Novel miRNAs as potential biomarkers in stage II colon cancer: microarray analysis

Güngörmez, Çiğdem; Aktaş, Hatice; Dilsiz, Nihat; Borazan, Ersin

doi:10.1007/s11033-019-04868-7

Cited by 49 publications

(43 citation statements)

References 42 publications

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“…We next assessed the functional relevance of miR-378a-5p on in vitro cell proliferation, migration, invasion, and clonogenic ability. Contrary to the results demonstrating miR-378a-5p ability to affect proliferation of several tumor histotypes 23,24 , we did not observe any effect of miR-378a-5p either on proliferation or clonogenic ability of M14 melanoma cells ( Supplementary Fig. 2).…”

Section: Mir-378a-5p Expression Correlates With Melanoma Progressioncontrasting

confidence: 99%

microRNA-378a-5p iS a novel positive regulator of melanoma progression

et al. 2020

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Evaluating the expression levels of miR-378a-5p both in a large melanoma patient cohort from The Cancer Genome Atlas database and in melanoma patients from our Institute, we found that miR-378a-5p is upregulated in metastatic melanoma specimens. miR-378a-5p expression was also increased in melanoma cells resistant to target therapy, and decreased in response to drug treatment. We also demonstrated that overexpression of miR-378a-5p enhances in vitro cell invasion and migration, and facilitates the ability of melanoma cells to form de novo vasculogenic structures. While performing downstream targeting studies, we confirmed the ability of miR-378a-5p to modulate the expression of known target genes, such as SUFU, FUS-1, and KLF9. Luciferase-3′UTR experiments also identified STAMBP and HOXD10 as new miR-378a-5p target genes. MMP2 and uPAR, two HOXD10 target genes, were positively regulated by miR-378a-5p. Genetic and pharmacologic approaches inhibiting uPAR expression and activity evidenced that the in vitro tumor-promoting functions of miR-378a-5p, were in part mediated by uPAR. Of note miR-378a-5p was also able to increase VEGF, as well as in vitro and in vivo angiogenesis. Finally, genetic and pharmacologic modulation of Bcl-2 evidenced Bcl-2 ability to regulate miR-378a-5p expression. In conclusion, to the best of our knowledge, this is the first study demonstrating that miR-378a-5p acts as an oncogenic microRNA in melanoma.

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Section: Mir-378a-5p Expression Correlates With Melanoma Progressioncontrasting

confidence: 99%

microRNA-378a-5p iS a novel positive regulator of melanoma progression

et al. 2020

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“…Alternatively, the risk of colorectal cancer is elevated in UC patients and increases with disease extension and duration (61). Inflammatory molecules have been implicated in tumor microenvironment (62), and in line with our data, miR-378 family members were found decreased in stage II tumor colon cancer (63). This new knowledge emphasizes the relevance of inflammatory molecules involved in UC cancer progression; however, more studies are necessary to understand the implications of miR-378 and IL-33 in colon cancer risk for UC patients.…”

Section: Discussionsupporting

confidence: 89%

Inhibition of miR-378a-3p by Inflammation Enhances IL-33 Levels: A Novel Mechanism of Alarmin Modulation in Ulcerative Colitis

et al. 2019

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Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by mucosa damage associated with an uncontrolled inflammatory response. This immunological impairment leads to altered inflammatory mediators such as IL-33, which is shown to increase in the mucosa of active UC (aUC) patients. MicroRNAs present a distorted feature in inflamed colonic mucosa and are potential IL-33 regulating candidates in UC. Therefore, we studied the microRNA and mRNA profiles in inflamed colonic samples of UC patients, evaluating the effect of a microRNA (selected by in silico analysis and its expression in UC patients), on IL-33 under inflammatory conditions. We found that inflamed mucosa (n = 8) showed increased expression of 40 microRNAs and 2,120 mRNAs, while 49 microRNAs and 1,734 mRNAs were decreased, as determined by microarrays. In particular, IL-33 mRNA showed a 3.8-fold increase and eight members of a microRNA family (miR-378), which targets IL-33 mRNA in the 3′UTR, were decreased (−3.9 to −3.0 times). We selected three members of the miR-378 family (miR-378a-3p, miR-422a, and miR-378c) according to background information and interaction energy analysis, for further correlation analyses with IL-33 expression through qPCR and ELISA, respectively. We determined that aUC (n = 24) showed high IL-33 levels, and decreased expression of miR-378a-3p and miR-422a compared to inactive UC (n = 10) and controls (n = 6). Moreover, both microRNAs were inversely correlated with IL-33 expression, while miR-378c does not show a significant difference. To evaluate the effect of TNFα on the studied microRNAs, aUC patients with anti-TNF therapy were compared to aUC receiving other treatments. The levels of miR-378a-3p and miR-378c were higher in aUC patients with anti-TNF. Based on these findings, we selected miR-378a-3p to exploring the molecular mechanism involved by in vitro assays, showing that over-expression of miR-378a-3p decreased the levels of an IL-33 target sequence β-gal-reporter gene in HEK293 cells. Stable miR-378a-3p over-expression/inhibition inversely modulated IL-33 content and altered viability of HT-29 cells. Additionally, in an inflammatory context, TNFα decreased miR-378a-3p levels in HT-29 cells enhancing IL-33 expression. Together, our results propose a regulatory mechanism of IL-33 expression exerted by miR-378a-3p in an inflammatory environment, contributing to the understanding of UC pathogenesis.

