miR-224 Is Significantly Upregulated and Targets Caspase-3 and Caspase-7 During Colorectal Carcinogenesis

Fassan, Matteo; Cui, Ri; Gasparini, Pierluigi; Mescoli, Claudia; Guzzardo, Vincenza; Vicentini, Caterina; Munari, Giada; Loupakis, Fotios; Braconi, Chiara; Scarpa, Marco; D’Angelo, Edoardo; Pucciarelli, Salvatore; Angriman, Imerio; Agostini, Marco; D’Incà, R.; Farinati, Fabio; Gafà, Roberta; Lanza, Giovanni; Frankel, Wendy L.; Croce, Carlo M.; Valeri, Nicola

doi:10.1016/j.tranon.2018.10.013

Cited by 17 publications

(9 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed hypermethylation at these CpG loci and increased miR-224/miR-452 expression in ER-compared to ER + tumors. Studies have reported both up-and down-regulation of miR-224 in various cancers, suggesting its cell type-speci c expression and function (43)(44)(45). Speci cally, in breast cancer, and consistent with our study, one study reported increased miR-224 expression in both triple negative breast cancer cell lines and tumor tissues, and that its knockdown in aggressive triple negative breast cancer cells reduced proliferation, migration and invasion (46).…”

Section: Discussionsupporting

confidence: 90%

Genome-wide DNA methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

Gong

Chen

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Aggressive high-grade, estrogen receptor negative (ER-) breast cancer is more common among American women of African ancestry (AA) than those of European ancestry (EA). The reasons remain largely unknown. Epigenetic mechanisms, particularly DNA methylation and altered microRNA (miRNA) expression, may contribute to racial differences in breast cancer. However, few studies have specifically characterized genome-wide DNA methylation-based modifications at the miRNA level in relation to ER+ and ER- breast cancer, and their functional role in the regulation of miRNA expression, especially among high risk AA women. Methods: In this study, genome-wide DNA methylation and miRNA expression profiling was performed using the Illumina Infinium HumanMethylation450 Bead Chip platform and miRNA sequencing (miRNA-seq) in breast tumors from both AA and EA women. Results: The genome-wide methylation screen identified a total of 7,191 unique CpGs mapped to 1,292 miRNA genes, which correspond to 2,035 unique mature miRNAs. Cluster analysis of these miRNA-associated methylation loci showed a clear pattern of ER-subtype differences. We identified differentially methylated loci (DMLs: (|delta β|)>0.10, FDR<0.05) between ER- and ER+ tumor subtypes, including 290 DMLs shared in both races, 317 and 136 were specific to AA and EA women, respectively. Integrated analysis of DNA methylation and corresponding miRNA expression identified certain DMLs whose methylation levels were significantly correlated with the expression of relevant miRNAs, such as multiple CpGs within miR-190b and miR-135b highly negatively correlated with their expression. Further target prediction and pathway analysis showed that these DNA methylation-dysregulated miRNAs are involved in multiple cancer-related pathways, including cell cycle G1-S growth factor, cytoskeleton remodeling, angiogenesis, EMT, and others such as signal transduction TGF-β, Wnt, NOTCH, and ESR1-mediated signaling pathways. Conclusions: Our results suggest that DNA methylation changes within miRNA genes are associated with altered miRNA expression, which may contribute to the network of subtype- and race-related tumor biological differences in breast cancer. These findings shed light on the epigenetic regulation of miRNA expression and provide insights into the relations of clinical-relevant miRNAs to their target genes and to serve as potential preventative and therapeutic targets.

show abstract

Section: Discussionsupporting

confidence: 90%

Genome-wide DNA methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

Gong

Chen

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…We observed hypermethylation at these CpG loci and increased miR-224/miR-452 expression in ER- compared to ER+ tumors. Studies have reported both up- and down-regulation of miR-224 in various cancers, suggesting its cell type-specific expression and function [ 43 – 45 ]. Specifically, in breast cancer, and consistent with our study, one study reported increased miR-224 expression in both triple negative breast cancer cell lines and tumor tissues, and that its knockdown in aggressive triple negative breast cancer cells reduced proliferation, migration and invasion [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Differential methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

