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Long non-coding RNA SNHG1 stimulates ovarian cancer progression by modulating expression of miR-454 and ZEB1.

ABSTRACT: Ovarian cancer (OC) is highly prevalent and is associated with high mortality rates due to metastasis and relapse. In this study, we assessed the role of long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) in OC to gain further insight into mechanisms that contribute to its aggressiveness. We analyzed the correlation between SNHG1, miR-454 and zinc finger E-box-binding homeobox 1 (ZEB1) using a dual-luciferase reporter assay. Alterations in cell metastasis and invasiveness were observed using wound-healing and Transwell invasion assays, respectively. Tumor xenografts allowed us to monitor liver metastasis of mice injected with A2780 cells. We found that SNHG1 is overexpressed in OC. Downregulation of SNHG1 promoted miR-454 expression and reduced ZEB1 levels. In addition, knockdown of SNHG1, also reduced the aggressiveness of A2780 and SK-OV3 cells. Furthermore, SNHG1 downregulation by siRNA hindered cell migration and invasion; however, this effect was reversed by co-transfection of miR-454 into A2780 and SK-OV3 cells. Moreover, SNHG1 increased ZEB1 expression by downregulating miR-454 and activated Akt signaling, thereby promoting epithelial-mesenchymal transition and enhancing the invasiveness of OC cells. Tumor xenograft analyses confirmed that SNHG1 affects OC proliferation and metastasis in vivo. In summary, our data demonstrate that SNHG1 plays crucial roles in tumor progression and may be a useful maker for OC prognosis.

SUBMITTER: Wu Y

PROVIDER: S-EPMC8096788 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Long non?coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) was reported to be a critical regulator of tumorigenesis and is frequently deregulated in several cancer types. However, the exact mechanism by which SNHG1 contributes to breast cancer progression has not been fully elucidated. The identification of the molecular mechanism of SNHG1 is important for understanding the development of breast cancer and for improving the prognosis of the patients with this disease. In the present study, increased expression levels of SNHG1 were noted in breast cancer tumors following analysis of differentially expressed lncRNAs between 1,063 tumor and 102 normal tissues derived from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA?BRCA) dataset. This finding was further validated using 50 pairs of normal and tumor tissues that were collected from patients with breast cancer. Notably, SNHG1 expression was significantly correlated with estrogen receptor (ER)/progesterone receptor (PR) negative status (ER?/PR?) and advanced clinical stage in breast cancer tissues. Knockdown of SNHG1 led to cell growth arrest, cell cycle redistribution and cell migration inhibition of breast cancer cells. The miRDB database predicted that miR?573 interacts with SNHG1. RT?PCR confirmed the negative regulation of miR?573 levels by SNHG1 in breast cancer cells and the Dual?luciferase reporter assay confirmed their complementary binding. The repression of miR?573 by SNGH1 decreased LIM domain only 4 (LMO4) mRNA and protein expression levels in the breast cancer cell lines tested and induced the expression of cyclin D1 and cyclin E. In vitro experiments indicated that LMO4 overexpression could reverse siSNHG1?induced cell growth arrest, cell cycle redistribution and inhibition of cell migration in breast cancer cells. Moreover, the tumor xenograft model indicated that SNHG1 knockdown inhibited MDA?MB?231 growth in vivo and LMO4 overexpression reversed the tumor growth inhibition induced by SNHG1 knockdown. The present study demonstrated that SNHG1 acts as a novel oncogene in breast cancer via the SNHG/miR?573/LMO4 axis and that it could be a promising therapeutic target for patients with breast cancer.

Project description:Neuroblastoma (NB) is an embryonal tumor with various clinical presentations and behaviors. Several genomic alterations has been well-studied in NB, among which genomic amplification of MYCN oncogene, is a strong prognostic biomarker with worsens outcome. Long noncoding RNAs (lncRNAs), constitute major proportion of the cellular transcripts with no coding capacity. One of their function is to guide transcription factors to the target genes and facilitate gene expression. However, relative contribution of lncRNA and MYCN to the advanced NB has remained unclear. Herein, by applying a network-based integrative analysis on MYCN amplified and MYCN nonamplified lncRNA expression profile from both RNA-seq and microarray platform, we identified lncRNA, SNHG1 to be differentially expressed and strongly correlated with MYCN in MYCN-amplified NB. The expression of SNHG1 was validated by RT-qPCR in NB cell lines. Survival analysis revealed that higher expression of SNHG1 significantly associates with poor patient survival. Moreover, knockdown of MYCN in MYCN-amplified NB cell lines inhibited SNHG1 expression. Furthermore, to unravel the role of SNHG1 in NB, we extracted SNHG1-interacting proteins by RNA-protein pull down assay coupled with doi:10.6342/NTU201701980 ! ! VI liquid chromatography-tandem mass spectrometry (LC-MS/MS). We identified 27 SNHG1-interacting proteins in common from three NB cell lines. However, only three SNHG1-interacting proteins, MATR3, YBX1 and HHRNPL have binding site detected by DeepBind motif analysis. Western blot confirms interaction of MATR3 with SNHG1. Additionally, we further validated the direct interaction between MATR3 and SNHG1 by RNA-immunoprecipation (IP). MATR3 is known to be involved in RNA transport and stabilization. Therefore, we proposed that MATR3 after interacting with SNHG1 might help in SNHG1 transcription and stabilization. In conclusion, our study unveils that SNHG1 could be a prognostic marker for high-risk NB and possibly stabilized by MATR3. Our results might provide future directions for the development of therapeutic strategies against high-risk NB.

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Long non-coding RNA SNHG1 stimulates ovarian cancer progression by modulating expression of miR-454 and ZEB1.

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