Abstract
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.
Highlights
Ranked as the second lethal malignancy among men in United States, prostate cancer (PCa) is one of the most popular human diseases, with approximately more than 220 000 newly diagnosed cases and 27 000 deaths
We demonstrated that Metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) conferred DTX resistance via AKAP12, which was modulated by miR-145-5p and related to cell invasiveness and chemoresistance of PCa cells
We firstly found that Long noncoding RNAs (lncRNAs) MALAT1 was overexpressed in DTX-resistant PCa cells and revealed its effect on mediating DTX resistance of PCa
Summary
Ranked as the second lethal malignancy among men in United States, prostate cancer (PCa) is one of the most popular human diseases, with approximately more than 220 000 newly diagnosed cases and 27 000 deaths. MiRNAs are small and nonprotein-coding RNAs containing 20-22 nucleotides in length, which negatively modulate genes expression at the post-transcriptional stage or induce mRNA degradation by binding the 30 untranslated regions (UTRs) of mRNAs.[21,22] They play an important role in biological processes[23] and are broadly involved in tumour proliferation, invasion, angiogenesis and drug resistance.[24,25,26,27] MiRNAs such as miR-148a,27 miR-200c,28 miR-205,28 miR-2129 and miR-3430 have been reported to modulate drug resistance of PCa. Recent studies have demonstrated that miR-145-5p is down-regulated in several cancer types, including bladder cancer,[31] breast cancer,[32] colon cancer 33 and ovarian cancer,[34] indicating that it is a tumour-suppressive miRNA. Our research for the first time confirmed that MALAT1 promoted DTX resistance, providing a potential therapeutic approach for PCa patients with DTX resistance
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