208777262
miR-190b promotes colorectal cancer progression through targeting forkhead box protein P2
microRNA-190b (miR-190b) is abnormally expressed in multiple types of cancer, however, its role in colorectal cancer (CRC) is largely unknown. In the present study, it was demonstrated that miR-190b expression was upregulated in CRC cell lines compared with the normal epithelial colon cell line. Knockdown of miR-190b decreased proliferation, colony formation and invasion, and increased apoptosis of CRC cells. Furthermore, forkhead box protein P2 (FOXP2) was predicted as a target of miR-190b and further validated by luciferase activity reporter assay and western blotting. Rescue experiments showed that knockdown of FOXP2 reversed the inhibitory effects of miR-190b inhibitor on the behavior of the CRC cell lines. Taken together, the present study demonstrated the oncogenic role of miR-190b in CRC through regulation of FOXP2 expression.
36175126
MicroRNA biogenesis pathways in cancer
MicroRNAs (miRNAs) are critical regulators of gene expression. Amplification and overexpression of individual 'oncomiRs' or genetic loss of tumour suppressor miRNAs are associated with human cancer and are sufficient to drive tumorigenesis in mouse models. Furthermore, global miRNA depletion caused by genetic and epigenetic alterations in components of the miRNA biogenesis machinery is oncogenic. This, together with the recent identification of novel miRNA regulatory factors and pathways, highlights the importance of miRNA dysregulation in cancer.
3754882
Up-regulation of miR-190b promoted growth, invasion, migration and inhibited apoptosis of Wilms' tumor cells by repressing the PTEN expression.
OBJECTIVE
Wilms' tumor (WT) is the most common malignant tumor in the children's urogenital system. MiR-190b was found to participate in the development and progression of several cancers. However, the molecular mechanism of miR-190b in WT is still unclear.


PATIENTS AND METHODS
We detected the miR-190b in WT tissue samples compared to adjacent normal samples as well as in WT patients' blood sample compared to normal volunteers using qRT-PCR. With over-expression and knockdown of miR-190b in WT-derived cell line SK-NEP-1, we next studied cell proliferation, cell circle, apoptosis, invasion and migration abilities change caused by miR-190b ectopic expression. Dual-luciferase assay and Western-blot analysis were used to explain the mechanism of miR-190b in WT.


RESULTS
MiR-190b was over-expressed in WT tissue and blood samples compared to normal group, relatively. Up-regulation of miR-190b in SK-NEP-1 cells significantly increased the growth and decreased the apoptosis of cells, while its down-regulation reduced cell proliferation and promoted cell apoptosis of SK-NEP-1. Also, cell invasion and migration abilities were significantly improved after miR-190b over-expression. Moreover, PTEN was proved to be a direct target of miR-190b and its protein level was remarkably decreased after miR-190b up-regulation.


CONCLUSIONS
miR-190b over-expressed in WT and promoted cell proliferation, invasion and migration while reduced cell apoptosis of WT cells by repressing PTEN repression, which might provide a potential target for WT diagnosis and therapy.
46868654
MicroRNA-190b inhibits tumor cell proliferation and induces apoptosis by regulating Bcl-2 in U2OS osteosarcoma cells.
Osteosarcoma (OS) is one of the most prevalent malignancies in bone with no established therapy so far. This study was aimed to clarify the role of miR-190b in tumor cell growth of OS. The miR-190b mimic, inhibitor and miR-control were transfected into human OS U2OS cells. Then U2OS cell proliferation was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and bromodeoxyuridine (BrdU) incorporation assay. The apoptotic U2OS cells were detected by flow cytometry. Additionally, cell-cycle regulators p27, p21 and apoptosis factors B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), caspase-3 were examined by western blotting. Overexpressing miR-190b observably reduced cell viability, BrdU-positive cells (both P < 0.05) and caused strong accumulation of cell-cycle inhibitor p27 in U2OS cells compared with the miR-control, whereas the miR-190b inhibitor exerted opposite effects. Further, a marked increase of 18% rate of apoptotic cells by the overexpressing miR-190b (P < 0.01) and 4% decrease by miR-190b inhibitor (P < 0.05) were detected. The protein expressions of Bcl-2 were downregulated, Bax, pro-caspase-3 and active caspase-3 were upregulated by overexpressing miR-190b in U2OS cell line, while miR-190b inhibitor achieved opposite effects. The present study demonstrates that miR-190b inhibits tumor cell proliferation and induces apoptosis by regulating Bcl-2 in U2OS cells, which points to miR-190b as a novel oncosuppressor for OS. The identified tumor suppressive capacity of miR-190b provides novel avenues for achieving better OS therapy.
