib inhibited tumor growth in p-METpositive and p-MET-negative HCC by decreasing angiogenesis, inhibiting proliferation, and promoting apoptosis, but it exhibited more profound efficacy in p-MET-positive HCC xenografts. Cabozantinib blocked the hepatocyte growth factor (HGF)-stimulated MET pathway and inhibited the migration and invasion of the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model.Conclusions: Patients with HCC with high level of p-MET are associated with resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET by cabozantinib has significant antitumor activities in HCC, and the activation of MET in HCC may be a promising efficacy-predicting biomarker.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

Xiang

Chen

Ren

et al. 2014

Clinical Cancer Research

203

159

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“…In this study, we first confirmed this correlation in three HCC cell lines with differently spontaneous metastatic potential, HepG 2 , MHCC97-L, and HCCLM3. HepG 2 cells exhibited a moderate metastatic potential, whereas HCCLM3 cells were highly invasive as shown by extensive metastases via both s.c. and orthotopic inoculation (26). In agreement with the difference in metastasis potentials, expression of RhoC, in both mRNA and protein levels, was significantly higher in HCCLM3 cell line when compared with HepG2 cell line and MHCC97-L. As previous study has shown that this cell model system can serve as a useful platform for the study of HCC metastasis (24,25).…”

Section: Discussionsupporting

confidence: 81%

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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“…[40][41][42] MET is the receptor for hepatocyte growth factor and several studies have shown that suppression of c-MET results in cell cycle arrest. 43,44 While efficient repression of any one of these targets elicits cell cycle arrest reminiscent of introduction of miR-34 family members, the actual knockdown of these targets by mir-34 microRNAs is minimal (~40%-50%) and not sufficient to induce the observed phenotype. It is more plausible that the robust cell cycle phenotype caused by miR-34 family members is the result of the cumulative effect of weak inhibition of multiple cell cycle genes.…”

Section: Micrornas and Tumor Suppression: Regulation Of Checkpoint Comentioning

confidence: 99%

MicroRNAs and Cell Cycle Regulation

Carleton¹,

Cleary²,

Linsley³

2007

Cell Cycle

322

205

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Knockdown of c-Met by adenovirus-delivered small interfering RNA inhibits hepatocellular carcinoma growth in vitro and in vivo

Cited by 76 publications

References 47 publications

Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

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

MicroRNAs and Cell Cycle Regulation

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