miR-21 coordinates tumor growth and modulates KRIT1 levels

Orso, Francesca; Balzac, Fiorella; Marino, Marco; Lembo, Antonio; Retta, Saverio Francesco; Taverna, Daniela

doi:10.1016/j.bbrc.2013.07.031

Cited by 23 publications

(18 citation statements)

References 42 publications

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“…The new gene in Figures 4E, F, G, H is Krev interaction trapped protein 1 (KRIT1), which is responsible for cerebrovascular disease (Goitre et al, 2010). Consistent with other partners in this four cliques, KRIT1 has been shown to be involved in cell growth, DNA damage, angiogenesis, and cell death (Goitre et al, 2010; Orso et al, 2013), indicating that it may function as a potential mechanism of susceptibility to ovarian tumorigenesis. Figure 4N contains a new gene DPM1 that encodes dolichol-phosphate mannosyltransferase.…”

Section: Resultssupporting

confidence: 70%

The Identification and Analysis of mRNA–lncRNA–miRNA Cliques From the Integrative Network of Ovarian Cancer

Zhou

Zheng

et al. 2019

Front. Genet.

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Ovarian cancer is one of the leading causes of cancer mortality in women. Since little clinical symptoms were shown in the early period of ovarian cancer, most patients were found in phases III–IV or with abdominal metastasis when diagnosed. The lack of effective early diagnosis biomarkers makes ovarian cancer difficult to screen. However, in essence, the fundamental problem is we know very little about the regulatory mechanisms during tumorigenesis of ovarian cancer. There are emerging regulatory factors, such as long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), which have played important roles in cancers. Therefore, we analyzed the RNA-seq profiles of 407 ovarian cancer patients. An integrative network of 20,424 coding RNAs (mRNAs), 10,412 lncRNAs, and 742 miRNAs were construed with variance inflation factor (VIF) regression method. The mRNA–lncRNA–miRNA cliques were identified from the network and analyzed. Such promising cliques showed significant correlations with survival and stage of ovarian cancer and characterized the complex sponge regulatory mechanism, suggesting their contributions to tumorigenicity. Our results provided novel insights of the regulatory mechanisms among mRNAs, lncRNAs, and miRNAs and highlighted several promising regulators for ovarian cancer detection and treatment.

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Section: Resultssupporting

confidence: 70%

The Identification and Analysis of mRNA–lncRNA–miRNA Cliques From the Integrative Network of Ovarian Cancer

Zhou

Zheng

et al. 2019

Front. Genet.

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“…Previous data have shown much higher relative RNA expression levels of the CCM1 gene in all cancer cell lines, compared to normal primary cell lines (5). In fact, CCM1 was found to act as a potential tumor suppressor inhibited in several cultured cancer cell lines by miR-21 (12), one of the most overexpressed small RNAs in a variety of solid cancers, including breast, colon, melanoma, cervix, ovarian, lung, pancreas, prostate and stomach cancers (13). Likewise, deficiency of Ccm1 in a mouse model showed an increased appearance of adenoma associated with increased β-catenin-mediated signaling (14), further supporting the potential role of CCM1 in tumorigenesis.…”

Section: Introductionmentioning

confidence: 85%

Emerging roles of CCM genes during tumorigenesis with potential application as novel biomarkers across major types of cancers

Abou‐Fadel

Gonzalez

et al. 2020

Oncol Rep

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Cerebral cavernous malformations (CCMs) are microvascular anomalies in the brain that result in increased susceptibility to stroke. Three genes have been identified as causes of CCMs: cerebral cavernous malformations 1 [(CCM1) also termed Krev interaction trapped 1 (KRIT1)], cerebral cavernous malformation 2 [(CCM2) also termed MGC4607] and cerebral cavernous malformation 3 [(CCM3) also termed programmed cell death 10 (PDCD10)]. It has been demonstrated that both CCM1 and CCM3 bind to CCM2 to form a CCM signaling complex (CSC) with which to modulate multiple signaling cascades. CCM proteins have been reported to play major roles in microvascular angiogenesis in human and animal models. However, CCM proteins are ubiquitously expressed in all major tissues, suggesting an unseen broader role of the CSC in biogenesis. Recent evidence suggests the possible involvement of the CSC complex during tumorigenesis; however, studies concerning this aspect are limited. This is the first report to systematically investigate the expression patterns of CCM proteins in major human tumors using real-time quantitative PCR, RNA-fluorescence in situ hybridization, immunohistochemistry and multicolor immunofluorescence imaging. Our data demonstrated that differential expression patterns of the CSC complex are correlated with certain types and grades of major human cancers, indicating the potential application of CCM genes as molecular biomarkers for clinical oncology. Our data strongly suggest that more efforts are needed to elucidate the role of the CSC complex in tumorigenesis, which may have enormous clinical potential for cancer diagnostic, prognostic and therapeutic applications.