19494871
MicroRNA-190b confers radio-sensitivity through negative regulation of Bcl-2 in gastric cancer cells
ObjectivesTo determine the role of miR-190b in radio-sensitivity of gastric cancer (GC).ResultsIn radio-resistant GC cells, down-regulation of miR-190b and up-regulation of Bcl-2 were observed. The protein expression of Bcl-2 was negatively regulated by miR-190b. Overexpression of miR-190b significantly decreased cell viability and enhanced radio-sensitivity of GC cells. Of note, these effects of miR-190b on GC cells radio-sensitivity were abolished by Bcl-2.ConclusionmiR-190b confers radio-sensitivity of GC cells, possibly via negative regulation of Bcl-2.
6513803
Genetic Characteristics of Mitochondrial DNA Was Associated with Colorectal Carcinogenesis and Its Prognosis
Clinical value of mitochondrial DNA has been described in colorectal cancer (CRC). To clarify its role in colorectal carcinogenesis, mitochondrial microsatellite instability (mtMSI) and other markers were investigated in CRCs and their precancerous lesions, as a multitier genetic study. DNA was isolated from paired normal and tumoral tissues in 78 tubular adenomas (TAs), 34 serrated polyps (SPs), and 100 CRCs. mtMSI, nucleus microsatellite instability (nMSI), KRAS mutation, and BRAF mutation were investigated in these tumors and their statistical analysis was performed. mtMSI was found in 30% of CRCs and 21.4% of precancerous lesions. Mitochondrial copy number was higher in SPs than TAs and it was associated with mtMSI in low grade TAs. KRAS and BRAF mutations were mutually exclusive in TAs and SPs. CRCs with mtMSI showed shorter overall survival times than the patients without mtMSI. In CRCs without nMSI or BRAF mutation, mtMSI was a more accurate marker for predicting prognosis. The genetic change of mitochondrial DNA is an early and independent event in colorectal precancerous lesions and mtMSI and mitochondrial contents are associated with the tubular adenoma-carcinoma sequence, resulting in poor prognosis. This result suggested that the genetic change in mitochondrial DNA appears to be a possible prognosis marker in CRC.
52824373
MiR-452 promotes an aggressive colorectal cancer phenotype by regulating a Wnt/β-catenin positive feedback loop
BackgroundAberrant activation of Wnt/β-catenin signaling pathway is considered to be an important issue in progression and metastasis of various human cancers, especially in colorectal cancer (CRC). MiR-452 could activate of Wnt/β-catenin signaling. But the mechanism remains unclear.MethodsThe expression of miR-452 in CRC and normal tissues was detected by real-time quantitative PCR. The effect of miR-452 on CRC growth and invasion was conducted by functional experiments in vitro and in vivo. Bioinformatics and cell luciferase function studies verified the direct regulation of miR-452 on the 3’-UTR of the GSK3β, which leads to the activation of Wnt/β-catenin signaling.ResultsMiR-452 was upregulated in CRC compared with normal tissues and was correlated with clinical significance. The luciferase reporter system studies affirmed the direct regulation of miR-452 on the 3’-UTR of the GSK3β, which activate the Wnt/β-catenin signaling. The ectopic upregulation of miR-452 significantly inhibited the expression of GSK3β and enhanced CRC proliferation and invasion in vitro and in vivo. Meanwhile, knockdown of miR-452 significantly recovered the expression of GSK3β and attenuated Wnt/β-catenin-mediated cell metastasis and proliferation. More important, T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors, which are crucial downstream molecules of the Wnt/β-catenin signaling pathway was verified as a valid transcription factor of miR-452’s promoter.ConclusionsOur findings first demonstrate that miR-452-GSK3β-LEF1/TCF4 positive feedback loop induce CRC proliferation and migration.
52192766
Species-specific function of microRNA-7702 in human colorectal cancer cells via targeting TADA1.
