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MiR-760 suppresses human colorectal cancer growth by targeting BATF3/AP-1/cyclinD1 signaling.

ABSTRACT: BACKGROUND:Recent studies have reported that microRNAs (miRNAs) often function as negative post-transcriptional regulators with altered expression levels found in colorectal cancer (CRC). There have been few studies on miRNAs that regulate the oncogenic alterations in CRC. Here, we aim to explore the anti-cancer miRNA and the potential mechanisms by which miRNAs modulate CRC progression. METHODS:We performed an integrated analysis of CRC miRNA expression datasets in The Cancer Genome Atlas (TCGA). The miRNA with the lowest expression, miR-760, was validated in an independent validation sample cohort of 76 CRC tissues. Functional assays, such as CCK-8 assay, colony formation assay, and CFSE staining, were used to determine the oncogenic role of miR-760 in human CRC progression. Furthermore, western blotting and dual-luciferase reporter assay were used to determine the mechanism by which miR-760 promotes proliferation of CRC cells. Xenograft nude mouse models were used to determine the role of miR-760 in CRC tumorigenicity in vivo. Immunohistochemical assays were conducted to study the relationship between miR-760 expression and basic leucine zipper transcriptional factor ATF-like 3 (BATF3) expression in human CRC samples. RESULTS:miR-760 was markedly downregulated in CRC tissues, and low miR-760 expression was associated with poor prognosis among CRC patients. Upregulation of miR-760 suppressed CRC cell proliferation, whereas downregulation of miR-760 promoted CRC proliferation in vitro. Additionally, we identified BATF3 as a direct target of miR-760, and that the essential biological function of miR-760 during CRC progression both in vitro and in vivo is to suppress the expression of BATF3 and downstream cyclinD1 via AP-1 transcription factor. Finally, we showed a significant correlation between miR-760 and BATF3 expression in CRC tissues. CONCLUSIONS:miR-760 inhibited CRC growth by downregulating BATF3/AP-1/ cyclinD1 signaling.

SUBMITTER: Cao L

PROVIDER: S-EPMC5902951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIsoliquiritigenin (ISL), a natural flavonoid isolated from the root of licorice (Glycyrrhiza uralensis), has shown various pharmacological properties including anti-oxidant, anti-inflammatory and anti-cancer activities. MicroRNAs (miRNAs), a class of small non-coding RNAs, have been reported as post-transcriptional regulators with altered expression levels in melanoma. This study aims to investigate the anti-melanoma effect of ISL and its potential mechanism.MethodsWe investigated the effect of ISL on the proliferation and apoptosis of melanoma cell lines with functional assays, such as CCK-8 assay, colony formation assay and flow cytometry. The protein level of apoptosis related genes were measured by western blotting. High-throughput genome sequencing was used for screening differentially expressed miRNAs of melanoma cell lines after the treatment of ISL. We performed functional assays to determine the oncogenic role of miR-301b, the most differentially expressed miRNA, and its target gene leucine rich repeats and immunoglobulin like domains 1 (LRIG1), confirmed by bioinformatic analysis, luciferase reporter assay, western blotting and immunohistochemical assay in melanoma. Immunocompromised mouse models were used to determine the role of miR-301b and its target gene in melanoma tumorigenesis in vivo. The relationship between miR-301b and LRIG1 was further verified in GEO data set and tissue specimens.ResultsFunctional assays indicated that ISL exerted significant growth inhibition and apoptosis induction on melanoma cells. MiR-301b is the most differentially expressed miRNA after the treatment of ISL and significantly downregulated. The suppressive effect of ISL on cell growth is reversed by ectopic expression of miR-301b. Intratumorally administration of miR-301b angomir enhances the inhibitory effect of ISL on tumor growth in vivo. Bioinformatic analysis showed that miR-301b may target LRIG1, miR-301b suppresses the luciferase activity of reporter constructs containing 3'UTR of LRIG1 as well as the expression level of LRIG1. And the anti-cancer effect of ISL is mitigated when LRIG1 is silenced in vivo and in vitro. Analysis of the melanoma samples obtained from patients shows that LRIG1 is negatively correlated with miR-301b.ConclusionsISL may inhibit the proliferation of melanoma cells by suppressing miR-301b and inducing its target LRIG1.

