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Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling.

ABSTRACT: The activation of cancer-associated fibroblasts (CAFs) is a key event in tumor progression, and alternative extracellular matrix (ECM) proteins derived from CAFs induce ECM remodeling and cancer cell invasion. Here we found that miR-200 s, which are generally downregulated in activated CAFs in breast cancer tissues and in normal fibroblasts (NFs) activated by breast cancer cells, are direct mediators of NF reprogramming into CAFs and of ECM remodeling. NFs with downregulated miR-200 s displayed the traits of activated CAFs, including accelerated migration and invasion. Ectopic expression of miR-200 s in CAFs at least partially restored the phenotypes of NFs. CAF activation may be governed by the targets of miR-200 s, Fli-1 and TCF12, which are responsible for cell development and differentiation; Fli-1 and TCF12 were obviously elevated in CAFs. Furthermore, miR-200 s and their targets influenced collagen contraction by CAFs. The upregulation of fibronectin and lysyl oxidase directly by miR-200 or indirectly through Fli-1 or TCF12 contributed to ECM remodeling, triggering the invasion and metastasis of breast cancer cells both in vitro and vivo. Thus, these data provide important and novel insights into breast CAF activation and ECM remodeling, which trigger tumor cell invasion.

SUBMITTER: Tang X

PROVIDER: S-EPMC4815985 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesTo explore the correlation between tumor endothelial marker 1 (TEM1) and matrix metalloproteinase 2 (MMP-2) in uterine sarcoma and their roles in the progression of uterine sarcoma.MethodsUterine leiomyosarcoma (uLMS, n = 25) and uterine leiomyoma (n = 25) specimens were collected from a total of 50 patients. Immunohistochemistry assay was conducted to determine the expression of TEM1, MMP-2 and MMP-9. TEM1 over expression (hTEM1) and low expression (shRNA-TEM1) MES-SA cell lines were established as in vitro uterine sarcoma models. MMP-2 mRNA, protein expression and enzymatic activity were verified using qPCR, Western blot and gelatin zymography respectively. MMP-2 expression was downregulated using MMP-2 siRNA in hTEM1 MES-SA cells to better study the role of MMP-2. The invasive and migratory capacities of hTEM1, shRNA-TEM1, and hTEM1 treated with MMP-2 siRNA MES-SA cells were determined using transwell assays. Extracellular matrix (ECM) remodeling mediated by TEM1 was examined using cell-ECM adhesion and fluorescent gelatin-ECM degradation assays. The immunofluorescence of F-actin was examined to analyze the formation of invadopodia. Subcutaneous and intraperitoneal xenografts were established to validate the role of TEM1 in promoting uterine sarcoma metastasis.ResultsTEM1 and MMP-2 were expressed in 92% (n = 23) and 88% (n = 22) of uterine leiomyosarcoma specimens, respectively. Both TEM1 and MMP-2 were highly expressed in 100% (n = 17) of high stage (III-IV) uterine leiomyosarcoma specimens. In addition, TEM1 expression was positively correlated with MMP-2 expression in uterine leiomyosarcoma. The successful establishment of in vitro uterine sarcoma models was confirmed with qPCR and Western blotting tests. TEM1 promoted the invasion and metastasis of uterine sarcoma in vivo and in vitro. MMP-2 expression and activity were up-regulated in hTEM1 cells but down-regulated in shRNA-TEM1 cells. Importantly, MMP-2 knockdown impaired the invasive and migratory capacity of hTEM1 cells. TEM1 promoted ECM remodeling by increasing cell-ECM adhesion and ECM degradation. TEM1 overexpression also induced the formation of invadopodia.ConclusionTEM1 was co-expressed and positively correlated with MMP-2 in uterine leiomyosarcoma specimens. In addition, both TEM1 and MMP-2 were associated with tumor development. TEM1 promoted uterine sarcoma progression by regulating MMP-2 activity and ECM remodeling.

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Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling.

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