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LINC01016 promotes the malignant phenotype of endometrial cancer cells by regulating the miR-302a-3p/miR-3130-3p/NFYA/SATB1 axis.

ABSTRACT: Long noncoding RNAs (lncRNAs) have been implicated in tumorigenesis and cancer progression and are tightly associated with the phenotypes of numerous cancers. However, the functional roles underlying these effects are unknown. The expression levels of LINC01016, miR-302a-3p, miR-3130-3p, NFYA, and SATB1 were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) in 33 endometrial cancer tissues and 20 normal tissues. Bioinformatics analyses, luciferase reporter analyses, chromatin immunoprecipitation (ChIP) assays, and qRT-PCR assays were performed to verify potential binding sites. The qRT-PCR and western blot were used to identify the regulatory mechanisms of LINC01016 in cell biological behavior, which were also examined by cell counting kit -8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) assays, flow cytometry, wound healing assays, and transwell assays. LINC01016 was substantially upregulated in endometrial cancer tissues, and LINC01016 silencing abolished the malignant behavior of endometrial cancer cells. LINC01016 positively rescued the downstream gene nuclear factor YA (NFYA) by competitively "sponging" miR-302a-3p and miR-3130-3p. In turn, these two miRNAs could inhibit LINC01016 transcription, thus forming two reciprocal repression cycles, which influenced the biological behavior of endometrial cancer cells. MiR-302a-3p and miR-3130-3p could specifically bind with the 3'-UTR regions of NFYA, and NFYA could upregulate the expression of special AT-rich sequence-binding protein 1 (SATB1) as a transcriptional factor. This study was the first to show that the LINC01016-miR-302a-3p/miR-3130-3p/NFYA/SATB1 axis played a crucial role in the occurrence of endometrial cancer. These findings may provide relevant insights into the diagnosis and therapy of endometrial cancer.

SUBMITTER: Pan X

PROVIDER: S-EPMC5833433 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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LINC01016 promotes the malignant phenotype of endometrial cancer cells by regulating the miR-302a-3p/miR-3130-3p/NFYA/SATB1 axis.

Pan Xin X Li Da D Huo Jianing J Kong Fanfei F Yang Hui H Ma Xiaoxin X

Cell death & disease 20180221 3

Long noncoding RNAs (lncRNAs) have been implicated in tumorigenesis and cancer progression and are tightly associated with the phenotypes of numerous cancers. However, the functional roles underlying these effects are unknown. The expression levels of LINC01016, miR-302a-3p, miR-3130-3p, NFYA, and SATB1 were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) in 33 endometrial cancer tissues and 20 normal tissues. Bioinformatics analyses, luciferase reporter analyses, chromat ...[more]

PMID: 29467441

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Project description:BackgroundMetastasis is one of the main reasons for treatment failure in endometrial cancer. Notably, high mobility group AT-hook 2 (HMGA2) has been recognized as a driving factor of tumour metastasis. microRNAs (miRNAs) are powerful posttranscriptional regulators of HMGA2.MethodsThe binding sites of miR-302a-5p and miR-367-3p on HMGA2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. The expression levels of miR-302a-5p and miR-367-3p were detected using quantitative real-time PCR and in situ hybridization. Western blotting and immunohistochemistry were used to detect the levels of HMGA2 and epithelial-mesenchymal transition pathway-related proteins. Co-immunoprecipitation was used to detect protein interactions. The roles of miR-302a-5p and miR-367-3p in the regulation of HMGA2 during the progression of endometrial cancer were investigated using both in vitro and in vivo assays.ResultsIn the present study, high HMGA2 expression was correlated with poor clinical outcomes in endometrial cancer. The binding sites of miRNAs on HMGA2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. In the endometrial cancer cell lines Ishikawa and HEC-1A, the overexpression of miR-302a-5p/367-3p significantly inhibited the expression of HMGA2 mRNA. In endometrial cancer tissues, we showed that miR-302a-5p and miR-367-3p were significantly downregulated and thus inversely correlated with HMGA2. The miR-302a-5p and miR-367-3p expression levels were closely correlated with FIGO stage and lymph node metastasis. High expression of miR-302a-5p/367-3p was correlated with high survival rates in endometrial cancer. In addition, miR-302a-5p/367-3p suppressed the malignant behaviour of endometrial carcinoma cells via the inhibition of HMGA2 expression.ConclusionOur findings indicate that miR-302a-5p/367-3p-mediated expression of HMGA2 regulates the malignant behaviour of endometrial carcinoma cells, which suggests that the miR-302a-5p/367-3p-HMGA2 axis may be a predictive biomarker of endometrial cancer metastasis and patient survival and a potential therapeutic target in metastatic endometrial cancer.

Project description:BackgroundEmerging evidence shows that abnormal expression of long non-coding RNA is involved in the occurrence and development of various tumors. LncRNA MONC is abnormally expressed in head and neck squamous cell carcinoma, lung cancer, colorectal cancer, and acute megakaryocytic leukemia, but the biological function and potential regulatory mechanism of MONC in endometrial cancer stem cells (ECSCs) and endometrial cancer cells (ECCs) have not been studied. In this study, we aimed to explore the tumor suppressive effect and mechanism of MONC in regulating ECSCs and ECCs.MethodsWe used qRT-PCR to detect the expression of MONC, miR-636 and GLCE in normal human endometrial tissues and endometrial carcinoma (EC) tissues. Luciferase assay was used to verify the binding sites between MONC and miR-636 and between miR-636 and GLCE. Double fluorescence in situ hybridization was used to locate MONC and miR-636 in cells. ECSCs were obtained by flow cytometry sorting assay. Sphere formation assay, CCK-8 assay, transwell invasion assay, cell cycle analysis and apoptosis assay were used to detect the effects of MONC/miR-636/GLCE axis on the malignant biological behavior of ECSCs and ECCs. The effect of MONC on the epithelial-to-mesenchymal transition (EMT) process was detected using western blot. Finally, we conducted in vivo verification through Tumor xenografts in BALB/C nude mice.ResultsIn this study, we found MONC is low expression in endometrial carcinoma (EC) and patients in the MONC high-expression group had a better prognosis. MONC and miR-636 are relatively co-localized in the cytoplasm. MONC directly inhibits the malignant biological behavior of ECSCs and ECCs by directly inhibiting miR-636. Simultaneously, miR-636 may indirectly reduce the expression of MONC. Down-regulation of miR-636 may promote GLCE expression by targeting the 3'-untranslated region (UTR) of the downstream gene GLCE, thereby inhibiting the progression of ECSCs. MONC combined with miR-636 inhibited tumor epithelial-to-mesenchymal transition (EMT) process. In addition, we verified the tumor suppressive effect of MONC in nude mice, miR-636 can rescue the tumor suppressive effect of overexpressing MONC.ConclusionsIn conclusion, this study showed that MONC inhibits the malignant phenotypes of ECSCs and ECCs by regulating the miR-636/GLCE axis. Thus the MONC/miR-636/GLCE axis may provide novel treatment avenues for human EC.

Dataset Information

LINC01016 promotes the malignant phenotype of endometrial cancer cells by regulating the miR-302a-3p/miR-3130-3p/NFYA/SATB1 axis.

Publications

LINC01016 promotes the malignant phenotype of endometrial cancer cells by regulating the miR-302a-3p/miR-3130-3p/NFYA/SATB1 axis.

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