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“…As for miR-6126 and miR-1273g-3p, our findings provided the first evidence of alterations of these miRNAs in plasma from PanC patients. To date, the deregulation of miR-6126 in PanC has not yet been described, and the only evidence on miR-6216 deregulation in cancer is about the over-expression of miR-6126 in tissues from colon cancer patients compared to controls, and in healthy ovarian tissue compared to ovarian cancer samples where it acts as a tumor suppressor via integrin β1 (32,33). Similarly, few data are available on miR-1273g-3p in PanC patients.…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of Circulating miR-1273g-3p and miR-122-5p in Pancreatic Cancer

et al. 2020

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The burden of pancreatic cancer (PanC) requires innovation in the current diagnostic approach. This study aimed to uncover new circulating microRNAs (miRNAs) that would distinguish patients with PanC from healthy subjects (HS) compared with the cancer antigen 19-9 (CA 19-9), and predict patients' clinical phenotypes and outcomes. MiRNA expression profiles in plasma were investigated by using a two-stage process. In a discovery phase, miRNAs levels were analyzed using the GeneChip TM miRNA 4.0 Affymetrix assay in 10 pools of plasma samples from PanC patients and HS; in a validation phase, significantly altered miRNAs were re-tested in independent cohorts of cancer patients and controls by droplet digital PCR (ddPCR). The diagnostic performance of the resulting miRNAs was compared to CA 19-9 determinations, and the associations of miRNAs plasma levels with patients' clinical phenotypes and outcomes were also taken into account. Bioinformatics selection of miRNAs differentially expressed in plasma uncovered miR-18a-5p, miR-122-5p, miR-1273g-3p, and miR-6126 as candidate oncogenic miRNAs in PanC. The ddPCR technology confirmed the significant over-expression of miR-122-5p, miR-1273g-3p, and miR-6126 in PanC compared to HS, in line with the trend of the CA 19-9 levels. Plasma levels of miR-1273g-3p, in combination with CA 19-9, showed higher power in distinguishing PanC patients from HS compared to the CA 19-9 tested alone, with a gain in both sensitivity and negative predictive value indicating a low false-negative rate (SE = 90.2% and NPV = 92.3% vs. SE = 82.1% and NPV = 87.9%). None of the oncogenic miRNAs were able to distinguish between a neoplastic and a proliferative/inflammatory disease of the pancreas, and were not able to stratify subjects according to the clinical risk for the disease. The only valuable association in PanC patients was found between miR-1273g-3p and tumor stage, and increased miR-122-5p levels emerged as independent negative prognostic factor for PanC patients (HR = 1.58, 95% CI = 1.03-2.43, p = 0.037). Our data highlighted a role for circulating miR-1273g-3p and miR-122-5p as new diagnostic and prognostic biomarkers for PanC.

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Novel miRNAs as potential biomarkers in stage II colon cancer: microarray analysis

Cited by 49 publications

References 42 publications

microRNA-378a-5p iS a novel positive regulator of melanoma progression

microRNA-378a-5p iS a novel positive regulator of melanoma progression

Inhibition of miR-378a-3p by Inflammation Enhances IL-33 Levels: A Novel Mechanism of Alarmin Modulation in Ulcerative Colitis

Clinical Significance of Circulating miR-1273g-3p and miR-122-5p in Pancreatic Cancer

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