TGF-β-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells

Kim, Eun-Sook; Kim, Mi-Sung; Moon, Aree

doi:10.3892/ijo.25.5.1375

Cited by 162 publications

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“…The overexpression of MMP-2 and MMP-9 correlates with the invasive behavior of many cancers including breast, cervical, pancreatic and prostate. [24][25][26] The secretion of proteinases that have the capacity to degrade basement membrane/basal lamina components would certainly seem to favor metastasis.…”

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confidence: 99%

Retracted: RNAi‐mediated downregulation of urokinase plasminogen activator receptor and matrix metalloprotease‐9 in human breast cancer cells results in decreased tumor invasion, angiogenesis and growth

Kunigal

Lakka

Gondi

et al. 2007

Intl Journal of Cancer

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The serine protease urokinase-type plasminogen activator (uPA) plays a significant role in tumor cell invasion and metastasis when bound to its specific receptor, uPAR (also known as CD87). In addition to the uPA-uPAR system, matrix metalloproteinases (MMPs) are involved in tumor cell invasion and metastasis. In this study, we achieved specific inhibition of uPAR and MMP-9 using RNAi technology. We introduced small interfering RNA to downregulate the expression of uPAR and MMP-9 (pUM) in breast cancer cell lines (MDA MB 231 and ZR 75 1). In vitro angiogenesis studies indicated a decrease in the angiogenic potential of the treated cells; in particular, a remarkable decrease was observed in the cells treated with bicistronic construct (pUM) in comparision to the controls. Additionally, bicistronic construct inhibited the formation of capillary-like structures in in vivo models of angiogenesis. Similarly, the invasive potential and migration decreased dramatically when treated with the bicistronic construct as shown by matrigel invasion and migration assays. These results suggest a synergistic effect from the simultaneous downregulation of uPAR and MMP-9. We also assessed the levels of phosphorylated forms of MAPK, ERK and AKT signaling pathway molecules and found reduction in the levels of these molecules in cells treated with the bicistronic construct as compared to the control cells. Furthermore, targeting both uPAR and MMP-9 totally regressed orthotopic breast tumors in nude mice. In conclusion, our results provide evidence that the simultaneous downregulation of uPAR and MMP-9 using RNAi technology may provide an effective tool for breast cancer therapy. ' 2007 Wiley-Liss, Inc.Key words: RNAi; uPAR; MMP-9; invasion; angiogenesis; tumor growthThe hallmark of tumor progression is uncontrolled extracellular matrix (ECM) degradation, which plays a critical role in the loss of basement membrane, thereby aiding in tumor metastasis. The aggressiveness of a tumor is primarily dependent on its ability to invade adjacent tissue and to metastasize to distant sites. During the process of cancer invasion and metastasis, natural barriers such as interstitial connective tissue and basement membranes must be degraded. It is now widely believed that the breakdown of these barriers is catalyzed by proteolytic enzymes released from the primary tumor. Therefore, the breakdown or dissolution of the basement membrane by tumor cells is considered a reliable sign of malignancy in vivo and a relevant index of malignant behavior in vitro. The degradation of the basement membrane by ECM-degrading proteases leading to tumor invasion is now well established. Although it is widely accepted that a proteolytic cascade consisting of enzymes of the plasmin-generating system and the family of matrix metalloproteinases (MMPs) are involved, 1,2 it is still unclear which enzymes of those expressed are actively involved in the invasive process and whether different tumors utilize specific proteolytic pathways for matrix degradation and invasion.Oth...

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confidence: 99%

Retracted: RNAi‐mediated downregulation of urokinase plasminogen activator receptor and matrix metalloprotease‐9 in human breast cancer cells results in decreased tumor invasion, angiogenesis and growth

Kunigal

Lakka

Gondi

et al. 2007

Intl Journal of Cancer

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“…Second, TGF-b cannot inhibit MCF10A cell proliferation but, instead, can induce cell migration and invasion. 31 The expression level of WWP1 in MCF10A is low; furthermore, WWP1 overexpression promotes the MCF10A cell proliferation. It is clear that TGF-b resistance in MCF10A is not mediated by WWP1 overexpression.…”

