Mechanical compression induces VEGFA overexpression in breast cancer via DNMT3A-dependent miR-9 downregulation

Kim, Baek Gil; Gao, Ming; Kang, Suki; Choi, Yoon Young; Lee, Juhyun; Kim, Ji Eun; Han, Hyunho; Mun, Seong Gyeong; Cho, Nam Hoon

doi:10.1038/cddis.2017.73

Cited by 64 publications

(56 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The qPCR expression data of selected miRs gives preliminary results about the involvement of these miRs in OSCC pathogenesis. miR-9 which is having a dynamic expression profile through different cancer types was found to be up-regulated in our study compared to controls that may be justified as miR-9 upregulation is involved in angiogenesis, metastasis in various cancer types [45] and also it was found to be upregulated in OSF compared to OSCC which is an interesting outcome and probably supports the mechano-transduction of miR-9 [46]as miR-9 is said to be down regulated due to mechanical compression in the tissue and may be OSF has a higher mechanical stress than OSCC due to very high extra cellular matrix (ECM) deposition. However, mechanistic studies using cell lines and animal models may be useful in validating the course of pathogenesis.…”

Section: Discussionsupporting

confidence: 65%

In-silico, interactomic and clinical validation based approach for screening and identification of miR biomarkers involved in Oral submucous fibrosis to Oral squamous cell carcinoma transition

Ukey

Vishnoi

Choudhury

et al. 2020

Preprint

View full text Add to dashboard Cite

Oral Squamous Cell Carcinoma (OSCC) is common preventable disease when diagnosed early, but mostly its progression follows transition from oral potentially malignant disorders (OPMDs) like Oral Submucous Fibrosis (OSF). However, it is difficult to predict possibilities of progression in these premalignant lesions hence, identification of molecular biomarkers would have major clinical impact in early diagnosis and better prognosis. In this context microRNAs(miRs) provide better opportunities in malignancy prediction and demarcation in OSF to OSCC transition as they perform key regulatory roles in many tumorigenic processes. Here, we computationally screened differentially expressed miRs of OSCC and OSF from public databases followed by construction of protein interaction networks and enrichment analyses. The relevant miRs were validated using qPCR of total 93 samplesincluding 34 OSCC, 30 OSF and 29 control blood and tissue samples. We identified significant down regulation of miR-133a-3p in OSCC compared to controls and interesting up-regulation compared to OSCC and control. miR-9-5p was up-regulated in OSF as well as OSCC and down-regulated in OSF compared to OSCC. Therefore, these two miRs may serve as risk stratification biomarkers with validation in larger categorical datasets.

show abstract

Section: Discussionsupporting

confidence: 65%

In-silico, interactomic and clinical validation based approach for screening and identification of miR biomarkers involved in Oral submucous fibrosis to Oral squamous cell carcinoma transition

Ukey

Vishnoi

Choudhury

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Dnmt3a is a methyltransferase that is responsible for the de novo methylation of promoter CpGs with different targets. The expression of miRNA can be regulated by Dnmt3a-dependent promoter methylation 67 , 68 . In NIH 3T3 fibroblasts, Dnmt3a induced methylation of the miR-17 promoter to decrease its expression 68 .…”

