MiR-148a attenuates paclitaxel resistance of hormone-refractory, drug-resistant prostate cancer PC3 cells by regulating MSK1 expression.
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 miR-148a 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.
Fujita
Yasunori
Y
Department of Longevity and Aging Research, Gifu International Institute of Biotechnology, Kakamigahara, Gifu 504-0838, Japan.
Kojima
Keitaro
K
Ohhashi
Riyako
R
Hamada
Nanako
N
Nozawa
Yoshinori
Y
Kitamoto
Aya
A
Sato
Akira
A
Kondo
Shinji
S
Kojima
Toshio
T
Deguchi
Takashi
T
Ito
Masafumi
M
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000166:cytology; D006728:Hormones / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D006728:Hormones; D035683:MicroRNAs; D019893:Ribosomal Protein S6 Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D017239:Paclitaxel
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