Project description:MicroRNAs serve an important role in the development of several diseases. Numerous genes regulate the skeletal muscle differentiation of C2C12 myoblasts. The role of miR?760 in rheumatoid arthritis (RA) has not been reported, to the best of our knowledge. Therefore, the aim of the present study was to examine the role of miR?760 in regulating skeletal muscle proliferation in RA. Potential genes functionally involved in the tarsal joint of a collagen?induced RA model were identified using Gene Expression Omnibus. Reverse transcription?quantitative PCR and western blot analyses were performed to determine the mRNA and protein expression levels. The proliferation, cell cycle progression and migration of C2C12 myoblasts were detected using Cell Counting Kit?8, flow cytometry and wound?healing assays, respectively. TargetScan was used to predict the potential target genes of miR?760, and this was verified using a dual?luciferase reporter assay. In the present study, myosin?18b (Myo18b) expression was determined to be downregulated in the RA model. Silencing Myo18b decreased the proliferation, abrogated the cell cycle progression, and reduced the migration and differentiation of C2C12 myoblasts. Expression levels of cyclin?dependent kinase 2, cyclin D1, matrix metalloproteinase (MMP)?2, MMP?9, myogenin and myosin heavy chain 6 were all decreased when Myo18b was silenced. Furthermore, overexpression of Myo18b induced opposing effects on C2C12 myoblasts. It was shown that Myo18b was a target gene of miRNA?760. Overexpression of miR?760 decreased proliferation, cell cycle progression, migration and differentiation in C2C12 myoblasts, and decreased the expression of Myo18b. The opposite results were observed when miR?760 was downregulated. In conclusion, miR?760 inhibited proliferation and differentiation by targeting Myo18b in C2C12 myoblasts. The results of the present study may contribute to understanding the mechanisms underlying RA skeletal muscle proliferation, and miR?760/Myo18b may serve as potential targets for treating patients with RA.

Project description:Oral squamous cell carcinoma (OSCC) is one of the most common malignancies and has a poor prognosis. Circular RNA (circRNA) has been increasingly recognized as a crucial contributor to carcinogenesis. circRNA_0000140 has been aberrantly expressed in OSCC, but its role in tumor growth and metastasis remains largely unclear. Sanger sequencing, actinomycin D, and RNase R treatments were used to confirm head-to-tail junction sequences and the stability of circ_0000140. In vitro cell activities, including proliferation, migration, invasion, and apoptosis, were determined by colony formation, transwell, and flow cytometry assays. The expression levels of circ_0000140, Hippo signaling pathway, and serial epithelial-mesenchymal transition (EMT) markers were measured by quantitative real-time PCR, western blotting, immunofluorescence, and immunohistochemistry. Dual luciferase reporter assays and Argonaute 2-RNA immunoprecipitation assays were performed to explore the interplay among circ_0000140, miR-31, and LATS2. Subcutaneous tumor growth was observed in nude mice, in which in vivo metastasis was observed following tail vein injection of OSCC cells. circ_0000140 is derived from exons 7 to 10 of the KIAA0907 gene. It was down-regulated in OSCC tissues and cell lines, and correlated negatively with poor prognostic outcomes in OSCC patients. Gain-of-function experiments demonstrated that circ_0000140 enhancement suppressed cell proliferation, migration, and invasion, and facilitated cell apoptosis in vitro. In xenograft mouse models, overexpression of circ_0000140 was able to repress tumor growth and lung metastasis. Furthermore, mechanistic studies showed that circ_0000140 could bind with miR-31 and up-regulate its target gene LATS2, thus affecting OSCC cellular EMT. Our findings demonstrated the roles of circ_0000140 in OSCC tumorigenesis as well as in metastasis, and circ_0000140 exerts its tumor-suppressing effect through miR-31/LATS2 axis of Hippo signaling pathway in OSCC.

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MiR-760 suppresses human colorectal cancer growth by targeting BATF3/AP-1/cyclinD1 signaling.

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