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Eur J Pharmacol. 2018 Jul 5;830:59-67. doi: 10.1016/j.ejphar.2018.04.027. Epub 2018 Apr 25.

Metformin, a first-line drug for type 2 diabetes mellitus, disrupts the MALAT1/miR-142-3p sponge to decrease invasion and migration in cervical cancer cells.

Author information

1
The College of Pharmacy in Guangzhou Medical University, Guangzhou 510150, China; Foshan Maternal and Child Health Research Institute, Affiliated Hospital of Southern Medical University, Foshan 528000, China. Electronic address: xiachenglai@126.com.
2
The College of Pharmacy in Guangzhou Medical University, Guangzhou 510150, China.

Abstract

The molecular mechanisms underlying the anti-neoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. To explore the novel anti-neoplastic mechanisms of metformin, the transwell chamber and wound-healing assays were used to evaluate its effects on the migration and invasion of human cervical cancer cells. Real-time PCR and Western blotting were used to measure the gene and protein expression, respectively, of microRNA (miRNA) miR-142-3p, long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript-1 (MALAT1), and high-mobility group AT-hook 2 (HMGA2). The dual-luciferase reporter assay system was used to examine the direct interaction between miR-142-3p and lncRNA MALAT1 and HMGA2. Immunofluorescence was used to detect the protein expression of HMGA2. In addition, tumor xenografts in a nude mouse model were developed to evaluate the anti-tumor efficacy of metformin. We found that metformin could suppress cervical cancer migration and invasion. During the process of tumor metastasis, miR-142-3p was significantly upregulated, whereas lncRNA MATAL1 and HMGA2 were suppressed by metformin. The binding site that allow the direct interaction between miR-142-3p and MALAT1 were located in the 3' untranslated region (3' UTR) of lncRNA MATAL1 and HMGA2 at base pairs (bp) 4452-5255, while that between miR-142-3p and HMGA2 was located at bp 1562-2521 of HMGA2. Metformin markedly inhibited the growth and angiogenesis of SiHa xenografts in nude mice. In conclusion, this study provides evidence that metformin can prevent the MALAT1/miR-142-3p sponge from developing anti-neoplastic properties in human cervical cancer cells and cervical cancer cell xenografts in nude mice. Thus, our findings demonstrate the novel anti-tumor effects of metformin in cervical cancer.

KEYWORDS:

HMGA2; Metformin; lncRNA MATAL1; miR-142-3p

PMID:
29704494
DOI:
10.1016/j.ejphar.2018.04.027
[Indexed for MEDLINE]

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