Abstract
BackgroundTranscription factors (TFs) may be engaged in reciprocal regulatory circuits with certain miRNAs to maintain cellular homeostasis. Disequilibrium of the reciprocities by certain tumor-related stimuli may give rise to deregulation of downstream cellular signaling pathways, thus promoting malignant tumor phenotypes. Specificity Protein 1 (SP1) is the most representative member of the tumor-related transcription factors. Previous studies disclosed that SP1 can transcriptionally regulate miRNAs and coding genes to facilitate tumor progression. In our study, we used bioinformatic analysis to predict several SP1-binding sites within the miR-320a promoter and found that SP1 is a predicted target gene of miR-320a. Therefore, we hypothesize a reciprocal regulatory link between SP1 and miR-320a that participates in colorectal cancer (CRC) developmentMethodsWe performed bioinformatic analysis, quantitative polymerase chain reaction (qPCR), immunoblotting, dual-luciferase reporter assays, and a series of in vitro and in vivo functional assays to describe a novel SP1/miR-320a reciprocal interaction in CRCResultsFirst, we found that miR-320a was significantly downregulated in CRC tissues and cell lines. Consistent with findings in other cancers, miR-320a exhibited inhibitory effects on cell growth and invasion of CRC in vitro and in vivo. Moreover, we identified SP1 as a target gene of miR-320a, and ectopic SP1 expression partly abolished miR-320a-induced inhibitory effects. Conversely, we confirmed that SP1 interacts with the miR-320a promoter, leading to depression of miR-320a. This illustrates a double-negative feedback loop between miR-320a and SP1. Additionally, based on the fact that SP1 promotes MACC1 transcription, we determined via immunoblotting that the oncogenic MACC1/MET signaling pathway was inactivated in the context of miR-320a-induced SP1 downregulationConclusionTaken together, our study is the first to describe a miR-320a/SP1 negative reciprocal interaction, which contributes to cell growth and invasion in CRC through modulation of the MACC1/MET signaling pathway.
Highlights
Transcription factors (TFs) may be engaged in reciprocal regulatory circuits with certain miRNAs to maintain cellular homeostasis
Results miR‐320a was aberrantly downregulated in CRCmiR-320a has been demonstrated to be decreased in multiple cancer types
Results showed that compared to adjacent normal epithelial tissues, miR-320a was significantly decreased in colorectal cancer (CRC) tissues, (P = 0.0034, Fig. 1b) but Specificity Protein 1 (SP1) was increased in CRC tissues (P = 0.027) (Fig. 1c)
Summary
Transcription factors (TFs) may be engaged in reciprocal regulatory circuits with certain miRNAs to maintain cellular homeostasis. Disequilibrium of the reciprocities by certain tumor-related stimuli may give rise to deregulation of downstream cellular signaling pathways, promoting malignant tumor phenotypes. Previous studies disclosed that SP1 can transcriptionally regulate miRNAs and coding genes to facilitate tumor progression. MiRNAs represent a cluster of small non-coding RNAs acting canonically as negative regulators of gene expression via inducing mRNA degradation or inhibiting mRNA translation [2]. Emerging studies have indicated that miRNAs can promote or suppress cancerous physiological processes, depending on the target genes and downstream signaling pathways [3]. MiR-320a has been shown to negatively regulate invasion of tumor cells by blocking HMGB1 or STAT signaling [6, 12]. Considering the versatility of miR-320a as a cancer-related miRNA, there is a need to explore the potential mechanisms of miR-320a regulation and to identify novel miR-320a-targeting genes
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