Long noncoding RNA MALAT1 enhances the docetaxel resistance of prostate cancer cells via miR-145-5p-mediated regulation of AKAP12.

Our present work was aimed to study on the regulatory role of MALAT1/miR-145-5p/AKAP12 axis on docetaxel (DTX) sensitivity of prostate cancer (PCa) cells. The microarray data (GSE33455) to identify differentially expressed lncRNAs and mRNAs in DTX-resistant PCa cell lines (DU-145-DTX and PC-3-DTX) was retrieved from the Gene Expression Omnibus (GEO) database. QRT-PCR analysis was performed to measure MALAT1 expression in DTX-sensitive and DTX-resistant tissues/cells. The human DTX-resistant cell lines DU145-PTX and PC3-DTX were established as in vitro cell models, and the expression of MALAT1, miR-145-5p and AKAP12 was manipulated in DTX-sensitive and DTX-resistant cells. Cell viability was examined using MTT assay and colony formation methods. Cell apoptosis was assessed by TUNEL staining. Cell migration and invasion was determined by scratch test (wound healing) and Transwell assay, respectively. Dual-luciferase assay was applied to analyse the target relationship between lncRNA MALAT1 and miR-145-5p, as well as between miR-145-5p and AKAP12. Tumour xenograft study was undertaken to confirm the correlation of MALAT1/miR-145-5p/AKAP12 axis and DTX sensitivity of PCa cells in vivo. In this study, we firstly notified that the MALAT1 expression levels were up-regulated in clinical DTX-resistant PCa samples. Overexpressed MALAT1 promoted cell proliferation, migration and invasion but decreased cell apoptosis rate of PCa cells in spite of DTX treatment. We identified miR-145-5p as a target of MALAT1. MiR-145-5p overexpression in PC3-DTX led to inhibited cell proliferation, migration and invasion as well as reduced chemoresistance to DTX, which was attenuated by MALAT1. Moreover, we determined that AKAP12 was a target of miR-145-5p, which significantly induced chemoresistance of PCa cells to DTX. Besides, it was proved that MALAT1 promoted tumour cell proliferation and enhanced DTX-chemoresistance in vivo. There was an lncRNA MALAT1/miR-145-5p/AKAP12 axis involved in DTX resistance of PCa cells and provided a new thought for PCa therapy.

Xue D ，Lu H ，Xu HY ，Zhou CX ，He XZ ... -  《-》

LncRNA LOXL1-AS1/miR-let-7a-5p/EGFR-related pathway regulates the doxorubicin resistance of prostate cancer DU-145 cells.

Our study aimed to investigate the effects of lncRNA LOXL1-AS1/miR-let-7a-5p/EGFR-axis on prostate cancer (PCa) progression. Microarray analysis was conducted to determine differentially expressed lncRNAs and mRNAs. Gene Set Enrichment analysis was implemented for verification of dys-regulated signaling pathways between DU-145 cells and doxorubicin-resistant prostate cancer DU-145 cells. Relative expression of lncRNA LOXL1-AS1 in doxorubicin-resistant prostate cancer DU-145 cells was analyzed by qRT-PCR. CCK-8 assay and flow cytometry analysis were employed to detect cell proliferation and apoptosis, respectively. Cell migration was performed by transwell assay. Furthermore, targeted relationships between lncRNA LOXL1-AS1 and miR-let-7a-5p, as well as miR-let-7a-5p and EGFR were predicted using bioinformatics analysis and validated by dual-luciferase reporter gene assay. Besides, tumor xenograft assay was utilized for verification of the roles of LOXL1-AS1 in PCa progression in vivo. Microarray analysis showed that lncRNA LOXL1-AS1 and EGFR were both downregulated, while miR-let-7a-5p was upregulated in doxorubicin-resistant prostate cancer DU-145 cells. MiR-let-7a-5p could target both lncRNA LOXL1-AS1 and EGFR to affect PCa progression. Upregulation of lncRNA LOXL1-AS1 promoted cell proliferation and migration, while suppressed cell apoptosis. Besides, it was further confirmed that EGFR was downregulated in drug-resistant PCa cells and negatively correlated with miR-let-7a-5p. Tumor xenograft assay verified that silence of lncRNA LOXL1-AS1 inhibited the tumor growth in vivo in DU-145 cells. Our results demonstrated that the lncRNALOXL1-AS1/miR-let-7a-5p/EGFR axis significantly affected proliferation, migration, and apoptosis of drug-resistant DU-145 Cells, which may provide us with a potential treatment strategy for drug-resistant PCa patients. © 2019 IUBMB Life, 2019.

