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MiR-223 suppresses endometrial carcinoma cells proliferation by targeting IGF-1R.

ABSTRACT: MicroRNAs were recently found to participate in oncogenesis and growth of various tumors. We hypothesized that microRNA-223 (miR-223) plays a role in endometrial carcinoma growth. In this study, we transfected RL95-2 cells with lentivirus containing miR-223 precursor to establish a miR-223 over-expression model. Proliferation of the cells was greatly inhibited when miR-223 was over-expressed, and cell cycle progress was blocked in G0/G1 phase. To investigate the mechanisms involved, we scanned the putative target genes of miR-223 using bioinformatics, and confirmed that insulin-like growth factor-1 receptor (IGF-1R) was a functional target of miR-223 using quantitative PCR, Western blot and luciferase reporter assay. Meanwhile, over-expressed miR-223 was found to regulate the expression of IGF-1R by repressing protein translation. Silencing IGF-1R with small interfering RNA resulted in similar effect as miR-223 overexpression. Therefore, our data suggest that miR-223 regulates RL95-2 cells proliferation and cell cycle progress by targeting IGF-1R.

SUBMITTER: Huang K

PROVIDER: S-EPMC4297351 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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MiR-223 suppresses endometrial carcinoma cells proliferation by targeting IGF-1R.

Huang Kai K Dong Xiyuan X Sui Cong C Hu Dan D Xiong Ting T Liao Shujie S Zhang Hanwang H

American journal of translational research 20141122 6

MicroRNAs were recently found to participate in oncogenesis and growth of various tumors. We hypothesized that microRNA-223 (miR-223) plays a role in endometrial carcinoma growth. In this study, we transfected RL95-2 cells with lentivirus containing miR-223 precursor to establish a miR-223 over-expression model. Proliferation of the cells was greatly inhibited when miR-223 was over-expressed, and cell cycle progress was blocked in G0/G1 phase. To investigate the mechanisms involved, we scanned t ...[more]

PMID: 25628794

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Project description:Primary bone tumor, also known as osteosarcoma (OS), is the most common primary malignancy of bone in children and young adults. Current treatment protocols yield a 5-year survival rate of near 70% although approximately 80% of patients have metastatic disease at the time of diagnosis. However, long-term survival rates have remained virtually unchanged for nearly four decades, largely due to our limited understanding of the disease process. One major signaling pathway that has been implicated in human OS tumorigenesis is the insulin-like growth factor (IGF)/insulin-like growth factor-1 receptor (IGF1R) signaling axis. IGF1R is a heterotetrameric α2β2 receptor, in which the α subunits comprise the ligand binding site, whereas the β subunits are transmembrane proteins containing intracellular tyrosine kinase domains. Although numerous strategies have been devised to target IGF/IGF1R axis, most of them have failed in clinical trials due to the lack of specificity and/or limited efficacy. Here, we investigated whether a more effective and specific blockade of IGF1R activity in human OS cells can be accomplished by employing dominant-negative IGF1R (dnIGF1R) mutants. We engineered the recombinant adenoviruses expressing two IGF1R mutants derived from the α (aa 1-524) and β (aa 741-936) subunits, and found that either dnIGF1Rα and/or dnIGF1Rβ effectively inhibited cell migration, colony formation, and cell cycle progression of human OS cells, which could be reversed by exogenous IGF1. Furthermore, dnIGF1Rα and/or dnIGF1Rβ inhibited OS xenograft tumor growth in vivo, with the greatest inhibition of tumor growth shown by dnIGF1Rα. Mechanistically, the dnIGF1R mutants down-regulated the expression of PI3K/AKT and RAS/RAF/MAPK, BCL2, Cyclin D1 and most EMT regulators, while up-regulating pro-apoptotic genes in human OS cells. Collectively, these findings strongly suggest that the dnIGF1R mutants, especially dnIGF1Rα, may be further developed as novel anticancer agents that target IGF signaling axis with high specificity and efficacy.

Dataset Information

MiR-223 suppresses endometrial carcinoma cells proliferation by targeting IGF-1R.

Publications

MiR-223 suppresses endometrial carcinoma cells proliferation by targeting IGF-1R.

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