Colorectal cancer (CRC) is highly invasive, and an increasing number of studies report that microRNAs (miRNAs) are involved in CRC cell invasion and metastasis. However, these studies focus on miRNAs with clear functional targets, often overlooking obscure miRNAs. Using TCGA data analysis, we compared differentially expressed miRNAs in colon and rectal adenocarcinoma (stages N0 and N1/N2) to identify miRNAs involved in invasion and metastasis; one identified candidate miRNA was miR-7702. Bioinformatics analysis identified TADA1 as a possible target gene of miR-7702. The relationship between TADA1 and miR-7702 was analyzed using the Oncomine database, CRC tissues at different stages, and CRC cell lines with different metastatic properties. We used a dual luciferase-reporter assay to verify the interaction between miR-7702 and TADA1. We altered miR-7702 and TADA1 expression levels using transfection, and measured cell migration and invasion abilities. The results revealed a negative correlation between miR-7702 and TADA1 in CRC. miR-7702 was significantly downregulated in human CRC cell lines with high invasion capacity. Its overexpression suppressed human CRC cell migration and invasion by directly inhibiting TADA1. This regulatory effect of miR-7702 on TADA1 was observed in human CRC cells but not in mouse cells. These findings indicate that miR-7702 acts as a tumor suppressor in CRC by inhibiting cell migration and invasion, possibly through direct TADA1 inhibition. Our results demonstrate for the first time that miR-7702 and TADA1 are biologically functional in human CRC cells and reveal that the presence and function of miR-7702 may be species-specific.
21674002
Downregulation of FOXP2 promotes breast cancer migration and invasion through TGFβ/SMAD signaling pathway
Cancer metastasis and relapse are the primary cause of mortality for patients with breast cancer. The present study performed quantitative proteomic analysis on the differentially expressed proteins between highly metastatic breast cancer cells and parental cells. It was revealed that forkhead box P2 (FOXP2), a transcription factor in neural development, may become a potential inhibitor of breast cancer metastasis. The results demonstrated that patients with a lower level of FOXP2 expression had significantly poorer relapse-free survival (P=0.0047). The transcription of FOXP2 was also significantly downregulated in breast cancer tissue compared with normal breast tissue (P=0.0005). In addition, FOXP2 may inhibit breast cancer cell migration and invasion in vitro. It was also revealed that the underlying mechanism may include the epithelial-mesenchymal transition process driven by the tumor growth factor β/SMAD signaling pathway. In conclusion, the present study identified FOXP2 as a novel suppressor and prognostic marker of breast cancer metastasis. These results may provide further insight into breast cancer prevention and the development of novel treatments.
22806760
microRNA‑196b promotes cell migration and invasion by targeting FOXP2 in hepatocellular carcinoma.
Accumulating evidence indicates that microRNAs (miRNAs) play important roles in tumorigenesis and metastasis. Recent research has shown that miR‑196b is implicated in metastasis by regulating the migration and invasion of cancer cells. However, the clinical significance of miR‑196b and its role as well as the underlying mechanisms in hepatocellular carcinoma (HCC) remain largely unknown. Here, we detected miR‑196b expression in HCC and matched non-tumor tissues with qRT‑PCR. We found that miR‑196b displayed higher expression in HCC patient tissues and cells. Clinical analysis revealed that high miR‑196 expression was correlated with venous infiltration, advanced TNM stage and poor prognosis. Functionally, we demonstrated that miR‑196b promoted the migration and invasion of HCC cells in vitro. Moreover, miR‑196b knockdown restrained pulmonary metastasis in vivo. Mechanistically, we confirmed that miR‑196b could directly bind to 3'UTR of forkhead box P2 (FOXP2) mRNA and repress its expression. miR‑196b and FOXP2 showed a negative correlation in HCC tissues. More importantly, upregulation of FOXP2 antagonized miR‑196b‑mediated migration and invasion in Hep3B cells. Furthermore, FOXP2 knockdown partially reversed the anti‑metastatic function of the miR‑196b inhibitor on HCCLM3 cells. Taken together, we demonstrated that miR‑196b may function as a prognostic biomarker and suppressed FOXP2 expression, subsequently leading to the metastasis of HCC. Our findings highlight a novel mechanism of miR‑196b in the progression of HCC and identify miR‑196b/FOXP2 axis as a promising target for HCC.