Liposarcoma can be an aggressive, debilitating and fatal malignancy. In this study, we identifed microRNAs (miRNAs) associated with the differentiation status of liposarcoma to gain insight into the basis for its progression. miRNA expression profiles determined in human tumors and normal fat specimens identified a de-differentiated tumor expression signature consisting of 35 miRNAs. Deregulated miRNA expression was confirmed in a second independent sample cohort. The miR-155 was the most overexpressed miRNA and functional investigations assigned an important role in the growth of de-differentiated liposarcoma cell lines. Transient or stable knockdown of miR-155 retarded tumor cell growth, decreased colony formation and induced G1-S cell cycle arrest in vitro and blocked tumor growth in murine xenografts in vivo. We identified casein kinase 1α (CK1α) as a direct target of miR-155 control which enhanced β-catenin signaling and cyclin D1 expression, promoting tumor cell growth. In summary, our results point to important functions for miR-155 and β-catenin signaling in progression of liposarcoma, revealing mechanistic vulnerabilities that might be exploited for both prognostic and therapeutic purposes.
Triple-negative breast cancer (TNBC) is an incurable disease with the highest mortality rates among all breast cancer subtypes. Currently, there is no FDA-approved targeted therapies for TNBC. Significant genetic heterogeneity with six genetically defined sub-groups is considered the major reason for treatment failures and high mortality rates in TNBC patients and has been the major limitation in the identification of common molecular targets and development of targeted therapies for this cancer. Recently, interest in the development of non-coding miRNA based therapeutics has increased significantly. miRNA molecules are short, non-coding RNAs that have emerged as critical regulators of gene expression, affecting a multitude of biological processes, including cell proliferation, survival, motility, and tumorigenesis, by acting as oncogenes or tumor suppressors. Recently, first in human miRNA-targeted therapeutics were found safe and well tolerated in phase I clinical trials, suggesting that miRNA based therapeutic interventions may provide novel therapeutic options, especially for TNBC patients. However, successful clinical application of miRNA-based therapeutics requires development of safe and effective nano-delivery systems. To identify potential molecular targets we extensively analyzed miRNA databases and recently discovered that miR-329 expression is associated with significantly longer survival in patients with TNBC. More important, we found that miR-329 expression is lost or significantly reduced in the majority of TNBC cell lines. We demonstrated that in vitro expression of miR-329 significantly suppressed cell proliferation, invasion and migration. To identify molecular mechanism of miR-329 based therapy we utilized 5 different target prediction algorithms and identified that miR-329 has a binding site at 3'-UTR of EF2K gene which encodes Eukaryotic Elongation factor-2 kinase (EF2K). We found that EF2K is significantly upregulated in TNBC patients and is associated with shorter overall survival in TNBC patients. Remarkably, silencing of EF2K by siRNA recapitulated the effects of ectopic expression of miR-329 mimic and successfully suppressed growth and invasion of various TNBC cells. Furthermore, in vivo therapeutic delivery of miR-329 mimic incorporated albumin-based nanoparticles led to significant tumor suppressive effects in multiple TNBC xenograft models (MDA-MB-231 and MDA-MB-436) in mice. Importantly, albumin-based miR-329 nano-therapy in mice did not lead to any detectable side effects during the therapy, suggesting that miR-329 based therapy is safe and clinically feasible approach. Currently, we are conducting luciferase-based gene reporter assay to demonstrate that miR-329 specifically binds to 3'-UTR of EF2K mRNA and inhibits EF2K expression. We are also analyzing the tumors collected after albumin based nanoparticles-miR-329 treatment for miR-329 expression and EF2K downregulation as well as intra-tumoral proliferation markers (Ki67) and apoptosis by TUNEL. Based on clinical significance and our preliminary data, we conclude that miR-329 acts as a tumor suppressor in TNBC, and its reduced expression leads to expression of EF2K signaling. In addition, miR-329-based nano-therapy provides a safe and significant anti-tumor efficacy and may be a potential therapy for TNBC. Citation Format: Goknur Kara, Nermin Kahraman, Emir Baki Denkbas, George Calin, Bulent Ozpolat. MiR-329 mimic based nano-therapy inhibits growth and progression of triple negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5985.
Background MicroRNAs (miRNAs) play an important role in the regulation of tumorigenesis and metastatic process. MiR-21 is an oncomiR that is overexpressed by breast cancer tumor tissue and is associated with high tumor grade and negative hormone receptor status. MiR-21 can control angiogenesis by regulating vascular endothelial growth factor (VEGF) as well as the expression and secretion of basic fibroblast growth factor (bFGF). MiR-19a is a member of the miR-17-92 family that was shown to suppress breast cancer cell proliferation. As angiogenesis factors act as attractants of circulating tumor cells (CTCs), a strong predictor of overall survival in metastatic breast cancer (MBC), we investigated the relationship between CTC count, levels of VEGF and bFGF, and the expression of miR-21 and miR-19a in sera of MBC patients. Methods RNA was extracted from sera collected from 33 MBC patients and 10 healthy donors (HD) using Total RNA purification Kit (Norgene Biotek Corporation, ON, Canada). The expression levels of miR-21, miR-19a and miR-192 were evaluated in triplicate by qRT-PCR using the TaqMan MicroRNA Assay (Applied Biosystems, Foster City, CA). Mir-192 was used to normalize the expression levels of miR-21 and miR-19a. The fold-change values were calculated using 2-DCt, where DCt= mean CTtarget-miRNA - mean CTmiR-192. CTCs were detected by CellSearch System (Veridex LLC, Warren, NJ). Serum VEGF and bFGF were determined using a multiplex bead assay (Millipore, Billerica, MA). Mann-Whitney U test was used to compare the miRNAs expression level between MBC patients and HD. Spearman's correlation was used to determine the association between the expression of miRNAs and growth factors. Results There was a significantly higher median level of miR-21 in MBC patients compared with HD (22.8 versus 7.2, P=0.003), while the expression level of miR-19a was similar for both groups. On average, the relative abundance of miR-21 in sera (ratio of MBC versus HD) is 3.1-fold overexpression. Furthermore, levels of miR-21 was positively correlated with the serum levels of VEGF (Spearman Rho= 0.364; P= 0.038) and bFGF (Spearman Rho= 0.367; P = 0.036). CTCs were detected in 23 patients, ranged from 1 to 134 per 7.5 mL of peripheral blood. Patients with no CTCs had a significantly higher median level of miR-19a than patients with no CTC (6.5 vs 2.8, P =0.047). Conclusion Our results support the notion that miR-21 overexpression may play a role in angiogenesis and metastasis by upregulating VEGF and bFGF in MBC. Undetectable CTC count may be related to overexpression of miR-19a, an epigenetic suppressor of breast tumor proliferation. Whereas overexpression of miR-19a may limit the tumor cells from entering the peripheral circulation, increasing miR-21 in the serum could accelerate the disease progression by promoting angiogenesis in MBC patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-09-01.
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