et al. 2021

View full text Add to dashboard Cite

Aggressive high-grade, estrogen receptor negative (ER-) breast cancer is more common among American women of African ancestry (AA) than those of European ancestry (EA). Epigenetic mechanisms, particularly DNA methylation and altered microRNA (miRNA) expression, may contribute to racial differences in breast cancer. However, few studies have specifically characterized genome-wide DNA methylation-based modifications at the miRNA level in relation to ER+ and ER- subtype, and their functional role in the regulation of miRNA expression, especially among high risk AA women. In this study, we evaluated DNA methylation patterns of miRNA encoding genes and their effect on expression in breast tumors from both AA and EA women. The genome-wide methylation screen identified a total of 7,191 unique CpGs mapped to 1,292 miRNA genes, corresponding to 2,035 unique mature miRNAs. We identified differentially methylated loci (DMLs: (|delta β|)>0.10, FDR<0.05) between ER- and ER+ tumor subtypes, including 290 DMLs shared in both races, 317 and 136 were specific to AA and EA women, respectively. Integrated analysis identified certain DMLs whose methylation levels were significantly correlated with the expression of relevant miRNAs, such as multiple CpGs within miR-190b and miR-135b highly negatively correlated with their expression. These results were then validated in the TCGA dataset. Target prediction and pathway analysis showed that these DNA methylation-dysregulated miRNAs are involved in multiple cancer-related pathways, including cell cycle G1-S growth factor regulation, cytoskeleton remodeling, angiogenesis, EMT, and ESR1-mediated signaling pathways. In summary, our results suggest that DNA methylation changes within miRNA genes are associated with altered miRNA expression, which may contribute to the network of subtype- and race-related tumor biological differences in breast cancer. These findings support the involvement of epigenetic regulation of miRNA expression and provide insights into the relations of clinical-relevant miRNAs to their target genes, which may serve as potential preventative and therapeutic targets.

show abstract

“…Nevertheless, several lines of evidence have demonstrated miR-592 may participate in CRC tumorigenesis ( 37 , 38 ) and metastasis ( 39 , 40 ). Furthermore, a study identified a potential role for miR-224 in CRC progression ( 41 ). Finally, high expression levels miR-224 have been associated with worse survival of patients in CRC ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNAs Expression Patterns Predict Tumor Mutational Burden in Colorectal Cancer

et al. 2021

View full text Add to dashboard Cite

BackgroundTumor mutational burden (TMB) could be a measure of response to immune checkpoint inhibitors therapy for patients with colorectal cancer (CRC). MicroRNAs (miRNAs) participate in anticancer immune responses. In the present study, we determined miRNA expression patterns in patients with CRC and built a signature that predicts TMB.MethodsNext generation sequencing (NGS) on formalin-fixed paraffin-embedded samples from CRC patients was performed to measure TMB levels. We used datasets from The Cancer Genome Atlas to compare miRNA expression patterns in samples with high and low TMB from patients with CRC. We created an miRNA-based signature index using the selection operator (LASSO) and least absolute shrinkage method from the training set. We used an independent test set as internal validation. We used real-time polymerase chain reaction (RT-PCR) to validate the miRNA-based signature classifier.ResultsTwenty-seven samples from CRC patients underwent NGS to determine the TMB level. We identified four miRNA candidates in the training set for predicting TMB (N = 311). We used the test set (N = 204) for internal validation. The four-miRNA-based signature classifier was an accurate predictor of TMB, with accuracy 0.963 in the training set. In the test set, it was 0.902; and it was 0.946 in the total set. The classifier was superior to microsatellite instability (MSI) for predicting TMB in TCGA dataset. In the validation cohort, MSI status more positively correlated with TMB levels than did the classifier. Validation from RT-qPCR showed good target discrimination of the classifier for TMB prediction.ConclusionTo our knowledge, this is the first miRNA-based signature classifier validated using high quality clinical data to accurately predict TMB level in patients with CRC.

show abstract

miR-224 Is Significantly Upregulated and Targets Caspase-3 and Caspase-7 During Colorectal Carcinogenesis

Cited by 17 publications

References 36 publications

Genome-wide DNA methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

Genome-wide DNA methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

Differential methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

MicroRNAs Expression Patterns Predict Tumor Mutational Burden in Colorectal Cancer

Contact Info

Product

Resources

About