ETV5 as a regulator of matrix metalloproteinase 2 in human chondrosarcoma

Abstract

Chondrosarcoma is a unique type of bone cancer in that it does not respond to chemotherapy or radiation therapy, and therefore many affected patients die from metastatic disease. Metastasis has been correlated with the upregulation of the matrix metalloproteinase (MMP) family of proteases, which can degrade extracellular components. ETV5 is a transcription factor which has shown to be overexpressed in various types of invasive tumors. We hypothesized that ETV5 regulates MMP2 in human chondrosarcoma with the protease acting as a downstream effector. Gene knock-down of ETV5 in human chondrosarcoma cells reduces MMP2 mRNA expression as well as decreased protein production and significantly decreased MMP2 activity. With plasmid transfected ETV5 upregulation, MMP2 expression is similarly upregulated at the gene expression and protein levels. Data from our bone resorption studies revealed that when a matrix metalloproteinase-2 inhibitor is added to the growth media of chondrosarcoma cells, collagen released from bone chips incubated with the cells decreased by 27%. This data suggests that ETV5 has a significant role in regulating MMP2 expression and therefore matrix resorption in human chondrosarcoma, and thus may be a targetable upstream effector of the metastatic cascade in this cancer. Keywords: bone resorption; transcription factor; gelatinase; metastasis; collagen Chondrosarcoma is a type of bone cancer originating from cartilaginous tissue, and accounts for 25-30% of all cancers originating from the skeletal system. [1][2][3] Chondrosarcoma is a unique type of bone cancer, as it is nonresponsive to chemotherapy or radiation therapy. 2,4-7 Most chondrosarcomas (80-90%) are conventional (primary) chondrosarcomas, 7 which occur in the medullar cavity or at the bone surface. 8 Chondrosarcoma appears most often in the long bones 1,2 but has also been found in the ribs, spine 9 as well as the pelvis and scapula. 1 The current method of treatment is resection of the affected bone, which is not always possible depending on numerous factors including patient comorbidities and the anatomic extent of the tumor within the skeleton and surrounding soft-tissue. 2,5 Metastasis of chondrosarcoma occurs most commonly to the lungs leading to a 50% overall 5-year survival rate 3 and a 30% 10-year survival rate. 4,6 Metastasis is, at least in part, results from the upregulation of proteases within the tumor, which degrade the surrounding tissue and cause dissemination of cancer cells into the bloodstream. 10 Of these proteases, the matrix metalloproteinase (MMP) family can degrade extracellular components including many types of gelatin, elastin, and collagen 10,11 and is commonly associated with more metastatic types of cancers. 12 Specifically, matrix metalloproteinase 2 (MMP2) has been noted to be highly expressed in pancreatic cancer, 13 which lead to poor prognoses. This is partly due to the fact that MMP2 is capable of degrading type-I collagen fragments 10,14 which is abundant in the ECM as well as at the bone surf...

The Epigenetic Regulation of SOX9 by miR‐145 in Human Chondrosarcoma

“…Therefore, the relatively low intrinsic levels of miR‐145 in chondrosarcoma may trigger downstream MMP‐2 overexpression either by allowing SOX9 overexpression, or by directly affecting EVT5 and/or MMP‐2 expression. This is a particularly interesting finding given that we have shown that MMP‐2 is responsible, at least in part, for bone matrix destruction in chondrosarcoma [Power et al, ].…”

Gene Expression Profiling in Peripheral Blood Cells and Synovial Membranes of Patients with Psoriatic Arthritis

“…Interestingly genes that promote these processes resulted up-regulated, i.e. the CUB domain containing protein 1, CDCP1 (FC 3.6) [67]; gelsolin, GSN (FC 3.65) [68]; the fatty acid binding protein 5, FABP5 (FC 12.73) [69], and the ets variant 5, ETV5 (FC 7.03), a pro-invasive transcription factor tought to be involved in bone invasion [70]. …”

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