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“…The luciferase assay for KRIT1 was omitted, as it was previously performed by others [ 21 ]. Moreover, luciferase assays for FOXO1 and NFE2L2 were omitted, as we had found normal mRNA levels for FOXO1 and NFE2L2 in HUVECs transfected with anti-miR-21 (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Glucose-sensing microRNA-21 disrupts ROS homeostasis and impairs antioxidant responses in cellular glucose variability

Sala

Mrakic‐Sposta

Micheloni

et al. 2018

Cardiovasc Diabetol

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BackgroundAntioxidant enzymes play a fundamental role in counteracting oxidative stress induced by high glucose. Although mitochondrial superoxide dismutase (SOD2) is the principal defence against the toxicity of superoxide anions, the mechanism of its inactivation in diabetic subjects is still poorly understood. Recently, microRNA-21 has been associated with diabetes, although its function remains unclear. We sought to explore the mechanism underlying defective SOD2 antioxidant response in HUVECs during exposures to constant high glucose and oscillating glucose (as glucose variability model, GV) and the role of miR-21 in increasing the susceptibility to oxidative stress by disrupting reactive oxygen species (ROS) homeostasis.MethodsHUVECs exposed for 1 week to constant high glucose and GV were subjected to quantitative electron paramagnetic resonance for ROS measurements. Superoxide anions, SOD2 protein levels and mitochondrial membrane potential (ΔΨm) were also evaluated. Endogenous miR-21 and its putative ROS-homeostatic target genes (KRIT1, FoxO1, NFE2L2 and SOD2) were tested using mimic-miR-21 and quantified by qPCR. Luciferase assays were performed to test miR-21/3′-UTR-SOD2 binding.ResultsWe observed upregulation of microRNA-21, overproduction of superoxide anions and total ROS generation, depolarisation of the mitochondrial membrane potential (ΔΨm) and defective SOD2 antioxidant response in HUVECs subjected to constant high glucose and GV exposures. We also found that exogenous mimic-microRNA-21 targeted putative microRNA-21 ROS-homeostatic target genes, e.g., KRIT1, NRF2 and SOD2, which were significantly downregulated. All these effects were reverted by a microRNA-21 inhibitor, which improved SOD2 and KRIT1 expression, reduced the levels of ROS production and ameliorated ΔΨm.ConclusionsOur data demonstrate the association of microRNA-21 with oscillating and high glucose and early mitochondrial dysfunction. We found that microRNA-21 may promote the suppression of homeostatic signalling that normally limits ROS damage. These data provide novel clues about the inhibition of microRNA-21 as a new therapeutic approach to protect against cellular oxidative injury in glucose variability and diabetes.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0748-2) contains supplementary material, which is available to authorized users.

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miR-21 coordinates tumor growth and modulates KRIT1 levels

Abstract: HighlightsmiR-21 targets KRIT1.miR-21 and KRIT1 expression anticorrelate in human breast tumors.KRIT1 is involved in miR-21-mediated tumor cell growth.

Cited by 23 publications

References 42 publications

The Identification and Analysis of mRNA–lncRNA–miRNA Cliques From the Integrative Network of Ovarian Cancer

The Identification and Analysis of mRNA–lncRNA–miRNA Cliques From the Integrative Network of Ovarian Cancer

Emerging roles of CCM genes during tumorigenesis with potential application as novel biomarkers across major types of cancers

Glucose-sensing microRNA-21 disrupts ROS homeostasis and impairs antioxidant responses in cellular glucose variability

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