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An integrated analysis to predict micro-RNAs targeting both stemness and metastasis in breast cancer stem cells.

ABSTRACT: Several evidences support the idea that a small population of tumour cells representing self-renewal potential are involved in initiation, maintenance, metastasis, and outcomes of cancer therapy. Elucidation of microRNAs/genes regulatory networks activated in cancer stem cells (CSCs) is necessary for the identification of new targets for cancer therapy. The aim of the present study was to predict the miRNAs pattern, which can target both metastasis and self-renewal pathways using integration of literature and data mining. For this purpose, mammospheres derived from MCF-7, MDA-MB231, and MDA-MB468 were used as breast CSCs model. They had higher migration, invasion, and colony formation potential, with increasing in stemness- and EMT-related genes expression. Our results determined that miR-204, -200c, -34a, and -10b contemporarily could target both self-renewal and EMT pathways. This core regulatory of miRNAs could increase the survival rate of breast invasive carcinoma via up-regulation of OCT4, SOX2, KLF4, c-MYC, NOTCH1, SNAI1, ZEB1, and CDH2 and down-regulation of CDH1. The majority of those target genes were involved in the regulation of pluripotency, MAPK, WNT, Hedgehog, p53, and transforming growth factor β pathways. Hence, this study provides novel insights for targeting core regulatory of miRNAs in breast CSCs to target both self-renewal and metastasis potential and eradication of breast cancer.

SUBMITTER: Rahimi M

PROVIDER: S-EPMC6433858 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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An integrated analysis to predict micro-RNAs targeting both stemness and metastasis in breast cancer stem cells.

Rahimi Mahsa M Sharifi-Zarchi Ali A Firouzi Javad J Azimi Mahnaz M Zarghami Nosratollah N Alizadeh Effat E Ebrahimi Marzieh M

Journal of cellular and molecular medicine 20190201 4

Several evidences support the idea that a small population of tumour cells representing self-renewal potential are involved in initiation, maintenance, metastasis, and outcomes of cancer therapy. Elucidation of microRNAs/genes regulatory networks activated in cancer stem cells (CSCs) is necessary for the identification of new targets for cancer therapy. The aim of the present study was to predict the miRNAs pattern, which can target both metastasis and self-renewal pathways using integration of ...[more]

PMID: 30710426

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Project description:BackgroundCancer stem-like cell is a key barrier for therapeutic resistance and metastasis in various cancers, including breast cancer, yet the underlying mechanisms are still elusive. Through a genome-wide lncRNA expression profiling, we identified that LINC00115 is robustly upregulated in chemoresistant breast cancer stem-like cells (BCSCs).MethodsLncRNA microarray assay was performed to document abundance changes of lncRNAs in paclitaxel (PTX)-resistant MDA-MB-231 BCSC (ALDH+) and non-BCSC (ALDH-). RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to determine the binding proteins of LINC00115. The clinical significance of the LINC00115 pathway was examined in TNBC metastatic lymph node tissues. The biological function of LINC00115 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA sequencing, mass spectrometry, and the CRISPR/Cas9-knockout system. The therapeutic potential of LINC00115 was examined through xenograft animal models.ResultsLINC00115 functions as a scaffold lncRNA to link SETDB1 and PLK3, leading to enhanced SETDB1 methylation of PLK3 at both K106 and K200 in drug-resistant BCSC. PLK3 methylation decreases PLK3 phosphorylation of HIF1α and thereby increases HIF1α stability. HIF1α, in turn, upregulates ALKBH5 to reduce m6A modification of LINC00115, resulting in attenuated degradation of YTHDF2-dependent m6A-modified RNA and enhanced LINC00115 stability. Thus, this positive feedback loop provokes BCSC phenotypes and enhances chemoresistance and metastasis in triple-negative breast cancer. SETDB1 inhibitor TTD-IN with LINC00115 ASO sensitizes PTX-resistant cell response to chemotherapy in a xenograft animal model. Correlative expression of LINC00115, methylation PLK3, SETDB1, and HIF1α are prognostic for clinical triple-negative breast cancers.ConclusionsOur findings uncover LINC00115 as a critical regulator of BCSC and highlight targeting LINC00115 and SETDB1 as a potential therapeutic strategy for chemotherapeutic resistant breast cancer.

Project description:BackgroundBone is the most common site of metastatic breast cancer, and it is a leading cause of breast cancer-related death. This study aimed to explore bone metastasis-related long non-coding RNAs (lncRNAs) in breast cancer.MethodsFour mRNA datasets and two lncRNA datasets of bone metastasis, lung metastasis and liver metastasis of breast cancer were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) in group of bone metastasis vs lung metastasis and bone metastasis vs liver metastasis, as well as the overlap of the two groups, were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and protein-protein interaction (PPI) network construction of DEmRNAs were conducted. The cis nearby-targeted DEmRNAs of DElncRNAs were obtained. Quantitative real-time polymerase chain reactions (qRT-PCR) was used to detect the expression levels of selected DEmRNAs and DElncRNAs. LOC641518-lymphoid enhancer-binding factor 1 (LEF1) pair was selected to verify its role in migration and invasion capability of breast cancer cells by wounding healing assay and transwell invasion assay.ResultsA total of 237 DEmRNAs were obtained in bone metastasis compared with both lung metastasis and liver metastasis. A total of three DElncRNAs in bone metastasis compared with both lung metastasis and liver metastasis were obtained. A total of seven DElncRNA-nearby-targeted DEmRNA pairs and 15 DElncRNA-nearby-targeted DEmRNA pairs in group of bone metastasis vs lung metastasis and bone metastasis vs liver metastasis, were detected, respectively. Four cis LncRNA-mRNA interaction pairs were identified, which are LOC641518-LEF1, FLJ35024-Very Low Density Lipoprotein Receptor (VLDLR), LOC285972-Retinoic Acid Receptor Responder 2 (RARRES2) and LOC254896-TNF receptor superfamily member 10c (TNFRSF10C). qRT-PCR using clinical samples from our hospital confirms the bioinformatics prediction. siRNA knocking down LOC641518 down-regulates LEF1 mRNA expression, and reduces the migration and invasion capability of breast cancer cells.ConclusionsWe concluded that four LncRNA-mRNA pairs, including LOC641518-LEF1, may play a central role in breast cancer bone metastasis.

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An integrated analysis to predict micro-RNAs targeting both stemness and metastasis in breast cancer stem cells.

Publications

An integrated analysis to predict micro-RNAs targeting both stemness and metastasis in breast cancer stem cells.

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