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MiR-639 Expression Is Silenced by DNMT3A-Mediated Hypermethylation and Functions as a Tumor Suppressor in Liver Cancer Cells.

ABSTRACT: Emerging evidence has indicated that abnormal methylation of DNA contributes to hepatocarcinogenesis. However, the regulatory mechanisms are not well known. Here, we revealed that microRNA-639 (miR-639) expression is downregulated in liver cancer tissues and cells. The repression of miR-639 expression was attributed to hypermethylation in its promoter region, and DNA methyltransferase (DNMT3A) was found to mediate this hypermethylation. Repression of miR-639 expression promoted cell growth and migration/invasion in vitro and the growth of tumors in xenograft mouse models. Furthermore, miR-639 bound to the 3' UTR of both MYST2 and ZEB1 and suppressed their expression. MYST2 promoted the growth of liver cancer cells and ZEB1 facilitated the migration/invasion of liver cancer cells. Ectopic expression of MYST2 and ZEB1 counteracted the repression of malignancy induced by miR-639, which coincided with the reciprocal correlation between miR-639 and MYST2 and ZEB1 expression in clinical hepatocellular carcinoma (HCC) tissues. Thus, DNMT3A-mediated hypermethylation suppressed miR-639 expression, derepressing the expression of MSYT2 and ZEB1, which promoted tumorigenesis of liver cancer. These findings may shed light on the mechanism of abnormal expression of miRNAs involved in the malignancy of liver cancer and provide new biomarkers for liver cancer.

SUBMITTER: Xiao J

PROVIDER: S-EPMC7001092 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Previous microRNA (miR) microarray analysis revealed that miR?218 is downregulated in cervical cancer tissues. The present study aimed to further evaluate the expression of miR?218 in cervical cancer specimens, determine the association between its expression with disease progression, and investigate the roles of miR?218 in cervical cancer cells. Tissue specimens were obtained from 80 patients with cervical squamous cell carcinoma, 30 patients with high?grade cervical intraepithelial neoplasia [(CIN) II/III] and 15 patients with low?grade CIN (CINI); in addition, 60 plasma samples were obtained from patients with cervical cancer, and 15 normal cervical tissue specimens and 30 plasma samples were obtained from healthy women. These samples were used for analysis of miR?218 expression via reverse transcription?-quantitative PCR. In addition, tumor cells were transfected with miR?218 mimics, human papillomavirus (HPV)16 E6/E7 small interfering RNA, or their respective negative controls to determine the viability, colony formation, migration and invasion of cells using MTT, colony formation, wound healing and Transwell assays, respectively. Target genes of miR?218 were bioinformatically predicted and analyzed using Gene Ontology (GO) terms. The results revealed that miR?218 was downregulated in the tumor tissues and plasma of patients with cervical cancer, with expression associated with the advanced clinicopathological characteristics of patients, including HPV positivity, tumor size, blood vessel invasion and lymph node metastasis. Furthermore, miR?218 overexpression reduced tumor cell viability and xenograft growth, and suppressed tumor cell migration and invasion. HPV was detected in 75% of the 80 patients with cervical cancer, and HPV positivity was inversely associated with miR?218 expression. In addition, bioinformatics analysis predicted that roundabout guidance receptor 1 (ROBO1) was a target gene of miR?218; miR?218 overexpression significantly reduced ROBO1 levels. Furthermore, GO analysis revealed that ROBO1 was involved in regulating cell proliferation, adhesion and migration, and the cell cycle. In conclusion, the findings of the present study suggested that miR?218 may possess antitumor activities in cervical cancer.

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MiR-639 Expression Is Silenced by DNMT3A-Mediated Hypermethylation and Functions as a Tumor Suppressor in Liver Cancer Cells.

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