Epigenetic silencing of miR-490-3p promotes development of an aggressive colorectal cancer phenotype through activation of the Wnt/β-catenin signaling pathway

Zheng, Kaiyu; Zhou, Xinying; Yu, Jinlong; Li, Qiang; Wang, Hui; Li, Mingyi; Shao, Zonghong; Zhang, Feifei; Luo, Yuhao; Shen, Zetao; Chen, Fei; Shi, Fujun; Cui, Chunhui; Zhao, Dachuan; Lin, Zhiqun; Zheng, Wei; Zou, Zhaowei; Huang, Zong-hai; Zhao, Liang

doi:10.1016/j.canlet.2016.03.024

Cited by 66 publications

(62 citation statements)

References 33 publications

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“…To our knowledge, activation of the Wnt/β-catenin signaling pathway ha an important impact on the EMT in gastric carcinoma and contributes to carcinogenesis in colorectal cancers [23, 24]. These findings from our study have identified that the role of Prrx2 in EMT in breast cancer might be reld to the regulation of β-catenin nuclear translocation and the activation of the Wnt/β-catenin signaling pathway.…”

Section: Discussionmentioning

confidence: 54%

Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition

Lv¹,

Wang

Liu

et al. 2017

Cell Physiol Biochem

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Background/Aims: Epithelial-mesenchymal transition (EMT) is recognized as a crucial mechanism in breast cancer progression and metastasis. Paired-related homeobox 2 (Prrx2) has been identified as a new EMT inducer in cancer, but the underlying mechanisms are still poorly understood. Methods: The expression of Prrx2 was assessed by immunohistochemistry in breast cancer tissues to evaluate the clinicopathological significance of Prrx2, as well as the correlation between Prrx2 and EMT. Short hairpin RNA knockdown of Prrx2 was used to examine cellular effects of Prrx2, detecte the expression of Wnt/β-catenin signaling and EMT-associated proteins, and observe cell proliferation, invasion and migration abilities in vitro and in vivo. Results: Clinical association studies showed that Prrx2 expression was related to tumor size, lymph node metastasis, tumor node metastasis stages, EMT and poor survival. Results also showed that knockdown of Prrx2 could alter cell morphology, suppressed the abilities of cell proliferation, invasion and migration in breast cancer. Moreover, silencing of Prrx2 induced the mesenchymal-epithelial transition and prevented nuclear translocation of β-catenin, inhibited wnt/β-catenin signaling pathway. Conclusion: Our study indicated that Prrx2 may be an important activator of EMT in human breast cancer and it can serve as a molecular target of therapeutic interventions for breast cancer.

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Section: Discussionmentioning

confidence: 54%

Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition

Lv¹,

Wang

Liu

et al. 2017

Cell Physiol Biochem

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“…Deregulation of miR-490-3p has been observed in many types of cancers, such as lung cancer (18), colorectal cancer (19) and gastric cancer (20). Zhang et al demonstrated that the urinary level of miR-490 is positively associated with focal segmental glomerulosclerosis (FSGS) disease activity, and thus miR-490 might be a promising biomarker for evaluating FSGS disease activity (21).…”

Section: Discussionmentioning

confidence: 99%

The diagnostic and prognostic value of plasma microRNA‑125b‑5p in patients with multiple myeloma

