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  • MicroRNA miRNA is an abundant group of small nucleotide nonc

    2024-05-14

    MicroRNA (miRNA) is an abundant group of small (22-nucleotide) noncoding RNA molecules that directly binds with 3′ untranslated region (UTR) of target messenger RNAs (mRNAs) to regulate gene expression, playing an important role in variety of biological processes including cell proliferation, apoptosis, differentiation, invasion, migration and so on [8], [9], [10], [11]. Accumulating studies showed that miRNAs are dysregulated in a variety of cancers and play an critical role in tumorigenesis [12], [13], [14], [15], [16], [17]. Recent studies demonstrated that miRNAs have been recognized as critical regulators in development and progression of cancer including osteosarcoma [18], [19], [20], [21], [22], [23]. Therefore, identification of novel miRNAs involved in osteosarcoma progression may contribute to development of prognostic biomarker and therapeutic strategy for osteosarcoma. The AMD3100 levels of miR-24 has been reported to be dysregulated in various kinds of cancers [24], [25], [26]. For example, miR-24 functions as oncogene and was upregulated in breast cancer [27], oral carcinoma [24], glioma [26] and so on. Moreover, miR-24 was reported as tumor suppressor and significantly downregulated in gastric cancer [28], laryngeal carcinoma [29] and nasopharyngeal carcinoma [30]. Recently, Song et al. showed that miR-24 inhibits osteosarcoma cell proliferation both in vitro and in vivo [31]. However, the molecular mechanism that miR-24 regulate metastasis of osteosarcoma remains unclear. Here, we showed that Ack1 is a direct target of miR-24 in osteosarcoma. Functional assay showed that overexpressed miR-24 in osteosarcoma inhibited Ack1 expression, thus suppressing cell migration and invasion via AKT/MMPs pathway. Therefore, this study revealed a novel pathway comprising miR-24/Ack1/AKT/MMPs in osteosarcoma, may be a promising gene therapeutic target against osteosarcoma progression.
    Materials and methods
    Results
    Discussion Ack1, a nonreceptor tyrosine kinase, was originally identified as a Cdc42-interacting protein and a Cdc42 effector. Ack1 has been reported to be overexpressed in various human cancers and involve cancers cell metastasis [4], [6]. However, little is known about the expression levels and mechanism of Ack1 in osteosarcoma. In this study, we found that Ack1 is overexpressed in osteosarcoma tissues and cells. In addition, the clinical data showed that high expression level of Ack1 is closely associated with clinical stage and positive distant metastasis, and negatively correlated with overall survival. These results indicated that high Ack1 expression may represent a novel indicator of poor prognosis in osteosarcoma and may act as a therapeutic target for osteosarcoma patients. Accumulating studies showed that miRNAs play critical role in tumorigenesis and progression by regulating target gene expression [36]. Ack1 has been reported to involve tumorigenesis of various cancers, however, only miR-7 was identified as the direct target miRNA of Ack1 in schwannoma [37]. Here, we used bioinformatics databases www.microRNA.org and TargetScan and predict the miR-24 contain the complementary sequence and could bind to the 3’ -UTR of Ack1 mRNA. Next, luciferase experiments revealed that miR-24 directly targeted the 3′-UTR of Ack1 mRNA. Therefore, we investigated the regulation of miR-24 on Ack1 expression. Our results showed that the miR-24 mimics downregulated, whereas the miR-24 inhibitor upregulated, the expression levels of Ack1. Consistent with previous results [31], we found that the expression of miR-24 was significantly decreased in osteosarcoma tissues. Further analysis showed that a significant inverse correlation between miR-24 and Ack1 expression was observed in the above osteosarcoma specimens. These data indicate for the first time that Ack1 is a target of miR-24 in osteosarcoma. MiR-24 identified as a tumor suppressor in various cancers [24], [25], [26]. Previous study showed that miR-24 inhibits osteosarcoma cell proliferation by AMD3100 targeting LPAATbeta [31]. However, the effects of miR-24 on osteosarcoma cell invasion and migration remain unclear. Here, we found that miR-24 mimics evidently suppressed osteosarcoma cell invasion and migration, which was simulated by Ack1 siRNA and rescued by Ack1 plasmid. In addition, AKT, which was shown to be the downstream regulator of Ack1, also involves in tumorigenesis of various cancers [38], [39]. Our study showed that miR-24-repressed Ack1 expression resulted in the downregulation of p-Ack1, MMP2 and MMP9 expression. These results suggested that miR-24 regulated osteosarcoma metastasis by repressing Ack1 expression via AKT/MMPs pathway.