Fibulin-5 Suppresses Lung Cancer Invasion by Inhibiting Matrix Metalloproteinase-7 Expression

Yue, Wen; Sun, Qi; Landreneau, Rodney J.; Wu, Chuanyue; Siegfried, Jill M.; Yu, Jian; Zhang, Lin

doi:10.1158/0008-5472.can-09-0398

Cited by 90 publications

(109 citation statements)

References 41 publications

(54 reference statements)

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“…The detection of changes in fibulin-5 and EMILIN-1 suggests that microfibril assembly is initiated after only 20 mins reperfusion post-40I in the rodent model. Fibulin-5 expression can also inhibit the expression of MMP-7 (64).…”

Section: Discussionmentioning

confidence: 99%

Quantitative N-linked Glycoproteomics of Myocardial Ischemia and Reperfusion Injury Reveals Early Remodeling in the Extracellular Environment

Parker

Palmisano

Edwards

et al. 2011

Molecular & Cellular Proteomics

104

122

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changes. These were mainly from predicted extracellular matrix and basement membrane proteins that are implicated in cardiac remodeling. Analysis of N-glycans released from myocardial proteins suggest that the observed changes were not due to significant alterations in N-glycan structures. Altered proteins included the collagen-laminin-integrin complexes and collagen assembly enzymes, cadherins, mast cell proteases, proliferation-associated secreted protein acidic and rich in cysteine, and microfibril-associated proteins. The data suggest that cardiac remodeling is initiated earlier during reperfusion than previously hypothesized.

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Section: Discussionmentioning

confidence: 99%

Quantitative N-linked Glycoproteomics of Myocardial Ischemia and Reperfusion Injury Reveals Early Remodeling in the Extracellular Environment

Parker

Palmisano

Edwards

et al. 2011

Molecular & Cellular Proteomics

104

122

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“…The function of Fbln5 in cancer is largely context-dependent. Others have reported that Fbln5 is down-regulated in some cancers; however, these studies focused largely on mRNA expression in tumor lysates and cell lines and on tissue microarray analysis (27,28). In our previous studies, we found that Fbln5 is produced mainly by stromal fibroblasts and endothelial cells, whereas epithelium-derived tumor cells produce essentially no Fbln5 (25).…”

mentioning

confidence: 87%

“…Tumors-Fbln5 is expressed aberrantly in a number of malignancies (21,22,25,27,31,32). Expression analysis of various cell types has identified fibroblasts and endothelial cells as major producers of Fbln5 (25).…”

