Effect of gestational antiandrogen treatment on Dicer1 expression in the porcine fetal gonads

Differential microRNA expression in colon adenocarcinoma (CA) was previously reported. MicroRNA biogenesis and function requires a set of proteins designated as the microRNA machinery, which includes DICER1 and PRKRA. Loss of heterozygosity at 14q32.13 DICER1 locus was detected in up to 60% of CA cases. The in silico gene array analysis of CA showed down-regulation of DICER1 and an up-regulation of PRKRA. Immunohistochemically, DICER1 expression was abnormal in 65% of CA (95 of 147 cases). PRKRA was deregulated in 70% of CA (32 of 46 cases). Expression of DICER1 and PRKRA was correlated with clinicopathologic features of CA. DICER1 up-regulation was seen more commonly in women. Only 10 of 46 cases immunostained for both DICER1 and PRKRA showed normal levels of both DICER1 and PRKRA. Microsatellite status of 32 cases was determined. Microsatellite instable cases showed DICER1 up-regulation more commonly when compared to microsatellite stable cases; however, this trend was not statistically significant. Abnormal DICER1 and/or PRKRA expression might explain the observed changes in microRNA profile. The status of the endogenous DICER1 and PRKRA in CA may help to predict the response to future RNA interference-based therapy.

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Evaluating genomic biomarkers associated with resistance or sensitivity to chemotherapy in patients with advanced breast and colorectal cancer

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155220951845 ◽

2020 ◽

pp. 107815522095184

Author(s):

Jolene Guenter ◽

Shirin Abadi ◽

Howard Lim ◽

Stephen Chia ◽

Ryan Woods ◽

...

Keyword(s):

Breast Cancer ◽

Colorectal Cancer ◽

Cancer Patients ◽

Genomic Analysis ◽

Breast Cancer Patients ◽

Genomic Biomarkers ◽

Colorectal Cancer Patients ◽

Chemotherapy Agents ◽

Genomic Patterns ◽

Dicer1 Expression

Introduction Carcinogenesis is driven by an array of complex genomic patterns; these patterns can render an individual resistant or sensitive to certain chemotherapy agents. The Personalized Oncogenomics (POG) project at BC Cancer has performed integrative genomic analysis of whole tumour genomes and transcriptomes for over 700 patients with advanced cancers, with an aim to predict therapeutic sensitivities. The aim of this study was to utilize the POG genomic data to evaluate a discrete set of biomarkers associated with chemo-sensitivity or-resistance in advanced stage breast and colorectal cancer POG patients. Methods This was a retrospective multi-centre analysis across all BC CANCER sites. All breast and colorectal cancer patients enrolled in the POG program between July 1, 2012 and November 30, 2016 were eligible for inclusion. Within the breast cancer population, those treated with capecitabine, paclitaxel, and everolimus were analyzed, and for the colorectal cancer patients, those treated with capecitabine, bevacizumab, irinotecan, and oxaliplatin were analyzed. The expression levels of the selected biomarkers of interest ( EPHB4, FIGF, CD133, DICER1, DPYD, TYMP, TYMS, TAP1, TOP1, CKDN1A, ERCC1, GSTP1, BRCA1, PTEN, ABCB1, TLE3, and TXNDC17) were reported as mRNA percentiles. Results For the breast cancer population, there were 32 patients in the capecitabine cohort, 15 in the everolimus cohort, and 12 in the paclitaxel cohort. For the colorectal cancer population, there were 29 patients in the bevacizumab cohort, 12 in the oxaliplatin cohort, 29 in the irinotecan cohort, and 6 in the capecitabine cohort. Of the biomarkers evaluated, the strongest associations were found between Bevacizumab-based therapy and DICER1 (P = 0.0445); and between capecitabine therapy and TYMP (P = 0.0553). Conclusions Among breast cancer patients, higher TYMP expression was associated with sensitivity to capecitabine. Among colorectal cancer patients, higher DICER1 expression was associated with sensitivity to bevacizumab-based therapy. This study supports further assessment of the potential predictive value of mRNA expression of these genomic biomarkers.

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MicroRNA-Independent Modulation of DICER1 Expression by hAgo2

Molecular and Cellular Biology ◽

10.1128/mcb.00221-20 ◽

2020 ◽

Vol 40 (20) ◽

Author(s):

Chee-Hing Yang ◽

Hui-Chun Li ◽

Tzu-Shan Ku ◽

Cheng-Hao Wu ◽

Kei-Choon Sim ◽

...

Keyword(s):

