Gli1 enhances migration and invasion via up-regulation of MMP-11 and promotes metastasis in ERα negative breast cancer cell lines.
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ABSTRACT:
SUBMITTER: Kwon YJ
PROVIDER: S-EPMC3081062 | 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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Project description:Androgen deprivation therapy (ADT) is the standard treatment for advanced prostate cancer (PCa), yet many patients relapse with lethal metastatic disease. With this loss of androgens, increased cell plasticity has been observed as an adaptive response to ADT. This includes gain of invasive and migratory capabilities, which may contribute to PCa metastasis. Hyperinsulinemia, which develops as a side-effect of ADT, has been associated with increased tumor aggressiveness and faster treatment failure. We investigated the direct effects of insulin in PCa cells that may contribute to this progression. We measured cell migration and invasion induced by insulin using wound healing and transwell assays in a range of PCa cell lines of variable androgen dependency (LNCaP, 22RV1, DuCaP, and DU145 cell lines). To determine the molecular events driving insulin-induced invasion we used transcriptomics, quantitative real time-PCR, and immunoblotting in three PCa cell lines. Insulin increased invasiveness of PCa cells, upregulating Forkhead Box Protein C2 (FOXC2), and activating key PCa cell plasticity mechanisms including gene changes consistent with epithelial-to-mesenchymal transition (EMT) and a neuroendocrine phenotype. Additionally, analysis of publicly available clinical PCa tumor data showed metastatic prostate tumors demonstrate a positive correlation between insulin receptor expression and the EMT transcription factor FOXC2. The insulin receptor is not suitable to target clinically however, our data shows that actions of insulin in PCa cells may be suppressed by inhibiting downstream signaling molecules, PI3K and ERK1/2. This study identifies for the first time, a mechanism for insulin-driven cancer cell motility and supports the concept that targeting insulin signaling at the level of the PCa tumor may extend the therapeutic efficacy of ADT.
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Project description:PurposeThe function of curcumin on the gastric cancer cell line, SGC-7901 is unknown. The present study aimed to observe the effects of curcumin on gastric cancer cells through the Shh and Wnt signaling pathways.MethodsSGC-7901 cells were transfected with si-Gli1 and si-?-catenin siRNA, then cells were stimulated with curcumin and its effects on cell migration, invasion, cytoskeleton remodeling, EMT, apoptosis and cell cycle were investigated by ?transwell assays, immunofluorescence and flow cytometry assays. The interaction between Gli1 and ?-catenin was observed by co-immunoprecipitation.ResultsWe show that curcumin suppressed the expression of Shh, Gli1 and Foxm1 in the Shh signaling pathway, and the expression of ?-catenin in the Wnt signaling pathway in SGC-7901 cells, both in mRNA and protein. As a result, cellular migration, invasion and cytoskeletal remodeling ability decreased. Our results revealed that when stimulated with curcumin, cells showed decreased cellular migration and invasion, while enhanced apoptosis. In addition, curcumin induced cytoskeletal remodeling and S phase cell cycle arrest. The inhibition of Shh and Wnt signaling pathway and the addition of curcumin also inhibited the epithelial–mesenchymal transition process. Furthermore, a physical interaction was observed between Gli1 of the Shh signaling and ?-catenin of the Wnt signaling in these cells, but curcumin inhibited the interaction of these two proteins.ConclusionThe present study indicated that curcumin plays an anti-tumor role through Gli1-?-catenin pathway in gastric cancer SGC-7901 cells.
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Project description:Endometriosis (EMs) is a benign disease with the characteristics of invasion and migration, and its pathogenesis is related to hypoxia. The abnormal activation of glioma-associated oncogene homolog 1 (GLI1) plays an important role in the metastasis of multiple types of tumors. However, it is not clear whether GLI1 regulates the migration and invasion of endometrial stromal cells under hypoxic condition. Therefore, we use comprehensive analysis to explore the effects of hypoxic on GLI1 expression and their regulation on the pathogenesis of EMs. In this study, from immunohistochemistry, RT-qPCR, and western blot analysis, we discovered that the expression of hypoxia-induced factor-1α (HIF-1α) and GLI1 was significantly increased in eutopic and ectopic endometrium of patients with EMs. In human primary eutopic endometrial stromal cells (ESCs), hypoxia can increase the expression of HIF-1α and GLI1 in a time-dependent manner. And hypoxia could promote GLI1 expression in a HIF-1α-dependent manner. Moreover, data from transwell assays manifested that the migration and invasion ability of ESCs was significantly enhanced under hypoxia, and this effect could be reversed by silencing GLI1. Furthermore, the expression of MMP2 and MMP9 was also increased under hypoxia, while silencing GLI1 could reverse this event. In summary, our research verified that GLI1, which activated by hypoxia, may contribute to the migration and invasion of ESCs through the upregulation of MMP2 and MMP9 and can be a novel therapeutic target in EMs.
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