RNAi mediated MMP-1 silencing inhibits human chondrosarcoma invasion

Yuan, Ji; Dutton, Charyl M.; Scully, Sean P.

doi:10.1016/j.orthres.2005.04.004

Cited by 33 publications

(36 citation statements)

References 7 publications

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“…Our data further support the role of Frzb in modulating EMT-related events, depending on specific cellular context. Third, several MMPs are additional Wnt target genes that play an important role in promoting sarcoma invasion (25)(26)(27)(28). Thus, we also examined the effects of Frzb and DNLRP5 on MMPs expression.…”

Section: Resultsmentioning

confidence: 99%

Frzb, a Secreted Wnt Antagonist, Decreases Growth and Invasiveness of Fibrosarcoma Cells Associated with Inhibition of Met Signaling

Guo¹,

Xie²,

Rubin³

et al. 2008

Cancer Research

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Soft tissue sarcomas (STS) have a strong propensity for aggressive growth and metastasis. We showed that the secreted Wnt antagonist Frzb exhibited potent antitumor activity against prostate cancer, an epithelial type of malignancy. In this study, we further showed the antitumor efficacy of Frzb in STS, a mesenchymal group of cancer. Frzb transfection of HT1080 ( fibrosarcoma) and SW872 (liposarcoma) cell lines and their conditioned media resulted in a significant reduction in cellular invasion, motility, and colony formation in soft agar compared with vector controltransfected cells. In a xenograft mouse model, Frzb dramatically suppressed tumor growth of HT1080 cells in nude mice. In a tail-vein injection metastatic model, Frzb-transfected HT1080 cells formed fewer and smaller lung nodules than vector control cells. In addition, we identified new mechanisms for Frzb antitumor activities. Frzb reduced c-Met expression and inhibited Met-mediated signaling, associated with up-regulation of epithelial markers (i.e., keratins 8 and 18) and down-regulation of mesenchymal markers (i.e., vimentin, N-cadherin, fibronectin, Slug, and Twist). Similar to Frzb, silencing of c-Met by short hairpin RNA or using a dominant-negative LRP5 receptor also suppressed Met signaling, leading to reduced cellular motility, invasion, and in vivo tumor growth. Given recent studies indicating an important role of c-Met in sarcoma development and progression, our data showed that Frzb expression was significantly inversely correlated with Met expression in both STS cell lines and tissues. These results suggested the usefulness of Frzb in modulating Met signaling as a new treatment strategy for STS. [Cancer Res 2008;68(9):3350-60]

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Section: Resultsmentioning

confidence: 99%

Frzb, a Secreted Wnt Antagonist, Decreases Growth and Invasiveness of Fibrosarcoma Cells Associated with Inhibition of Met Signaling

Guo¹,

Xie²,

Rubin³

et al. 2008

Cancer Research

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“…Consequently, a tumor therapy targeting MMP-2 would be particularly efficacious in the treatment of pancreatic cancer. As a very potent tool, RNAi technology can generate a cellular knockdown of a desired gene utilizing a plasmid-based system that stably expresses siRNA molecules to target specific mRNAs for degradation [9,10] . In this study, we developed a siRNA sequence, when stably integrated into cellular DNA, which can selectively target MMP-2 expression.…”

Section: Discussionmentioning

confidence: 99%

Suppression of matrix metalloproteinase-2 via RNA interference inhibits pancreatic carcinoma cell invasiveness and adhesion

Yuan¹,

Song²,

Wang³

et al. 2009

WJG

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AIM: To i n v e s t i g a t e t h e i n h i b i t o r y e f f e c t s o fRNA interference (RNAi) on expression of matrix metalloproteinase-2 (MMP-2 ) gene and invasiveness and adhesion of human pancreatic cancer cell line, BxPC-3. METHODS:RNAi was performed using the vector (pGPU6)-based small interference RNA (siRNA) plasmid gene silence system to specifically knock down MMP-2 expression in pancreatic cancer cell line, BxPC-3. Four groups of different specific target sequence in coding region of MMP-2 and one non-specific sequence were chosen to construct four experimental siRNA plasmids of pGPU6-1, pGPU6-2, pGPU6-3 and pGPU6-4, and one negative control siRNA plasmid of pGPU6 (-). MMP-2 expression was measured by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Cell proliferation and apoptosis were examined by methyl thiazolyl tetrazolium (MTT) and flow cytometry, respectively. The abilities of adhesion and invasion were detected by cell adhesion assay and cell invasion assay using Transwell chambers. RESULTS:The expression of MMP-2 was inhibited and the inhibitory effects of different sequence varied. pGPU6-1 group had the most efficient inhibitory effect, followed by pGPU6-2 and pGPU6-3 groups.Invasiveness and adhesion were more significantly reduced in pGPU6-1, pGPU6-2 and pGPU6-3 groups as compared with pGPU6 (-) and blank control groups. However, no difference concerning cell proliferation and apoptosis was observed after transfection between experiment groups and control groups. CONCLUSION:RNAi against MMP-2 successfully inhibited the mRNA and protein expression of MMP-2 in the pancreatic cancer cell line, BxPC-3, leading to a potent suppression of tumor cell adhesion and invasion without affecting cell proliferation and apoptosis. These findings suggest that the RNAi approach towards MMP-2 may be an effective therapeutic strategy for the clinical management of pancreatic tumor.

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“…Clinically, surgical resection remains the primary mode of therapy for chondrosarcoma. Due to the absence of an effective adjuvant therapy, this mesenchymal malignancy has a poor prognosis and therefore, it is important to explore a novel and adequate remedy (2).…”

Section: Introductionmentioning

confidence: 99%

Cyr61 increases migration and MMP-13 expression via αvβ3 integrin, FAK, ERK and AP-1-dependent pathway in human chondrosarcoma cells

et al. 2009

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RNAi mediated MMP-1 silencing inhibits human chondrosarcoma invasion

Cited by 33 publications

References 7 publications

Frzb, a Secreted Wnt Antagonist, Decreases Growth and Invasiveness of Fibrosarcoma Cells Associated with Inhibition of Met Signaling

Frzb, a Secreted Wnt Antagonist, Decreases Growth and Invasiveness of Fibrosarcoma Cells Associated with Inhibition of Met Signaling

Suppression of matrix metalloproteinase-2 via RNA interference inhibits pancreatic carcinoma cell invasiveness and adhesion

Cyr61 increases migration and MMP-13 expression via αvβ3 integrin, FAK, ERK and AP-1-dependent pathway in human chondrosarcoma cells

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