MiR-148a Attenuates Paclitaxel Resistance of Hormone-refractory, Drug-resistant Prostate Cancer PC3 Cells by Regulating MSK1 Expression

Abstract

MicroRNAs are involved in cancer pathogenesis and act as tumor suppressors or oncogenes. It has been recently reported that miR-148a expression is down-regulated in several types of cancer. The functional roles and target genes of miR-148a in prostate cancer, however, remain unknown. In this report, we showed that miR-148a expression levels were lower in PC3 and DU145 hormone-refractory prostate cancer cells in comparison to PrEC normal human prostate epithelial cells and LNCaP hormone-sensitive prostate cancer cells. Transfection with miR-148a precursor inhibited cell growth, and cell migration and invasion, and increased the sensitivity to anti-cancer drug paclitaxel in PC3 cells. Computer-aided algorithms predicted mitogen-and stress-activated protein kinase, MSK1, as a potential target of miR-148a. Indeed, miR-148a overexpression decreased expression of MSK1. Using luciferase reporter assays, we identified MSK1 as a direct target of miR-148a. Suppression of MSK1 expression by siRNA, however, showed little or no effects on malignant phenotypes of PC3 cells. In PC3PR cells, a paclitaxel-resistant cell line established from PC3 cells, miR-148a inhibited cell growth, and cell migration and invasion, and also attenuated the resistance to paclitaxel. MiR-148a reduced MSK1 expression by directly targeting its 3-UTR in PC3PR cells. Furthermore, MSK1 knockdown reduced paclitaxel-resistance of PC3PR cells, indicating that miR-148a attenuates paclitaxel-resistance of hormone-refractory, drug-resistant PC3PR cells in part by regulating MSK1 expression. Our findings suggest that miR148a plays multiple roles as a tumor suppressor and can be a promising therapeutic target for hormone-refractory prostate cancer especially for drug-resistant prostate cancer. MicroRNAs (miRNAs)2 are small non-coding RNAs composed of about 22-24 nucleotides and control protein expression through translational inhibition or mRNA degradation by binding to the 3Ј-untranslated region (3Ј-UTR) of target mRNAs (1). miRNAs regulate a number of biological processes such as development, proliferation, differentiation, and apoptosis. Aberrant expression of miRNA has been reported in a variety of cancers, some of which have been shown to act as tumor suppressors or oncogenes (2).MiR-148a expression is down-regulated in human breast cancer and undifferentiated gastric cancer (3, 4). DNA methylation-associated silencing of miR-148 expression is identified in human cancer cell lines established from lymph node metastasis of colon, melanoma, and head and neck cancer, suggesting its role for the development of metastasis (5). Direct targets of miR-148a so far reported include transcription growth factor-␤-induced factor 2 (TGIF2), DNA (cytosine-5-)-methyltransferase 3␤ (DNMT3b) and pregnane X receptor (PXR) (5-7). However, the functional roles and target genes of miR-148a in prostate cancer have not yet been documented.Mitogen-and stress-activated kinase 1 (MSK1), also known as ribosomal protein S6 kinase, 90kDa, polypeptide 5 (RPS6KA5), is a serine/threonine...

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

“…They play an important role in biological processes23 and are broadly involved in tumour proliferation, invasion, angiogenesis and drug resistance 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.…”

miR-148a is an androgen-responsive microRNA that promotes LNCaP prostate cell growth by repressing its target CAND1 expression

“…23 It has been recently shown that the overexpression of miR-148a precursor inhibited the growth of androgen-refractory PC3 cells, and even paclitaxel-resistant PC3 cells by repressing an miR-148a target mitogen-and stress-activated protein kinase 1. 24 It is interesting that ectopic miR-148a functions as a tumor suppressor in androgen-refractory PC3 cells, which originally contains a smaller amount of miR-148a than androgen-sensitive LNCaP cells. We consider that miR148a expression would be altered during the progression of cancer stages.…”

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing

“…exhibited the regulation pattern of stage-specific increasing expression with a dramatic reduction of expression in lymph node metastasizing prostate carcinoma. We, furthermore, selected miRNAs miR-15a and miR-148a because the functional role of these miRNAs in primary prostate carcinoma cases is currently under discussion (18)(19)(20). The changes in the expression levels of let-7c, miR-15a, miR-20a, miR-143, miR-145, miR-148a, miR-200b, and miR-375 observed by sequencing were analyzed by Northern blot analysis of the pooled RNAs employed in the generation of the cDNA libraries for sequencing as shown in Supplementary Fig.…”

“…2 and 3). miRNAs are short, noncoding RNAs of approximately [19][20][21][22][23][24][25] nucleotides that bind preferentially to specific sequences in the 3 0 -untranslated region (3 0 UTR) of mRNAs, resulting in either translational repression or mRNA degradation. Interaction of the miRNAs with their mRNA target ultimately leads to reduced protein synthesis via association with the Argonaute (Ago-) containing RNAinduced silencing complex (for a review, see ref.…”