Binding Site ◽

Binding Sites ◽

Untranslated Region ◽

Promoter Activity ◽

Reporter Assay ◽

Independent Mechanism ◽

Proteins Interactions ◽

Dicer1 Expression ◽

Dependent Pathway ◽

Posttranscriptional Level

ABSTRACT Many proteins, including DICER1 and hAgo2, are involved in the biogenesis of microRNAs (miRNAs). Whether hAgo2 regulates DICER1 expression is unknown. Exogenously overexpressed hAgo2 suppressed DICER1 expression at the levels of both protein and mRNA, and the reduction in hAgo2 expression enhanced DICER1 expression. Precursor miRNA processing mediated by DICER1 was also modulated by hAgo2. However, hAgo2 protein did not suppress DICER1 promoter activity. Therefore, hAgo2 protein probably regulates DICER1 expression at the posttranscriptional level. Indeed, hAgo2 protein inhibited the reporter assay of the DICER1 mRNA 3′ untranslated region (3′-UTR). Previous reports have demonstrated that miRNAs (e.g., let-7 and miR-103/107) inhibited DICER1 expression posttranscriptionally. However, hAgo2 still suppressed DICER1 expression in the cells depleted of these miRNAs. Moreover, the reporter activities of the DICER1 mRNA 3′-UTR without these miRNA binding sites were still suppressed by hAgo2. Therefore, in addition to an miRNA-dependent pathway, hAgo2 can also modulate DICER1 expression through an miRNA-independent mechanism. Downregulation of DICER1 expression was further proven to be dependent on both hAgo2 and AUF1 proteins. Interactions of hAgo2 and AUF1 proteins were demonstrated by the coimmunoprecipitation assay. As expected, hAgo2 could not suppress the DICER1 mRNA 3′-UTR reporter with a mutation in the potential AUF1-binding site. Thus, downregulation of DICER1 expression through the 3′-UTR requires both hAgo2 and AUF1.

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Myeloma cell sensitivity to bortezomib is associated with Dicer1 expression

Blood ◽

10.1182/blood-2014-04-571257 ◽

2014 ◽

Vol 124 (4) ◽

pp. 657-658

Author(s):

Gernot Stuhler ◽

Tatyana S. Nekova

Keyword(s):

Myeloma Cell ◽

Cell Sensitivity ◽

Dicer1 Expression

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miR-192 Directly Binds and Regulates Dicer1 Expression in Neuroblastoma

PLoS ONE ◽

10.1371/journal.pone.0078713 ◽

2013 ◽

Vol 8 (11) ◽

pp. e78713 ◽

Cited By ~ 23

Author(s):

Galina Feinberg-Gorenshtein ◽

Avital Guedj ◽

Keren Shichrur ◽

Marta Jeison ◽

Drorit Luria ◽

...

Keyword(s):

Dicer1 Expression

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Metastatik Akciğer Kanserli Hastaların Periferik Kanında Yeni Aday Biyomarker: Yüksek DICER1 Ekspresyon Düzeyi Anew Candidate Biomarker in Peripheral Blood of Patients with Metastatic Lung Cancer: A High DICER1 Expression Leve

AYDIN SAĞLIK DERGİSİ ◽

10.17932/iau.asd.2015.007/asd_v06i2003 ◽

2015 ◽

Vol 6 (2) ◽

pp. 123-138

Author(s):

Mukaddes AVŞAR SARAL ◽

Nurcan ÇIRAK ◽

Gözde KURU TÜRKCAN ◽

Demet AKDENİZ ÖDEMİŞ ◽

Şeref Buğra TUNÇER ◽

...

Keyword(s):

Lung Cancer ◽

Peripheral Blood ◽

Metastatic Lung Cancer ◽

Metastatic Lung ◽

Dicer1 Expression

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Brain Dicer1 is down-regulated in a mouse model of Alzheimer’s disease via Aβ42-induced repression of nuclear factor erythroid 2-related factor 2

10.21203/rs.3.rs-25902/v1 ◽

2020 ◽

Author(s):

Yan Wang ◽

Meiling Lian ◽

Jing Zhou ◽

shengzhou wu

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Luciferase Reporter ◽

Cultured Neurons ◽

Related Factor ◽

Mrna Levels ◽

Nuclear Factor ◽

Dicer1 Expression

Abstract Background Oxidative stress critically underlies the neurodegenerative pathogenesis of Alzheimer's disease (AD). Depletion of Dicer1, an endoribonuclease central to microRNA maturation, also leads to neurodegeneration. We therefore hypothesized that altered Dicer1 expression may play a role in AD. Results Using immunoblotting and quantitative real-time PCR, we found that Dicer1 protein and mRNA levels were reduced in the hippocampi of animals of the AD mouse model APPswe/PSEN1dE9 compared with littermate controls. SiRNA-meditated Dicer1 knockdown induced oxidative stress, reduced mitochondrial intermembrane potential, and increased apoptosis in cultured neurons. Aβ42 exposure decreased Dicer1 and also down-regulated the oxidative stress–induced transcriptional regulator nuclear factor erythroid 2-related factor 2 (Nrf2). Conversely, Nrf2 overexpression increased Dicer1 mRNA and protein levels and reverted the Aβ42-induced Dicer1 reduction. To further investigate Dicer1 regulation, we cloned Dicer1 promoter variants harboring the Nrf2-binding site, the antioxidant response elements (ARE), into a luciferase reporter and found that simultaneous transfection of Nrf2-expressing plasmid increased luciferase expression from these promoter constructs. ChIP assays indicated that Nrf2 directly interacted with the ARE motifs in the Dicer1 promoter. Furthermore, Dicer1 overexpression in cultured neurons reverted Aβ42-induced neurite deficits. Of note, injection of Dicer1-expressing adenovirus into the hippocampus of the AD mice significantly improved spatial learning. Conclusions These findings indicate that Dicer1 expression is reduced in the AD brain and that chronic Aβ exposure decreases Dicer1 levels in neurons via Nrf2–ARE signaling. Our results uncover a significant role for Dicer1 in AD and highlight that Dicer1 expression responds to oxidative stress in the brain.

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