Pro-tumorigenic role of lnc-ZNF30-3 as a sponge counteracting miR-145-5p in prostate cancer

Biology Direct

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Martha Romero¹  Matthieu Le Hars²  Marina Pinskaya²  Irina Groisman³  Fatemeh Rajabi³  Luis Jaime Castro-Vega⁴  David Tabatadze⁵ 

[1] Department of Pathology, Hospital Universitario-Fundación Santa Fe de Bogotá, Bogotá, Colombia;Institut Curie, Sorbonne Universités, Paris Sciences et Lettres Research University, CNRS UMR3244, Paris, France;Institut Curie, Sorbonne Universités, Paris Sciences et Lettres Research University, CNRS UMR3244, Paris, France;Cancer Genomics lab, Inserm U981, Gustave Roussy Cancer Center Grand Paris, Villejuif, France;Paris Brain Institute (ICM), Hôpital Pitié-Salpêtrière, Inserm U1127, CNRS UMR7225, Sorbonne Universités, Paris, France;ZATA Pharmaceuticals Inc, Worcester, MA, USA;

关键词: Prostate cancer;    miR-145;    lnc-ZNF30-3;    EMT;    TWIST1;   

DOI  :  10.1186/s13062-023-00393-7

 received in 2023-01-18, accepted in 2023-06-23,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundProstate cancer remains one of the deadliest neoplasms in developed countries. Identification of new molecular markers that predict the onset and progression of the disease could improve its clinical management. Low miR-145-5p expression is consistently found in primary tumors and metastases, but the regulatory mechanisms governing its functions remain largely unknown.MethodsBioinformatics analysis was conducted to identify [1] a set of novel potential competing endogenous lncRNAs for sponging of miRNA-145-5p in prostate cancer and [2] miR-145-5p and other EMT-related miRNAs response elements in lnc-ZNF30-3. Quantification of miR-145-5p, lnc-ZNF30-3, and TWIST1 expression levels in tumor tissues in RNA sequencing datasets of our and TCGA PRAD cohorts revealed a correlation with clinical outcome of prostate cancer patients. Biochemical and cell biology approaches, such as RNA pull-down, western blot, immunostaining, and wound healing assays were used for evaluation of the impact of TWIST1/miR-145/ lnc-ZNF30-3 interactions in prostate cancer cells altered in miRNA and lncRNA expression.ResultsWe identified a few potential lncRNA sponges of miR-145-5p, including lnc-ZNF30-3. It contains five response elements for miR-145-5p, but also other miRNAs targeting EMT transcription factors. Lnc-ZNF30-3 is significantly upregulated in prostate cancer cell lines and tumor tissues, and its high expression is correlated with poor patient prognosis. We demonstrated that lnc-ZNF30-3 is associated with AGO2 and specifically interacts with the miR-145-5p seed region. Knockdown of lnc-ZNF30-3 results in decreased migration of prostate cancer cells and downregulation of EMT drivers such as TWIST1 and ZEB1 at both the RNA and protein levels. These phenotypic and molecular features of lnc-ZNF30-3-depleted cells are partially rescued by miR-145-5p inhibition.ConclusionsCollectively, our results point to lnc-ZNF30-3 as a novel competing endogenous lncRNA for miR-145-5p and other miRNAs that target TWIST1 as well as other EMT transcription factors. Prostate cancer patients with high lncRNA expression in primary tumors show lower survival rate suggesting that lnc-ZNF30-3 may contribute to prostate cancer progression and metastasis.

【 授权许可】

CC BY   
© The Author(s) 2023

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