Dataset Information

Regulation of HMGA1 expression by microRNA-296 affects prostate cancer growth and invasion.

ABSTRACT:

Purpose

High-motility group AT-hook gene 1 (HMGA1) is a non-histone nuclear binding protein that is developmentally regulated. HMGA1 is significantly overexpressed in and associated with high grade and advance stage of prostate cancer (PC). The oncogenic role of HMGA1 is at least mediated through chromosomal instability and structural aberrations. However, regulation of HMGA1 expression is not well understood. Identification of microRNA-mediated HMGA1 regulation will provide a promising therapeutic target in treating PC.

Experimental design

In this study, we examined the functional relation between miR-296 and HMGA1 expression in several PC cell lines and a large PC cohort. We further examined the oncogenic property of HMGA1 regulated by miR-296.

Results

Here we report that miR-296, a microRNA predicted to target HMGA1, specifically represses HMGA1 expression by promoting degradation and inhibiting HMGA1translation. Repression of HMGA1 by miR-296 is direct and sequence specific. Importantly, ectopic miR-296 expression significantly reduced PC cell proliferation and invasion, in part through the downregulation of HMGA1. Examining PC patient samples, we found an inverse correlation between HMGA1 and miR-296 expression: high levels of HMGA1 were associated with low miR-296 expression and strongly linked to more advanced tumor grade and stage.

Conclusions

Our results indicate that miR-296 regulates HMGA1 expression and is associated with PC growth and invasion.

SUBMITTER: Wei JJ

PROVIDER: S-EPMC3196617 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Publications

Regulation of HMGA1 expression by microRNA-296 affects prostate cancer growth and invasion.

Wei Jian-Jun JJ Wu Xinyu X Peng Yi Y Shi Guizhi G Basturk Olca O Yang Ximing X Daniels Garrett G Osman Iman I Ouyang Jiangyong J Hernando Eva E Pellicer Angel A Rhim Johng S JS Melamed Jonathan J Lee Peng P

Clinical cancer research : an official journal of the American Association for Cancer Research 20101207 6

<h4>Purpose</h4>High-motility group AT-hook gene 1 (HMGA1) is a non-histone nuclear binding protein that is developmentally regulated. HMGA1 is significantly overexpressed in and associated with high grade and advance stage of prostate cancer (PC). The oncogenic role of HMGA1 is at least mediated through chromosomal instability and structural aberrations. However, regulation of HMGA1 expression is not well understood. Identification of microRNA-mediated HMGA1 regulation will provide a promising ...[more]

PMID: 21138859

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Project description:BackgroundProstate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression.MethodsImmunohistochemistry was performed to determine FRG1 expression in patient samples. FRG1 expression perturbation was done to investigate the effect of FRG1 on cell proliferation, migration and invasion, in DU145, PC3 and LNCaP cells. To understand the mechanism, we checked expression of various cytokines and MMPs by q-RT PCR, signaling molecules by western blot, in FRG1 perturbation sets. Results were validated by use of pharmacological inhibitor and activator and, western blot.ResultsIn prostate cancer tissue, FRG1 levels were significantly reduced, compared to the uninvolved counterpart. FRG1 expression showed variable effect on PC3 and DU145 cell proliferation. FRG1 levels consistently affected cell migration and invasion, in both DU145 and PC3 cells. Ectopic expression of FRG1 led to significant reduction in cell migration and invasion in both DU145 and PC3 cells, reverse trends were observed with FRG1 knockdown. In androgen receptor positive cell line LNCaP, FRG1 doesn't affect any of the cell properties. FRG1 knockdown led to significantly enhanced expression of GM-CSF, MMP1, PDGFA and CXCL1, in PC3 cells and, in DU145, it led to higher expression of GM-CSF, MMP1 and PLGF. Interestingly, FRG1 knockdown in both the cell lines led to activation of p38 MAPK. Pharmacological activation of p38 MAPK led to increase in the expression of GM-CSF and PLGF in DU145 whereas in PC3 it led to enhanced expression of GM-CSF, MMP1 and CXCL1. On the other hand, inhibition of p38 MAPK led to reduction in the expression of above mentioned cytokines.ConclusionFRG1 expression is reduced in prostate adenocarcinoma tissue. FRG1 expression affects migration and invasion in AR negative prostate cancer cells through known MMPs and cytokines, which may be mediated primarily via p38 MAPK activation.

Project description:As the second largest gynecological cancer, cervical cancer has been widely reported in recent years in which circular RNA is involved in the disease process. We earlier found that the expression of hsa_circ_0000511 in cervical cancer cells increased significantly, but its role in the process of cervical cancer is not clear. The purpose of this study is to explore its possible mechanisms in cervical cancer. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), cell counting kit-8 assay, Transwell test, cell transfection, RNA pull-down assay and dual-luciferase reporter assay, and Western blot analysis were used to detect the expression and distribution of hsa_circ_0000511 in SiHa and HeLa cells, the ability of invasion and proliferation, and the modulated relationships between hsa_circ_0000511 and hsa-mir-296-5p, hsa-mir-296-5p, and HMGA1. hsa_circ_0000511 had the highest expression in SiHa and HeLa cells, and the expression in the cytoplasm was significantly higher than that in the nucleus, and its expression was not affected by RNase R. When hsa_circ_0000511 was silenced, its expression in SiHa and HeLa cells was significantly decreased; the proliferation, invasion, and migration abilities of the two kinds of cells were significantly enhanced; and the protein expression of E-cadherin was significantly upregulated, while the protein expression of N-cadherin was significantly downregulated. The expression of hsa-mir-296-5p was lower in SiHa and HeLa cells; however, its expression was increased when hsa_circ_0000511 was inhibited and decreased when hsa_circ_0000511 was overexpressed, so did the ability of proliferation, invasion, and migration and the protein expression of E-cadherin. Interestingly, the protein expression of HMGA1 also changed in these two cells when hsa-mir-296-5p was inhibited or overexpressed. Our results indicate that the upregulated hsa_circ_0000511 can inhibit the proliferation, invasion, and migration of SiHa and HeLa cells by regulating hsa-mir-296-5p/HMGA1, suggesting that the hsa_circ_0000511/hsa-mir-296-5p/HMGA1 pathway may be a potential target for the treatment of cervical cancer.

Dataset Information

Regulation of HMGA1 expression by microRNA-296 affects prostate cancer growth and invasion.

Purpose

Experimental design

Results

Conclusions

Publications

Regulation of HMGA1 expression by microRNA-296 affects prostate cancer growth and invasion.

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