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Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways.

ABSTRACT: Human growth factor receptor-bound protein-7 (GRB7) is a pivotal mediator involved in receptor tyrosine kinase signaling and governing diverse cellular processes. Aberrant upregulation of GRB7 is frequently associated with the progression of human cancers. However, the molecular mechanisms leading to the upregulation of GRB7 remain largely unknown. Here, we propose that the epigenetic modification of GRB7 at the post-transcriptional level may be a crucial factor leading to GRB7 upregulation in ovarian cancers. Methods: The upstream miRNA regulators were predicted by in silico analysis. Expression of GRB7 was examined by qPCR, immunoblotting and immunohistochemical analyses, while miR-193a-3p levels were evaluated by qPCR and in situ hybridization in ovarian cancer cell lines and clinical tissue arrays. MS-PCR and pyrosequencing analyses were used to assess the methylation status of miR-193a-3p. Stable overexpression or gene knockdown and Tet-on inducible approaches, in combination with in vitro and in vivo tumorigenic assays, were employed to investigate the functions of GRB7 and miR-193a-3p in ovarian cancer cells. Results: Both miR-193a-3p and its isoform, miR-193b-3p, directly targeted the 3' UTR of GRB7. However, only miR-193a-3p showed a significantly inverse correlation with GRB7-upregulated ovarian cancers. Epigenetic studies revealed that methylation-mediated silencing of miR-193a-3p led to a stepwise decrease in miR-193a-3p expression from low to high-grade ovarian cancers. Intriguingly, miR-193a-3p not only modulated GRB7 but also ERBB4, SOS2 and KRAS in the MAPK/ERK signaling pathway to enhance the oncogenic properties of ovarian cancer cells in vitro and in vivo. Conclusion: These findings suggest that epigenetic silencing of miR-193a-3p by DNA hypermethylation is a dynamic process in ovarian cancer progression, and miR-193a-3p may be explored as a promising miRNA replacement therapy in this disease.

SUBMITTER: Chen K

PROVIDER: S-EPMC5743558 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Methylation-associated silencing of <i>miR-193a-3p</i> promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways.

Chen Kangmei K Liu Michelle Xin MX Mak Celia Sze-Ling CS Yung Mingo Ming-Ho MM Leung Thomas Ho-Yin TH Xu Dakang D Ngu Siew-Fei SF Chan Karen Kar-Loen KK Yang Huijuan H Ngan Hextan Yuen-Sheung HY Chan David Wai DW

Theranostics 20180101 2

Human growth factor receptor-bound protein-7 (GRB7) is a pivotal mediator involved in receptor tyrosine kinase signaling and governing diverse cellular processes. Aberrant upregulation of GRB7 is frequently associated with the progression of human cancers. However, the molecular mechanisms leading to the upregulation of GRB7 remain largely unknown. Here, we propose that the epigenetic modification of GRB7 at the post-transcriptional level may be a crucial factor leading to GRB7 upregulation in o ...[more]

PMID: 29290818

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Project description:Thyroid cancer (TC) is a frequently occurring malignant tumor with a rising steadily incidence. microRNA (miRNA/miR)‑193a‑3p is an miRNA that is associated with tumors, playing a crucial role in the genesis and progression of various cancers. However, the expression levels of miR‑193a‑3p and its molecular mechanisms in TC remain to be elucidated. The present study aimed to probe the expression of miR‑193a‑3p and its clinical significance in TC, including its underlying molecular mechanisms. Microarray and RNA sequencing data gathered from three major databases, specifically Gene Expression Omnibus (GEO), ArrayExpress and The Cancer Genome Atlas (TCGA) databases, and the relevant data from the literature were used to examine miR‑193a‑3p expression. Meta‑analysis was also conducted to evaluate the association between clinicopathological parameters and miR‑193a‑3p in 510 TC and 59 normal samples from the TCGA database. miRWalk 3.0, and the TCGA and GEO databases were used to predict the candidate target genes of miR‑193a‑3p. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and protein‑protein interaction network enrichment analyses were conducted by using the predicted candidate target genes to investigate the underlying carcinogenic mechanisms. A dual luciferase assay was performed to validate the targeting regulatory association between the most important hub gene cyclin D1 (CCND1) and miR‑193a‑3p. miR‑193a‑3p expression was considerably downregulated in TC compared with in the non‑cancer controls (P<0.001). The area under the curve of the summary receiver operating characteristic was 0.80. Downregulation of miR‑193a‑3p was also significantly associated with age, sex and metastasis (P=0.020, 0.044 and 0.048, respectively). Bioinformatics analysis indicated that a low miR‑193a‑3p expression may augment CCND1 expression to affect the biological processes of TC. In addition, CCND1, as a straightforward target, was validated through a dual luciferase assay. miR‑193a‑3p and CCND1 may serve as prognostic biomarkers of TC. Finally, miR‑193a‑3p may possess a crucial role in the genesis and progression of TC by altering the CCND1 expression.

Dataset Information

Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways.

Publications

Methylation-associated silencing of <i>miR-193a-3p</i> promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways.

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