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MiR-4319 induced an inhibition of epithelial-mesenchymal transition and prevented cancer stemness of HCC through targeting FOXQ1.

ABSTRACT: The heterogeneity existing in tumours is responsible for the poor response to treatment. Therefore, elucidating the molecular mechanisms of intratumoural heterogeneity in hepatocellular carcinoma (HCC) is vital for the discovery of new therapeutic methods for improving the prognosis of patients. Of note, cancer stem cells (CSCs) existing in HCC may explain the pathological properties of heterogeneity and recurrence. An increasing number of studies have confirmed that abnormally expressed microRNAs (miRNAs) take part in the carcinogenesis as well as the aggravation of HCC. However, little information is currently available about the specific miR-4319 in HCC. Herein, we demonstrated that the level of miR-4319 was remarkably decreased in HCC specimens and cells compared to that in normal counterparts and that the depression of miR-4319 in tumour specimens correlates with tumour size, histological grade and venous invasion. Through a series of functional experiments, we illustrated that miR-4319 repressed cell proliferation, accelerated apoptosis, inhibited epithelial-mesenchymal transition (EMT) and prevented cancer stemness in HCC cells by targeting FOXQ1 (Forkhead box Q1). An in vivo tumourigenesis assay uncovered that depletion of miR-4319 in Hep3B cells increased tumour growth and elevated the expression of EMT and CSC markers in comparison to those of the control group. Restoration of FOXQ1 expression also partially reversed the miR-4319-induced biological effects on HCC cells. Thus, miR-4319, as a posttranscriptional regulator, plays a profound role in suppressing the malignant progression of HCC, and our study highlights the miR-4319/FOXQ1 cascade as a potential therapeutic target for conquering HCC.

SUBMITTER: Han S

PROVIDER: S-EPMC6909970 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMicroRNA27b-3p (miR-27b) has been reported to be dysregulated in multiple types of human cancer. However, the expression levels, biological roles, and underlying mechanism of miR-27b in tongue squamous cell carcinoma (TSCC) remain to be elucidated.MethodsBioinformatics analyses and quantitative real-time PCR (qRT-PCR) were used to determine miR-27b expression in TSCC tissues and cell lines. The influence of miR-27b overexpression or inhibition on TSCC cell proliferation, migration, and invasion in vitro, and on tumor growth in vivo, was explored via CCK8, colony formation, wound healing, and transwell assays, and in xenograft tumors in nude mice, respectively. Luciferase reporter assays, qRT-PCR, and Western blotting were performed to clarify the potential mechanisms involving miR-27b in TSCC cells.ResultsmiR-27b was significantly downregulated in TSCC tissues and cell lines, and its expression was correlated with cancer status. Overexpression of miR-27b led to diminished proliferation, migration, and invasion, and notably reduced tumor growth in vivo. Bioinformatics analysis followed by luciferase reporter assays demonstrated that miR-27b expression was inversely correlated with that of integrin subunit α5 (ITGA5)and that miR-27b directly bound to the 3'-untranslated region of ITGA5 in TSCC cells. The bioinformatics analysis also indicated that ITGA5 was upregulated in TSCC and that its expression was correlated with epithelial-mesenchymal transition (EMT) and poor prognosis. Moreover, we found that miRNA-27b could reverse ITGA5-induced promotion of TSCC cell proliferation and migration. Finally, we demonstrated that regulation of miR-27b expression in TSCC may result in alterations in the expression of ITGA5 and EMT-related marker genes at the mRNA and protein levels.ConclusionThese results indicate that miR-27b hampers TSCC proliferation and migration via suppressing the EMT process by targeting ITGA5. These findings support consideration of miR-27b/ITGA5 as a valuable marker for the metastatic potential of TSCC, or as a therapeutic target for the treatment of TSCC.

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MiR-4319 induced an inhibition of epithelial-mesenchymal transition and prevented cancer stemness of HCC through targeting FOXQ1.

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