RNA interference-mediated targeting of urokinase plasminogen activator receptor and matrix metalloproteinase-9 gene expression in the IOMM-lee malignant meningioma cell line inhibits tumor growth, tumor cell invasion and angiogenesis.
نویسندگان
چکیده
Meningiomas are the most commonly occurring tumors of the central nervous system including the brain and spinal cord. Malignant meningiomas are highly aggressive and frequently recur after surgical resection of the tumor. Our previous studies have reported that urokinase plasminogen activator receptor (uPAR) and matrix metalloproteinase-9 (MMP-9) play important roles in tumor progression. In the present study, we have attempted to evaluate the roles of these molecules in the malignant meningioma tumor microenvironment and to determine the effectiveness of using single or bicistronic small interfering RNA constructs for uPAR and MMP-9 on tumor cell proliferation, migration, invasion, angiogenesis and regression of pre-established orthotopic tumors. Transfection of single or bicistronic constructs downregulated uPAR and MMP-9 in meningioma cells compared to controls. A significant reduction in tumor invasion was determined with matrigel gel and spheroid invasion assays in meningioma cells after transfection of these plasmids. Furthermore, downregulation of uPAR and MMP-9 reduced migration of tumor spheroids on vitronectin-coated plates. uPAR and MMP-9 downregulation suppressed capillary network formation, in both in vitro and in vivo models. Also, it is well known that tumor cells manipulate intracellular signaling pathways to aid in various processes involved in tumor progression. Our study revealed that downregulation of uPAR and MMP-9 leads to a decrease in the activation of some of the important enzymes participating in the MAPK and PI3 kinase pathways, which in turn, might decrease cell survival and proliferation. In addition, we analyzed the efficiency of RNAi-mediated targeting of uPAR and MMP-9 in pre-established tumor growth in vivo. We observed a significant regression of pre-established orthotopic tumors upon RNAi-mediated targeting of uPAR and MMP-9. In addition, the present study indicated that targeting both the proteins simultaneously augmented the therapeutic treatment of human meningiomas.
منابع مشابه
uPA/uPAR downregulation inhibits radiation-induced migration, invasion and angiogenesis in IOMM-Lee meningioma cells and decreases tumor growth in vivo.
Meningioma is a well-known tumor of the central nervous system, and is treated by surgical resection and/or radiation. Recently, ionizing radiation has been shown to enhance invasiveness of surviving tumor cells, and several proteolytic enzyme molecules, including urokinase plasminogen activator (uPA), seem to be upregulated after radiation. uPA and its receptor (uPAR) have been strongly implic...
متن کاملRNAi-mediated downregulation of urokinase plasminogen activator and its receptor in human meningioma cells inhibits tumor invasion and growth.
In recent years, RNA interference (RNAi) has emerged as an effective method to target specific genes for silencing. Several groups are actively exploring the use of small interfering RNA (siRNA) for therapeutic applications to treat cancer. Our previous studies have demonstrated the inhibition of various proteases, including serine proteases, cysteine proteases and matrix metalloproteases, via ...
متن کاملPlasminogen Activator Inhibitor-1: The Expression, Biological Functions, and Effects on Tumorigenesis and Tumor Cell Adhesion and Migration
Plasminogen activator inhibitor-1 (PAI-1) is a primary regulator of urokinase-type plasminogen activator (uPA). It inhibits uPA by forming a covalent complex, thus blocking uPA’s interaction with substrates. The half-life of active PAI-1 is < 1 h and it is easily transformed to a more stable inactive latent form. By binding with vitronectin, PAI-1 can be stabilized and remained its activity. PA...
متن کاملTargeting of the β6 gene to suppress degradation of ECM via inactivation of the MAPK pathway in breast adenocarcinoma cells
Integrin ανβ6 has emerged as a potential novel target for anticancer and plays a major role in promoting malignant tumor progression. Recent studies indicate that integrin ανβ6 occurs in many cancers. However, whether and how ανβ6 is regulated by genetic and epigenetic mechanisms in breast cancer remain unknown. In the present study, two different short hairpin RNAs (shRNAs) targeting the β6 ge...
متن کاملRegulation of Colon Carcinoma Cell Invasion by Hypoxia - Inducible Factor 11
Hypoxia-inducible factor 1 (HIF-1) transactivates genes the products of which mediate tumor angiogenesis and glycolytic metabolism. Overexpression of the HIF-1 subunit, resulting from intratumoral hypoxia and genetic alterations, has been demonstrated in common human cancers and is correlated with tumor angiogenesis and patient mortality. Here we demonstrate that hypoxia or HIF-1 overexpression...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- International journal of oncology
دوره 31 1 شماره
صفحات -
تاریخ انتشار 2007