Section: Fbln5 Expression In Pancreaticmentioning

confidence: 99%

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

Topalovski¹,

Hagopian²,

Wang

et al. 2016

Journal of Biological Chemistry

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The deposition of extracellular matrix (ECM) is a defining feature of pancreatic ductal adenocarcinoma (PDA), where ECM signaling can promote cancer cell survival and epithelial plasticity programs. However, ECM signaling can also limit PDA tumor growth by producing cytotoxic levels of reactive oxygen species. For example, excess fibronectin stimulation of ␣5␤1 integrin on stromal cells in PDA results in reduced angiogenesis and increased tumor cell apoptosis because of oxidative stress. Fibulin-5 (Fbln5) is a matricellular protein that blocks fibronectin-integrin interaction and thus directly limits ECMdriven reactive oxygen species production and supports PDA progression. Compared with normal pancreatic tissue, Fbln5 is expressed abundantly in the stroma of PDA; however, the mechanisms underlying the stimulation of Fbln5 expression in PDA are undefined. Using in vitro and in vivo approaches, we report that hypoxia triggers Fbln5 expression in a TGF-␤-and PI3K-dependent manner. Pharmacologic inhibition of TGF-␤ receptor, PI3K, or protein kinase B (AKT) was found to block hypoxia-induced Fbln5 expression in mouse embryonic fibroblasts and 3T3 fibroblasts. Moreover, tumor-associated fibroblasts from mouse PDA were also responsive to TGF-␤ receptor and PI3K/AKT inhibition with regard to suppression of Fbln5. In genetically engineered mouse models of PDA, therapy-induced hypoxia elevated Fbln5 expression, whereas pharmacologic inhibition of TGF-␤ signaling reduced Fbln5 expression. These findings offer insight into the signaling axis that induces Fbln5 expression in PDA and a potential strategy to block its production.The maintenance of solid tumors relies heavily on cues received from the surrounding environment. The ECM 2 is composed of structural proteins such as FN and collagen, which promote signaling through integrins and receptor tyrosine kinases (1, 2). ECM signaling is modulated by matricellular proteins, which regulate ECM-cell interactions without serving a direct structural function (3-5). The composition of the ECM is dynamic and varies between tumors and tumor types, contributing to intra-and intertumor heterogeneity, which presents challenges for effective therapeutic strategies. Furthermore, mouse studies have revealed anti-and pro-tumorigenic functions for ECM (5-7). In addition to ECM, stromal cells, including endothelial cells, immune cells, and fibroblasts, are present in the tumor microenvironment. These cells contribute to tumor growth, invasion, and chemoresponse (8 -10).During tumor progression, cancer cells release factors that maintain a microenvironment conducive for growth. For example, TGF-␤ is a cytokine expressed in many cancers that enhances the expression of multiple ECM molecules, including but not limited to FN, collagen, elastin, and fibulins (11-13). Fbln5 is a 448-amino acid secretory glycoprotein of the fibulin family of matricellular proteins. Fbln5 is unique among its members as it contains an RGD-integrin binding domain and can ligate a number of integrins (14). Fbln5 is ex...

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“…By contrast, a growing number of studies highlight the antitumor effects caused by Fibulin-5. For instance, Fibulin-5 inhibits invasion and proliferation of the human bladder cancer cell line 5637 (15), and hampers cancer invasion and tumor metastasis of lung cancer cell lines (16,17). Furthermore, Fibulin-5 can inhibit angiogenesis induced by HT1080 (18) and MCA102 (19) fibrosarcoma cell lines.…”

Section: Introductionmentioning

confidence: 99%

Fibulin-5 downregulates Ki-67 and inhibits proliferation and invasion of breast cancer cells

Mohamedi

Fontanil

Solares

et al. 2016

International Journal of Oncology

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Abstract.Fibulins not only function as molecular bridges within the cellular microenvironment but also influence cell behavior. Thus, fibulins may contribute to create a permissive microenvironment for tumor growth but can also stimulate different mechanisms that may impede tumor progression. This is the case with Fibulin-5, which has been shown to display both tumor-promoting and tumor-protective functions by mechanisms that are not totally defined. We show new evidence on the tumor-protective functions displayed by Fibulin-5 in MCF-7, T47D and MDA-MB-231 breast cancer cells including the inhibition of invasion and proliferation capacity and hampering the ability to form mammospheres. Reduction in the level of phosphorylation of Ser residues involved in the nuclear translocation of β-catenin may underlie these antitumor effects. We also found that Fibulin-5 reduces the level of expression of Ki-67, a nuclear protein associated with cell proliferation. Moreover, reduction in Fibulin-5 expression corresponds to an increase of Ki-67 detection in breast tissue samples. Overall, our data provide new insights into the influence of Fibulin-5 to modify breast cancer cell behavior and contribute to better understand the connections between fibulins and cancer.

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Fibulin-5 Suppresses Lung Cancer Invasion by Inhibiting Matrix Metalloproteinase-7 Expression

Cited by 90 publications

References 41 publications

Quantitative N-linked Glycoproteomics of Myocardial Ischemia and Reperfusion Injury Reveals Early Remodeling in the Extracellular Environment

Quantitative N-linked Glycoproteomics of Myocardial Ischemia and Reperfusion Injury Reveals Early Remodeling in the Extracellular Environment

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

Fibulin-5 downregulates Ki-67 and inhibits proliferation and invasion of breast cancer cells

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