et al. 2018

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Abstract. Aberrant expression of microRNAs (miRNAs) contributes to the progression and outcomes of several types of tumor, while circulating miRNAs have been reported to act as biomarkers for several types of cancer. To identify specific circulating miRNAs associated with multiple myeloma (MM), a miRNA microarray analysis was used, which identified 8 upregulated miRNAs and 4 downregulated miRNAs in the plasma of 6 patients with MM compared with 6 healthy individuals. Based on the microarray results, the 8 miRNAs (miR-125b-5p, miR-483-3p, miR-4326, miR-6894-3p, miR-4498, miR-490-3p, miR-7155-5p and miR-937-3p), which were notably upregulated in MM patients were chosen for a second clinical study in 20 healthy controls and 35 patients with MM using reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic analysis demonstrated that miR-125b-5p and miR-490-3p displayed considerable diagnostic accuracy for MM with areas under the curve of 0.954 (P<0.001) and 0.866 (P=0.028), respectively. In addition, the plasma level of miR-125b-5p was associated with the international staging system disease stage. Patients with higher levels of plasma miR-125b-5p had a significantly shorter event-free survival. However, miR-490-3p levels were not associated with event-free survival (P>0.05). In summary, miR-125b-5p may serve as a potential clinical biomarker for MM.

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“…Considering the tumor suppressive effects of CHRM2 reported earlier as well as of miR‐490‐3p (reported in the present study), the coregulation of CHRM2 and miR‐490‐3p could be of clinical importance for development of multipronged GBM treatment methodologies. Interestingly, miR‐490‐3p also becomes important as it has been shown to be downregulated in multiple tumors including gastric cancer, ovarian, osteosarcoma, breast, colorectal and endometrial cancer where it has been shown to play a tumor suppressive role . In contrast, its upregulated expression has also been reported in lung and hepatocellular carcinoma where it functioned as an oncomiR .…”

Section: Discussionmentioning

confidence: 99%

Polycomb complex mediated epigenetic reprogramming alters TGF‐β signaling via a novel EZH2/miR‐490/TGIF2 axis thereby inducing migration and EMT potential in glioblastomas

Vinchure

Sharma

Tabasum

et al. 2019

Intl Journal of Cancer

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Recent advancement in understanding cancer etiology has highlighted epigenetic deregulation as an important phenomenon leading to poor prognosis in glioblastoma (GBM). Polycomb repressive complex 2 (PRC2) is one such important epigenetic modifier reportedly altered in GBM. However, its defined mechanism in tumorigenesis still remains elusive. In present study, we analyzed our in‐house ChIPseq data for H3k27me3 modified miRNAs and identified miR‐490‐3p to be the most common target in GBM with significantly downregulated expression in glioma patients in both TCGA and GBM patient cohort. Our functional analysis delineates for the first time, a central role of PRC2 catalytic unit EZH2 in directly regulating expression of this miRNA and its host gene CHRM2 in GBM. In accordance, cell line treatment with EZH2 siRNA and 5‐azacytidine also confirmed its coregulation by CpG and histone methylation based epigenetic mechanisms. Furthermore, induced overexpression of miR‐490‐3p in GBM cell lines significantly inhibited key hallmarks including cellular proliferation, colony formation and spheroid formation, as well as epithelial‐to‐mesenchymal transition (EMT), with downregulation of multiple EMT transcription factors and promigratory genes (MMP9, CCL5, PIK3R1, ICAM1, ADAM17 and NOTCH1). We also for the first time report TGFBR1 and TGIF2 as two direct downstream effector targets of miR‐490‐3p that are also deregulated in GBM. TGIF2, a novel target, was shown to promote migration and EMT that could partially be rescued by miR‐490‐3p overexpression. Overall, this stands as a first study that provides a direct link between epigenetic modulator EZH2 and oncogenic TGF‐β signaling involving novel miR‐490‐3p/TGIF2/TGFBR1 axis, that being targetable might be promising in developing new therapeutic intervention strategies for GBM.

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Epigenetic silencing of miR-490-3p promotes development of an aggressive colorectal cancer phenotype through activation of the Wnt/β-catenin signaling pathway

Cited by 66 publications

References 33 publications

Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition

Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition

The diagnostic and prognostic value of plasma microRNA‑125b‑5p in patients with multiple myeloma

Polycomb complex mediated epigenetic reprogramming alters TGF‐β signaling via a novel EZH2/miR‐490/TGIF2 axis thereby inducing migration and EMT potential in glioblastomas

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