Section: Discussionmentioning

confidence: 99%

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle

et al. 2020

View full text Add to dashboard Cite

Rationale: Skeletal muscle insulin resistance is detectable before type 2 diabetes is diagnosed. Exposure to di(2-ethylhexyl) phthalate (DEHP), a typical environmental endocrine-disrupting chemical, is a novel risk factor for insulin resistance and type 2 diabetes. This study aimed to explore insulin signaling regulatory pathway in skeletal muscle of the DEHP-induced insulin-resistant mice and to investigate potential therapeutic strategies for treating insulin resistance. Methods: C57BL/6J male mice were exposed to 2 mg/kg/day DEHP for 15 weeks. Whole-body glucose homeostasis, oxidative stress and deregulated miRNA-mediated molecular transduction in skeletal muscle were examined. microRNA (miRNA) interventions based on lentiviruses and adeno-associated viruses 9 (AAV9) were performed. Results: Dnmt3a-dependent promoter methylation and lncRNA Malat1-related sponge functions cooperatively downregulated miR-17 in DEHP-exposed skeletal muscle cells. DEHP suppressed miR-17 to disrupt the Keap1-Nrf2 redox system and to activate oxidative stress-responsive Txnip in skeletal muscle. Oxidative stress upregulated miR-200a, which directly targets the 3'UTR of Insr and Irs1 , leading to hindered insulin signaling and impaired insulin-dependent glucose uptake in skeletal muscle, ultimately promoting the development of insulin resistance. AAV9-induced overexpression of miR-17 and lentivirus-mediated silencing of miR-200a in skeletal muscle ameliorated whole-body insulin resistance in DEHP-exposed mice. Conclusions: The miR-17/Keap1-Nrf2/miR-200a axis contributed to DEHP-induced insulin resistance. miR-17 is a positive regulator, whereas miR-200a is a negative regulator of insulin signaling in skeletal muscle, and both miRNAs have the potential to become therapeutic targets for preventing and treating insulin resistance or type 2 diabetes.

show abstract

“…First, we show that DNMT3Ab serves as an important regulator of GC cell metastasis. DNMT3A has been implicated in the dysregulation of several cellular processes in cancers [ 31 – 34 ]. Silencing DNMT3A results in dramatic inhibition of melanoma growth and metastasis [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer

Ying

Guo

et al. 2018

Oncogene

View full text Add to dashboard Cite

DNA methyltransferase 3A (DNMT3A) has been recognised as a key element of epigenetic regulation in normal development, and the aberrant regulation of DNMT3A is implicated in multiple types of cancers, especially haematological malignancies. However, its clinical significance and detailed functional role in solid tumours remain unknown, although abnormal expression has gained widespread attention in these cancers. Here, we show that DNMT3A isoform b (DNMT3Ab), a member of the DNMT3A isoform family, is critical for directing epithelial–mesenchymal transition (EMT)-associated metastasis in gastric cancer (GC). DNMT3Ab is positively linked to tumour-node-metastasis (TNM) stage, lymph node metastasis and poor prognosis in GC patients. Overexpression of DNMT3Ab promotes GC cell migration and invasion as well as EMT through repression of E-cadherin. Meanwhile, DNMT3Ab promotes lung metastasis of GC in vivo. Mechanistic studies indicate that DNMT3Ab mediates the epigenetic inaction of the E-cadherin gene via DNA hypermethylation and histone modifications of H3K9me2 and H3K27me3. Depletion of DNMT3Ab effectively restores the expression of E-cadherin and reverses TGF-β-induced EMT by reducing DNA methylation, H3K9me2 and H3K27me3 levels at the E-cadherin promoter. Importantly, DNMT3Ab cooperated with H3K9me2 and H3K27me3 contributes to the transcriptional regulation of E-cadherin in a Snail-dependent manner. Further, gene expression profiling analysis indicates that multiple metastasis-associated genes and oncogenic signalling pathways are regulated in response to DNMT3Ab overexpression. These results identify DNMT3Ab as a crucial regulator of metastasis-related genes in GC. Targeting the DNMT3Ab/Snail/E-cadherin axis may provide a promising therapeutic strategy in the treatment of metastatic GC with high DNMT3Ab expression.

show abstract

Mechanical compression induces VEGFA overexpression in breast cancer via DNMT3A-dependent miR-9 downregulation

Cited by 64 publications

References 58 publications

In-silico, interactomic and clinical validation based approach for screening and identification of miR biomarkers involved in Oral submucous fibrosis to Oral squamous cell carcinoma transition

In-silico, interactomic and clinical validation based approach for screening and identification of miR biomarkers involved in Oral submucous fibrosis to Oral squamous cell carcinoma transition

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle

DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer

Contact Info

Product

Resources

About