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MicroRNA-498 promotes proliferation and migration by targeting the tumor suppressor PTEN in breast cancer cells.

ABSTRACT: Triple negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis and high mortality rate. The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays an important role in cell proliferation and cell migration by negatively regulating the PI3K/Akt pathway. PTEN is downregulated by microRNAs in multiple cancers. However, few microRNAs have been reported to directly target PTEN in TNBC. In this study, microRNAs predicted to target PTEN were screened by immunoblotting and luciferase reporter assays. Expression levels of microRNA-498 (miR-498) were measured by TaqMan microRNA assays. We performed clonogenic, cell cycle and scratch wound assays to examine the oncogenic role of miR-498. We demonstrated that miR-498 directly targeted the 3'untranslated region of PTEN mRNA and reduced PTEN protein levels in TNBC cells. Compared with the non-tumorigenic breast epithelial cell line MCF-10A, TNBC cell lines overexpressed miR-498. Moreover, miR-498 promoted cell proliferation and cell cycle progression in TNBC cells in a PTEN-dependent manner. Suppressing miR-498 overexpression impaired the oncogenic effects of miR-498 on cell proliferation and cell migration. This study identified a novel microRNA (miR-498) overexpressed in TNBC cells and its oncogenic role in suppressing PTEN. These results provide new insight into the downregulation of PTEN and indicate a potential therapeutic target for treating TNBC.

SUBMITTER: Chai C

PROVIDER: S-EPMC6148990 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBreast cancer is the most common cancer type in female. As microRNAs play vital role in breast cancer, this study aimed to explore the molecular mechanism and clinical value of miR-21 in breast cancer.MethodsqRT-PCR was performed to detect miR-21 levels in plasma of 127 healthy controls, 82 benign breast tumor, 252 breast cancer patients, as well as in breast cancer cell lines. Transwell and wound healing assay were used to analyze breast cancer metastasis in response to miR-21 inhibitor. Colony formation and eFluor™ 670 based flow cytometric analysis were used to test breast cancer proliferation following miR-21 inhibitor treatment. Leucine zipper transcription factor-like 1 (LZTFL1), the target gene of miR-21 was predicted by MIRDB, TargetScan 5.1, PicTar and miRanda. Survival analysis of LZTFL1 levels in breast cancer prognosis was estimated with the Kaplan-Meier method by log-rank test according to data from the Cancer Genome Atlas. Luciferase activity assay was performed to confirm the regulation of miR-21 on LZTFL1. LZTFL1 siRNA and miR-21 inhibitor were co-transfected to breast cancer cells, then cell proliferation, migration and epithelial-mesenchymal transition (EMT) makers were tested. BALB/c nude mice were injected in situ with Hs578T cells stably overexpressing miR-21. Breast tumor growth, metastasis and the expression of EMT markers or LZTFL1 were detected in vivo.ResultsPlasma miR-21 levels were elevated in breast cancer patients compared with healthy controls and benign breast tumor patients, and the miR-21 levels were significantly decreased after surgery comparing with pre operation in 44 patients. Inhibition of miR-21 suppressed cell proliferation and metastasis in breast cancer cells. LZTFL1 was identified as a novel target gene of miR-21. Knockdown of LZTFL1 overcame the suppression of miR-21 inhibitor on cell proliferation, metastasis and the expression of EMT markers in breast cancer cells. miR-21 overexpression promoted breast cancer cell proliferation and metastasis in vivo.ConclusionsThese results indicate that plasma miR-21 level is a crucial biomarker for breast cancer diagnosis and targeting miR-21-LZTFL1-EMT axis might be a promising strategy in breast cancer therapy.Trial registrationRetrospectively registered.

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MicroRNA-498 promotes proliferation and migration by targeting the tumor suppressor PTEN in breast cancer cells.

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