MET/SMAD3/SNAIL circuit mediated by miR-323a-3p is involved in regulating epithelial–mesenchymal transition progression in bladder cancer

Li, Jiangfeng; Xu, Xin; Meng, Shuai; Liang, Zhen; Wang, Xiao; Xu, Mingjie; Wang, Song; Li, Shiqi; Zhu, Yi; Xie, Bo; Lin, Yiwei; Zheng, Xiangyi; Liu, Ben; Xie, Liping

doi:10.1038/cddis.2017.331

Cited by 50 publications

(65 citation statements)

References 48 publications

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“…We found that miR-381-3p was significantly down-regulated in BCa, which was induced by the hypermethylated status of CpG islands of MEG3-DMR. Previously we detected that IG-DMR contributed to the reduction of miR-323a-3p in BCa (5). Furthermore, it has been identified that IL-6 treatment induced the hypermethylation of IG-DMR, which blocked the expression of miR-370 in human cholangiocarcinoma (30).…”

Section: Discussionmentioning

confidence: 87%

“…Noncoding RNAs located at the DLK-DIO3-imprinted domain have also been suggested to play important roles in regulating various types of cancers (22). The most noncoding RNAs are miRNA clusters, and some of them have been investigated in BCa (5,7,8). MiR-381-3p was also a member of this miRNA cluster, located at chromosome 14q32.31.…”

Section: Discussionmentioning

confidence: 99%

“…The Trizol method was used to extract RNA from cell lines; specific RNA isolation steps and qRT-PCR processes have been previously described (5).…”

Section: Rna Isolation and Qrt-pcrmentioning

confidence: 99%

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Dual regulatory role of CCNA2 in modulating CDK6 and MET‐mediated cell‐cycle pathway and EMT progression is blocked by miR‐381‐3p in bladder cancer

Ying

Xie

et al. 2018

The FASEB Journal

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Emerging evidence has elucidated that microRNAs (miRNAs) transcribed from miRNA cluster at DLK-DIO3 imprinted domain are involved in various cancers. However, as one member of this cluster, the underlying mechanisms and functions of miR-381-3p in bladder cancer (BCa) still remains elusive. Here we demonstrate that the hypermethylated status of upstream maternally expressed gene 3 divergent methylation region reduces the expression of miR-381-3p in BCa by bisulfite-sequencing PCR. In vitro and in vivo experiments indicate that overexpression of miR-381-3p significantly inhibits cell proliferation via inducing G phase arrest and migration via down-regulating MET and CCNA2 induced EMT progression. CDK6/CCNA2/MET are all identified as the direct targets of miR-381-3p by bioinformatics analysis and dual-luciferase reporter assay. Furthermore, inhibition of CCNA2 mediated by miR-381-3p as the crucial biregulator not only participates in the proliferation regulation with CDK6 in cell cycle but also modulates the EMT progression via ROCK/AKT/β-catenin/SNAIL pathway, which establishes an EMT circuit combined with miR-381-3p/MET/AKT/GSK-3β/SNAIL pathway, and SNAIL is the last confocal target to induce EMT progression. To conclude, we propose 2 novel regulatory circuits mediated by miR-381-3p in BCa, which may assist in the development of more effective therapies against BCa in the future.-Li, J., Ying, Y., Xie, H., Jin, K., Yan, H., Wang, S., Xu, M., Xu, X., Wang, X., Yang, K., Zheng, X., Xie, L. Dual regulatory role of CCNA2 in modulating CDK6 and MET-mediated cell-cycle pathway and EMT progression is blocked by miR-381-3p in bladder cancer.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Dual regulatory role of CCNA2 in modulating CDK6 and MET‐mediated cell‐cycle pathway and EMT progression is blocked by miR‐381‐3p in bladder cancer

Ying

Xie

et al. 2018

The FASEB Journal

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“…7 In addition, we previously confirmed the tumour-suppressing role of a series of miRNAs, including miR-22, miR-148a-3p, miR-182-5p, miR-320c, miR-323a-3p, miR-409, miR-433 and miR-576, which are involved in regulating oncogenicity and progression of BCa. [8][9][10][11][12][13][14][15] MiR-502-5p is located at Xp11. 23 and has been reported to be associated with the tumorigenicity and progression of breast cancer, 16 colon cancer, 17 liver cancer 18 and non-Hodgkin lymphoma.…”

