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Network modeling identifies molecular functions targeted by miR-204 to suppress head and neck tumor metastasis.

ABSTRACT: Due to the large number of putative microRNA gene targets predicted by sequence-alignment databases and the relative low accuracy of such predictions which are conducted independently of biological context by design, systematic experimental identification and validation of every functional microRNA target is currently challenging. Consequently, biological studies have yet to identify, on a genome scale, key regulatory networks perturbed by altered microRNA functions in the context of cancer. In this report, we demonstrate for the first time how phenotypic knowledge of inheritable cancer traits and of risk factor loci can be utilized jointly with gene expression analysis to efficiently prioritize deregulated microRNAs for biological characterization. Using this approach we characterize miR-204 as a tumor suppressor microRNA and uncover previously unknown connections between microRNA regulation, network topology, and expression dynamics. Specifically, we validate 18 gene targets of miR-204 that show elevated mRNA expression and are enriched in biological processes associated with tumor progression in squamous cell carcinoma of the head and neck (HNSCC). We further demonstrate the enrichment of bottleneckness, a key molecular network topology, among miR-204 gene targets. Restoration of miR-204 function in HNSCC cell lines inhibits the expression of its functionally related gene targets, leads to the reduced adhesion, migration and invasion in vitro and attenuates experimental lung metastasis in vivo. As importantly, our investigation also provides experimental evidence linking the function of microRNAs that are located in the cancer-associated genomic regions (CAGRs) to the observed predisposition to human cancers. Specifically, we show miR-204 may serve as a tumor suppressor gene at the 9q21.1-22.3 CAGR locus, a well established risk factor locus in head and neck cancers for which tumor suppressor genes have not been identified. This new strategy that integrates expression profiling, genetics and novel computational biology approaches provides for improved efficiency in characterization and modeling of microRNA functions in cancer as compared to the state of art and is applicable to the investigation of microRNA functions in other biological processes and diseases.

SUBMITTER: Lee Y

PROVIDER: S-EPMC2848541 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Network modeling identifies molecular functions targeted by miR-204 to suppress head and neck tumor metastasis.

Lee Younghee Y Yang Xinan X Huang Yong Y Fan Hanli H Zhang Qingbei Q Wu Youngfei Y Li Jianrong J Hasina Rifat R Cheng Chao C Lingen Mark W MW Gerstein Mark B MB Weichselbaum Ralph R RR Xing H Rosie HR Lussier Yves A YA

PLoS computational biology 20100401 4

Due to the large number of putative microRNA gene targets predicted by sequence-alignment databases and the relative low accuracy of such predictions which are conducted independently of biological context by design, systematic experimental identification and validation of every functional microRNA target is currently challenging. Consequently, biological studies have yet to identify, on a genome scale, key regulatory networks perturbed by altered microRNA functions in the context of cancer. In ...[more]

PMID: 20369013

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Project description:ObjectiveTo investigate the effect of miR-204 on the invasion and metastasis of breast cancer by targeted regulation of HNRNPA2B1.MethodsThe bioinformatics database was used to obtain data of the expressions of miR-204 in breast cancer patients and the survival rate of the patients. RT-qPCR was used to detect the expression of miR-204 in breast cancer cell lines. The expression vector GV369-miR-204 was used to overexpress miR-204 in MDA-MB-231 cells. Transwell assay was performed to detect the effect of miR-204 on the migration and invasion ability of the breast cancer cells. The key genes (hub genes) of miR-204 were determined by bioinformatics method. A dual luciferase assay was used to analyze the targeting relationship between miR-204 and HNRNPA2B1. The expression of HNRNPA2B1 in MDA-MB-231 cells after miR-204 overexpression was detected by Western blotting, and Transwell assay was used to examine the changes in the cell invasion ability.ResultsThe expression of miR-204 was decreased in both breast cancer tissues, and was significantly lower in breast cancer MDA-MB-231 cells than in MCF-10A cells (P < 0.05). The decreased expression of miR-204 was associated with poorer prognosis of breast cancer patients (P < 0.05). Upregulation of miR-204 in MDA-MB-231 cells significantly inhibited the invasion and migration of the cells (P < 0.05). Analysis of the data from the Starbase revealed that the expression of miR-204-5p was negatively correlated with the expression of HNRNPA2B1, and the expression of HNRNPA2B1 was increased in breast cancer patients (P < 0.05) in association with a poorer prognosis of the patients (P < 0.05). Dual luciferase assay demonstrated that miR-204 could bind to HNRNPA2B1 in a target-specific manner. Western blotting and Transwell assay showed that miR-204 significant inhibited the migration and invasion ability of breast cancer cells by targeting HNRNPA2B1 (P < 0.05).ConclusionsmiR-204 expression is decreased in breast cancer tissues and cells, and its overexpression can inhibit the invasion and metastasis of breast cancer cells by targeted regulation of HNRNPA2B1.

Project description:BackgroundLung cancer is a leading cause of cancer-related mortality worldwide and non-small-cell lung carcinoma (NSCLC) is responsible for almost 80% of lung cancer-related deaths. Identifying novel molecules that can repress the invasiveness and metastasis of lung cancer will facilitate the development of new antilung cancer strategies. The aim of this study is to determine the roles of NUAK1 (a downstream of Akt) and miR-204 in the invasiveness and metastasis of NSCLC and to reveal the correlation between NUAK1 and miR-204.MethodsThe expression of NUAK1 in primary human NSCLC tissues was evaluated by immunohistochemistry. Real-time PCR was employed to measure the expression level of miR-204. The effect of NUAK1 and miR204 on the prognosis of NSCLC patients was evaluated by log-rank test. The siRNA transfection was used to manipulate the expression levels of NUAK1 and miR204 in cancer cells. Chemotaxis assay, Scratch assay, and Matrigel invasion assay were performed to evaluate the migration and invasion of cells. Cellular F-actin measurement was used to measure F-actin polymerisation in lung cancer cells. Western blot was used to detect the expression levels of corresponding proteins. The Luciferase assay and RNA immunoprecipitation were used to confirm the actual binding site of miR-204 to 3'UTR of NUAK1.ResultsIncreased expression of NUAK1 is correlated with the invasiveness and metastasis of human NSCLC. Knockdown of NUAK1 inhibited cell migration and invasion. In addition, this study showed that NUAK1 influenced mTOR phosphorylation and induced the phosphorylation of p70S6K1 and eukaryotic initiation factor 4E-binding protein1 (4E-BP1), two downstream targets of mTOR in NSCLC cells. At the same time, decreased expression of miR-204 promoted NSCLC progression and, contrarily, manipulated upregulation of miR-204-inhibited cell migration and invasion. There is clinical relevance between miR-204 downregulation and NUAK1 upregulation in human NSCLC. Furthermore, we found that miR-204 inhibited NSCLC tumour invasion by directly targeting and downregulating NUAK1 expression. Finally, our data suggested that the downregulation of miR-204 was due to hypermethylation of its promoter region.ConclusionsOur results indicate that NUAK1 is excessively expressed in NSCLC and plays important roles in NSCLC invasion. The miR-204 acts as a tumour suppressor by inhibiting NUAK1 expression in NSCLC. Both NUAK1 and miR-204 may serve as potential targets of NSCLC therapy.

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Network modeling identifies molecular functions targeted by miR-204 to suppress head and neck tumor metastasis.

Publications

Network modeling identifies molecular functions targeted by miR-204 to suppress head and neck tumor metastasis.

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