Section: Discussionmentioning

confidence: 99%

The amplified WWP1 gene is a potential molecular target in breast cancer

Chen

Zhou

Ross

et al. 2007

Intl Journal of Cancer

126

136

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The amplification of the q21 band of chromosome 8 (8q21) occurs in a large percentage of breast cancers. WWP1, an HECT domain-containing ubiquitin E3 ligase located in the 8q21 region, negatively regulates the TGF-b tumor suppressor pathway. To characterize the role of WWP1 in breast cancer, we analyzed WWP1 gene dosage and expression level as well as WWP1's function. A copy number gain of WWP1 was found in 51% (18/35) of breast cancer cell lines and in 41% (17/41) of primary breast tumors. Expression of WWP1 mRNA was analyzed with real-time RT-PCR, Northern blot, and Western blot. WWP1 mRNA is upregulated in 58% (19/33) of breast cancer cell lines, and overexpression of WWP1 is significantly correlated with a gene copy number gain. In a panel of cDNA from primary breast tumors and normal tissues, expression of WWP1 in tumors is significantly higher than that in normal tissues. Functionally, RNAi-mediated WWP1 knockdown significantly induced cell growth arrest and apoptosis in the MCF7 and HCC1500 breast cancer cell lines. Consistently, WWP1 inhibition activated caspases. Forced overexpression of WWP1 by the lentiviral system in 2 immortalized breast epithelial cell lines MCF10A and 184B5 promoted cell proliferation. These results suggest that genomic aberrations of WWP1 may contribute to the pathogenesis of breast cancer. ' 2007 Wiley-Liss, Inc.Key words: WWP1; breast cancer; gene amplification; overexpression; apoptosis A copy number gain or loss is a frequent genetic alteration in solid tumors including breast cancer. A copy number gain of 8q21 was detected in a high percentage of familial and sporadic breast tumors.1-3 Although several 8q21 genes, such as TPD52 and E2F5, have been reported to be amplified and overexpressed in breast cancer, 4,5 their roles have not been firmly established in breast tumorigenesis, and the underlying target genes of 8q21 amplification in breast cancer remain to be elucidated.Ubiquitin proteasome pathway (UPP)-mediated protein degradation plays an important role in breast cancer cell proliferation, apoptosis and carcinogenesis.6 Several oncogenic ubiquitin E3 ligases have been identified as diagnosis markers or potential drug targets in human breast cancer.7 For example, Skp2, an F-box protein in the SCF ubiquitin ligase complex, targets the CDK inhibitor p27 kip for degradation and is overexpressed in a subset of breast carcinomas. 8 The ring finger E3 ligase EFP mediates estrogen-induced cell growth and facilitates 14-3-3r tumor suppressor ubiquitination and proteolysis.9 EFP mRNA and protein were reported to be overexpressed and significantly correlated with poor prognosis of breast cancer patients. 10WW domain-containing protein 1 (WWP1) is an HECT (homologous to the E6-associated protein carboxyl terminus) domain-containing E3 ubiquitin ligase. Growing evidence suggests that WWP1 negatively regulates the TGF-b tumor suppressor pathway by mediating the ubiquitination and degradation of TGFb receptor 1 (TbR1), In our previous study, we found that WWP1 is amplified and overe...

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“…Many researchers have shown that TGF-ß induces the expression of MMPs (like MMP-2, MMP-9, MMP-10) in several human cancer cell lines, such as prostate (31), bladder (13), breast (32), endometrial (33), oral (29) and ovarian cancer (12). However, no previous study has investigated a possible correlation between serum levels of MMP-2 and TGF-ß in melanoma.…”

Section: Discussionmentioning

confidence: 99%

Co-regulated expression of matrix metalloproteinase-2 and transforming growth factor-β in melanoma development and progression

Malaponte¹

2010

Oncol Rep

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Abstract. Previous studies have found that matrix metalloproteinase-2 (MMP-2) and transforming growth factor-ß (TGF-ß) can be considered as biomarkers and indices of disease progression in several human cancers. In this study, we investigated the plasma levels of MMP-2 and TGF-ß and their correlation in 49 primary cutaneous melanoma and 10 metastatic melanoma. Plasma MMP-2 and TGF-ß levels in patients with primary melanoma were significantly higher than those of healthy controls. These protein levels were significantly higher in patients with metastatic melanoma. A positive correlation between plasma levels of MMP-2 and TGF-ß in melanoma patients supports the hypothesis that TGF-ß triggers the release of MMP-2. The immunohistochemistry analysis shows that MMP-2 and TGF-ß were highly expressed in tumor tissues as well as in matched plasma samples. This finding suggests that these proteins are released from tumor cells. Overall, our data indicate that MMP-2 and TGF-ß may represent novel diagnostic markers and therapeutic targets in melanoma and the determination of their concentration could be a useful diagnostic and prognostic indicator. TGF-ß, leading the tissue invasion mediated by MMP-2, is a strong promoter of tumor progression. Therefore, reducing or blocking the activity of TGF-ß may represent a promising target in therapeutic strategies for limiting the growth of melanoma.

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TGF-β-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells

Cited by 162 publications

References 0 publications

Retracted: RNAi‐mediated downregulation of urokinase plasminogen activator receptor and matrix metalloprotease‐9 in human breast cancer cells results in decreased tumor invasion, angiogenesis and growth

Retracted: RNAi‐mediated downregulation of urokinase plasminogen activator receptor and matrix metalloprotease‐9 in human breast cancer cells results in decreased tumor invasion, angiogenesis and growth

The amplified WWP1 gene is a potential molecular target in breast cancer

Co-regulated expression of matrix metalloproteinase-2 and transforming growth factor-β in melanoma development and progression

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