Section: Micrornas (Mirnas) Belonging To a Class Of Short Noncodingmentioning

confidence: 99%

CCND1, NOP14 and DNMT3B are involved in miR‐502‐5p–mediated inhibition of cell migration and proliferation in bladder cancer

Ying

Xie

et al. 2020

Cell Proliferation

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Objectives Downregulation of miR‐502‐5p has emerged as a critical factor in tumour progression in several cancers. Herein, we elucidated the role of miR‐502‐5p in bladder cancer. Materials and methods RT‐qPCR was performed to examine the expression of miR‐502‐5p in bladder cancer. And DNA methylation analysis showed that epigenetic mechanisms may contribute to the downregulation of miR‐502‐5p. Then, wound‐healing assay, transwell assay, colony formation assay, CCK8 assay and flow cytometry analysis were applied to evaluate the function of miR‐502‐5p in bladder cancer cell lines. Western blot was conducted to measure the protein levels of related genes. Furthermore, dual‐luciferase reporter assay, in vivo tumorigenesis assay and immunohistochemical staining were also conducted as needed. Results MiR‐502‐5p is frequently downregulated in BCa. Meanwhile, hypermethylation of CpG islands contributes to the downregulation of miR‐502‐5p. Functionally, overexpression of miR‐502‐5p inhibited cell proliferation and migration in vitro and repressed tumour growth in vivo. CCND1, DNMT3B and NOP14 were identified as direct targets of miR‐502‐5p. Interestingly, DNMT3B and miR‐502‐5p established a positive feedback loop in the regulation of bladder cancer. In addition, rescue experiments further validated the direct molecular interaction between miR‐502‐5p and its targets. Conclusions Our study proposed and demonstrated that the miR‐502‐5p–mediated regulatory network is critical in bladder cancer; this network may be useful in the development of more effective therapies against bladder cancer.

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“…The plasma levels of miR‐106b‐5p differed significantly between patients with CRC and those neoplasm free; miR‐335 has been proposed as tumor suppressor miRNA in CRC, where it discriminated between nonserrated and serrated polyps; plasma levels of this miRNA distinguish patients with CRC from healthy controls . miR‐323‐3p suppresses the expression of the SMAD family members 2 and 3 ( SMAD2 and SMAD3 ), acting on the transforming growth factor beta ( TGF‐β ) pathway and epithelial‐to‐mesenchymal progression, in pancreatic and bladder cancer . The two remaining miRNAs from the LgA signature, miR‐193a‐5p and miR‐423‐5p, have been found deregulated in CRC.…”

Section: Discussionmentioning

confidence: 99%

Plasma miRNA‐based signatures in CRC screening programs

Zanutto

Ciniselli

Belfiore

et al. 2019

Intl Journal of Cancer

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Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT‐positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real‐time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low‐grade adenoma [LgA], high‐grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two‐miRNA‐based signature for CL and six‐miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607–0.682), 0.670 (0.626–0.714) and 0.682 (0.580–0.785) for LgA, HgA and CL, respectively. A miRNA‐based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.

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MET/SMAD3/SNAIL circuit mediated by miR-323a-3p is involved in regulating epithelial–mesenchymal transition progression in bladder cancer

Cited by 50 publications

References 48 publications

Dual regulatory role of CCNA2 in modulating CDK6 and MET‐mediated cell‐cycle pathway and EMT progression is blocked by miR‐381‐3p in bladder cancer

Dual regulatory role of CCNA2 in modulating CDK6 and MET‐mediated cell‐cycle pathway and EMT progression is blocked by miR‐381‐3p in bladder cancer

CCND1, NOP14 and DNMT3B are involved in miR‐502‐5p–mediated inhibition of cell migration and proliferation in bladder cancer

Plasma miRNA‐based signatures in CRC screening programs

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