Bai T ，Liu Y ，Li B 《-》

Exosomal circRNA Scm-like with four malignant brain tumor domains 2 (circ-SFMBT2) enhances the docetaxel resistance of prostate cancer via the microRNA-136-5p/tribbles homolog 1 pathway.

Exosomal circular RNA was found to mediate cancer chemoresistance. However, whether exosomal circRNA Scm-like with four malignant brain tumor domains 2 (circ-SFMBT2) was involved in the chemoresistance of prostate cancer (PCa) remains unclear. The docetaxel (DTX) resistance of PCa cells was analyzed by Cell Counting Kit 8 assay. Quantitative real-time PCR was used to measure circSFMBT2, microRNA (miR)-136-5p and tribbles homolog 1 (TRIB1) expression. Cell proliferation, apoptosis, migration and invasion were analyzed by 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry, wound-healing assay and transwell assay. RNA interaction was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Protein expression was measured by western blot analysis. Exosomes-extracted from cells were identified by transmission electron microscope, nanoparticles tracking analysis and western blot. Xenograft mice models were constructed to analyze the effect of exosomal circSFMBT2 on the DTX sensitivity of PCa tumors in vivo. CircSFMBT2 was upregulated in DTX-resistant PCa cells, and its knockdown enhanced the DTX sensitivity of DTX-resistant PCa cells by suppressing cell proliferation, migration, invasion and enhancing apoptosis. CircSFMBT2 severed as miR-136-5p sponge to positively regulate TRIB1. The regulation of circSFMBT2 knockdown on the DTX sensitivity of DTX-resistant PCa cells could be reversed by miR-136-5p inhibitor or TRIB1 overexpression. Exosomal circSFMBT2 from DTX-resistant PCa could increase the DTX resistance of normal PCa cells. In addition, exosomal circSFMBT2 also enhanced the DTX resistance of PCa tumors in vivo, and it was highly expressed in the serum of DTX-resistance PCa patients. Exosomal circSFMBT2 enhanced the DTX resistance of PCa by miR-136-5p/TRIB1 axis, indicating that circSFMBT2 might be a potential target for the treatment of PCa chemoresistance.

Tan X ，Song X ，Fan B ，Li M ，Zhang A ，Pei L ... -  《-》

MiR-129-5p promotes docetaxel resistance in prostate cancer by down-regulating CAMK2N1 expression.

This study focuses on the effect of miR-129-5p on docetaxel-resistant (DR) prostate cancer (PCa) cells invasion, migration and apoptosis. In our study, the expression of CAMK2N1 was assessed by qRT-PCR in PCa patient tissues and cell lines including PC-3 and PC-3-DR. Cells transfected with miR-129-5p mimics, inhibitor, CAMK2N1 or negative controls (NC) were used to interrogate their effects on DR cell invasions, migrations and apoptosis during docetaxel (DTX) treatments. The apoptosis rate of the PCa cells was validated by flow cytometry. Relationships between miR-129-5p and CAMK2N1 levels were identified by qRT-PCR and dual-luciferase reporter assay. CAMK2N1 was found to be down-expressed in DR PCa tissue sample, and low levels of CAMK2N1 were correlated with high docetaxel resistance and clinical prediction of poor survival. CAMK2N1 levels were decreased in DR PCa cells treated with DXT. We further explored that up-regulation of miR-129-5p could promote DR PCa cells viability, invasion and migration but demote apoptosis. Involved molecular mechanism studies revealed that miR-129-5p reduced downstream CAMK2N1 expression to further impact on chemoresistance to docetaxel of PCa cells, indicating its vital role in PCa docetaxel resistance. Our findings revealed that miR-129-5p contributed to the resistance of PC-3-DR cells to docetaxel through suppressing CAMK2N1 expression, and thus targeting miR-129-5p may provide a novel therapeutic approach in sensitizing PCa to future docetaxel treatment.

Wu C ，Miao C ，Tang Q ，Zhou X ，Xi P ，Chang P ，Hua L ，Ni H ... -  《-》

Micro-RNA-186-5p inhibition attenuates proliferation, anchorage independent growth and invasion in metastatic prostate cancer cells.

Jones DZ ，Schmidt ML ，Suman S ，Hobbing KR ，Barve SS ，Gobejishvili L ，Brock G ，Klinge CM ，Rai SN ，Park J ，Clark GJ ，Agarwal R ，Kidd LR ... -  《BMC CANCER》