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Sp1-mediated up-regulation of lnc00152 promotes invasion and metastasis of retinoblastoma cells via the miR-30d/SOX9/ZEB2 pathway

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Abstract

Purpose

Previously, we found that long non-coding RNA (lncRNA) MEG3 may act as a tumour suppressor in retinoblastoma. Overall, however, little is known about the role of lncRNAs in retinoblastoma. Here, we aimed to determine the expression and clinical significance of lnc00152 in retinoblastoma.

Methods

Lnc00152 and its downstream targets were selected using GEO datasets. The level of lnc00152 in primary patient samples was determined using RT-qPCR. Odds ratios of invasion and metastasis were calculated using logistic regression analysis. Recurrence-free survival was assessed using Cox regression analysis. Scratch wound healing, transwell and tumorigenesis assays were used to determine migration and invasion abilities of retinoblastoma cells in vitro and in vivo. Levels of EMT-related proteins were measured using Western blotting. Binding sites between lnc00152 and its targets were validated using dual-luciferase reporter and RNA pull-down assays. Lnc00152 activating transcription factors were determined using ChIP assays.

Results

We found that Lnc00152 was significantly up-regulated in retinoblastoma tumour tissues, and was a risk factor for tumour invasion, metastasis and recurrence. Lnc00152 overexpressing retinoblastoma cells exhibited a tendency to transform into mesenchymal cells, with significantly increased migration and invasion capacities, significantly decreased E-cadherin expression levels, and significantly increased N-cadherin, SOX9 and ZEB2 expression levels. In addition, we found that lnc00152, which was activated by Sp1, could inhibit miR-30d as an endogenous miRNA ‘sponge’, thereby regulating the expression of SOX9 and ZEB2.

Conclusions

Our data indicate that Lnc00152 may be associated with retinoblastoma invasion, metastasis and prognosis. In addition, we conclude that Lnc00152, which can be activated by Sp1, can induce EMT via the miR-30d/SOX9/ZEB2 pathway and, by doing so, promote the invasion and metastasis of retinoblastoma cells.

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Acknowledgements

The project was supported by the National Natural Science Foundation of China (Grant No. 81902751 and Grant No. 81971385) and the Guangdong Natural Science Foundation (Grant No. 2018A0303100021 and Grant No. 2019A1515010412).

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Authors and Affiliations

  1. Department of Ophthalmology, The Second Clinical Medical College (Shenzhen People’s Hospital), Jinan University, 518020, Shenzhen, People’s Republic of China

    Yali Gao & Xiaoling Luo

  2. Department of Obstetrics and Gynaecology, The Second Clinical Medical College (Shenzhen People’s Hospital), Jinan University, 518020, Shenzhen, People’s Republic of China

    Jun Zhang

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  1. Yali Gao
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Correspondence to Jun Zhang.

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All procedures performed in studies involving human participants were in accordance with the standards of the ethic committee of the Shenzhen People’s Hospital. All patients signed inform consent forms.

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Gao, Y., Luo, X. & Zhang, J. Sp1-mediated up-regulation of lnc00152 promotes invasion and metastasis of retinoblastoma cells via the miR-30d/SOX9/ZEB2 pathway. Cell Oncol. 44, 61–76 (2021). https://doi.org/10.1007/s13402-020-00522-8

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