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Long non-coding RNA SNHG20 promotes ovarian cancer development by targeting microRNA-338-3p to regulate MCL1 expression.

ABSTRACT: Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs/miRs) were reported to be associated with the development of ovarian cancer (OC). Increasing evidence demonstrated that lncRNA SNHG20 and miR-338-3p were involved in OC. However, the functional mechanism of lncRNA SNHG20 and miR-338-3p in OC development remains unknown. The expression of SNHG20, miR-338-3p and myeloid cell leukemia 1 (MCL1) was detected by reverse transcription-quantitative PCR. MTT assay, flow cytometry and transwell migration and invasion assays were used to assess cell proliferation, apoptosis, migration and invasion, respectively. The relative protein expression was detected by western blot analysis. The interaction between miR-338-3p and SNHG20 or MCL1 was predicted by starBase v3.0, and subsequently confirmed by dual-luciferase reporter assay. Besides, mouse xenograft assay was carried out to explore the effect of SNHG20 on tumor growth in vivo. The levels of SNHG20 and MCL1 were upregulated, while miR-338-3p level was downregulated in OC tissues and cells. SNHG20 knockdown repressed OC cell proliferation, migration, invasion and epithelial-mesenchymal transition, and induced apoptosis. Interestingly, SNHG20 targeted miR-338-3p to regulate MCL1 expression. miR-338-3p depletion or MCL1 overexpression could reverse the effects of SNHG20 knockdown on OC cells. Besides, SNHG20 knockdown impeded tumor growth in vivo. In conclusion, the present study demonstrated that SNHG20 regulates OC development via modulation of the miR-338-3p/MCL1 axis, providing the theoretical basis for the treatment of OC.

SUBMITTER: Wang D

PROVIDER: S-EPMC7798103 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Long non-coding RNA SNHG20 promotes ovarian cancer development by targeting microRNA-338-3p to regulate MCL1 expression.

Wang Ding D Li Zhiying Z Li Hui H Lu Jiao J Qin Qi Q

Oncology letters 20201218 2

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs/miRs) were reported to be associated with the development of ovarian cancer (OC). Increasing evidence demonstrated that lncRNA SNHG20 and miR-338-3p were involved in OC. However, the functional mechanism of lncRNA SNHG20 and miR-338-3p in OC development remains unknown. The expression of SNHG20, miR-338-3p and myeloid cell leukemia 1 (MCL1) was detected by reverse transcription-quantitative PCR. MTT assay, flow cytometry and transwell migratio ...[more]

PMID: 33552251

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Project description:BackgroundFollicular development in mammalian ovaries is a complex and dynamic process, and the interactions and regulatory-feedback loop between the follicular microenvironment, granulosa cells (GCs), and oocytes can affect follicular development and normal ovary functions. Abnormalities in any part of the process may cause abnormal follicular development, resulting in infertility. Hence, exploring the pathogenesis of abnormal follicular development is extremely important for diagnosing and treating infertile women.MethodsRNA sequencing was performed with ovarian cortical tissues established in vitro. In situ-hybridization assays were performed to study microRNA-338-3p (miR-338-3p) expressed in GCs and oocytes. In vitro culture models were established with GCs and neonatal mouse ovaries to study the biological effects of miR-338-3p. We also performed in vivo experiments by injecting adeno-associated virus vectors that drive miR-338-3p overexpression into the mouse ovarian bursae.ResultsSequencing analysis showed that miR-338-3p was expressed at significantly higher levels in ovarian cortical tissues derived from patients with ovarian insufficiency than in cortical tissues derived from patients with normal ovarian function; miR-338-3p was also significantly highly expressed in the GCs of patients with diminished ovarian reserve (P < 0.05). In situ-hybridization assays revealed that miR-338-3p was expressed in the cytoplasm of GCs and oocytes. Using in vitro culture models of granulosa cells, we found that miR-338-3p overexpression significantly suppressed the proliferation and oestradiol-production capacity of GCs (P < 0.05). In vitro culture models of neonatal mouse ovaries indicated that miR-338-3p overexpression suppressed the early follicular development in mouse ovaries. Further analysis revealed that miR-338-3p might be involved in transforming growth factor β-dependent regulation of granulosa cell proliferation and, thus, early follicular development. Injecting miR-338-3p-overexpression vectors into the mouse ovarian bursae showed that miR-338-3p down-regulated the oocyte mitochondrial membrane potential in mice and disrupted mouse oestrous cycles.ConclusionmiR-338-3p can affect early follicular development and normal ovary functions by interfering with the proliferation and oestradiol production of GCs. We systematically elucidated the regulatory effect of miR-338-3p on follicular development and the underlying mechanism, which can inspire new studies on the diagnosis and treatment of diseases associated with follicular development abnormalities.

Project description:Dickkopf-1 (DKK1) is a powerful antagonist of canonical WNT signaling pathway, and is regarded as a biomarker for osteoporosis. Its expression is highly correlated with bone mass and osteoblasts maturation. In this study, mouse primary bone marrow cells and osteoblast cell lines were used. Luciferase reporter assay and western blotting methods were employed to validate if miRNA-433-3p epigenetically regulated DKK1 translation. Rat bone marrow derived osteoblasts were infected with lentivirus vector in which miR-433-3p was constructed. The authors constructed lentivirus mediated miRNA-433-3p stable expression and examined the alkaline phosphatase (ALP) activity and mineral deposition level in vitro. In situ hybridization method was used to observe miR-433-3p in primary osteoblasts. We built up an OVX rat model to mimic postmenopausal osteoporosis, and found aberrant circulating miR-433-3p and miR-106b, which were not reported previously. Results showed that miR-433-3p potentially regulated DKK1 mRNA, Furthermore, the correlation of serum DKK1 with circulating miR-433-3p level was significant (r = 0.7520, p = 0.046). In the luciferase reporter assay, we found that miR-433-3p siRNA decreased luminescence signal, indicating direct regulation of miR-433-3p on DKK1 mRNA. When the miR-433-3p binding site in DKK1 3'UTR was mutant, such reduction was prohibited. Western blotting result validated that miR-433-3p inhibited over 90% of DKK1 protein expression. Similarly, the change of protein expression was not observed in mutant group. The stable expression of lentivirus mediated miR-433-3p increased ALP activity and mineralization both in human and rat derived immortalized cells. We found that primary osteoblasts had higher miR-433-3p level compared with immortal cells through real-time PCR, as well as in situ hybridization experiment. Conclusively, our findings further emphasized the vital role of miR-433-3p in DKK1/WNT/?-catenin pathway through decreasing DKK1 expression and inducing osteoblasts differentiation.

Dataset Information

Long non-coding RNA SNHG20 promotes ovarian cancer development by targeting microRNA-338-3p to regulate MCL1 expression.

Publications

Long non-coding RNA SNHG20 promotes ovarian cancer development by targeting microRNA-338-3p to regulate MCL1 expression.

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