A microRNA/Runx1/Runx2 network regulates prostate tumor progression from onset to adenocarcinoma in TRAMP mice

Farina, Nicholas H.; Zingiryan, Areg; Akech, Jacqueline; Callahan, Cody; Lu, Huimin; Stein, Janet L.; Languino, Lucia R.; Lian, Jane B.

doi:10.18632/oncotarget.11992

Cited by 28 publications

(18 citation statements)

References 60 publications

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“…The goal of our study was to identify if RUNX1 plays a clinically important role in lung adenocarcinoma and lay the foundation for valuable translational investigation. While loss of RUNX1 has been associated with breast (Hong et al, ; Janes, ) and prostate (Farina et al, ; Takayama et al, ) cancers, our findings in lung have identified a key role for RUNX1 not previously reported in lung cancer. We show the loss of RUNX1 is a driver of aggressiveness and prognosis in lung adenocarcinoma, phenotypes that may be mediated through E2F1 pathways that support proliferation.…”

Section: Discussioncontrasting

confidence: 54%

Loss of RUNX1 is associated with aggressive lung adenocarcinomas

Ramsey

Butnor

Peng

et al. 2017

Journal Cellular Physiology

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The mammalian runt-related factor 1 (RUNX1) is a master transcription factor that regulates lineage specification of hematopoietic stem cells. RUNX1 translocations result in the development of myeloid leukemias. Recently, RUNX1 has been implicated as a tumor suppressor in other cancers. We postulated RUNX1 expression may be associated with lung adenocarcinoma etiology and/or progression. We evaluated the association of RUNX1 mRNA expression with overall survival data from The Cancer Genome Atlas (TCGA), a publically available database. Compared to high expression levels, Low RUNX1 levels from lung adenocarcinomas were associated with a worse overall survival (Hazard Ratio = 2.014 (1.042-3.730 95% confidence interval), log-rank p = 0.035) compared to those that expressed high RUNX1 levels. Further immunohistochemical examination of 85 surgical specimens resected at the University of Vermont Medical Center identified that low RUNX1 protein expression was associated with larger tumors (p = 0.038). Gene expression network analysis was performed on the same subset of TCGA cases that demonstrated differential survival by RUNX1 expression. This analysis, which reveals regulatory relationships, showed that reduced RUNX1 levels were closely linked to upregulation of the transcription factor E2F1. To interrogate this relationship, RUNX1 was depleted in a lung cancer cell line that expresses high levels of RUNX1. Loss of RUNX1 resulted in enhanced proliferation, migration, and invasion. RUNX1 depletion also resulted in increased mRNA expression of E2F1 and multiple E2F1 target genes. Our data implicate loss of RUNX1 as driver of lung adenocarcinoma aggression, potentially through deregulation of the E2F1 pathway.

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Section: Discussioncontrasting

confidence: 54%

Loss of RUNX1 is associated with aggressive lung adenocarcinomas

Ramsey

Butnor

Peng

et al. 2017

Journal Cellular Physiology

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“…In spite of the significant upregulation of miR-375 in the serum of castration-resistant PCa patients [48] , we observed a significant reduction of miR-375-3p with tricirbine treatment in the advanced tumor-bearing TRAMP mice. Interestingly, during their investigation for the miRNA-Runx1/2 signaling network in the regulation of PCa progression in TRAMP mice and by looking at the temporal miRNAs expression in TRMAP's tumors, Farina et al have also noticed a significant reduction in miR-375-3p expression as the tumor develops in these mice compared to wild-type controls [49] . Although its expression was measured up to 21-week-old mice, the expression of Runx1/2, which are targets for miR-375-3p, was elevated in 33week-old TRAMPs indicating the potential reduction of miR-375-3p during that stage.…”

Section: Discussionmentioning

confidence: 99%

Modulation in the microRNA repertoire is responsible for the stage-specific effects of Akt suppression on murine neuroendocrine prostate cancer

Alwhaibi

Gao

Artham

et al. 2018

Heliyon

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Recent studies indicate a stage-specific, differential role for the oncogene Akt on various cancers. In prostate cancer (PCa), suppression of Akt activity in the advanced stages promoted transforming growth factor-β (TGFβ) pathway-mediated epithelial-to-mesenchymal transition (EMT) and metastasis to the lungs. In the current study, we performed Affymetrix analysis to compare the expression profile of microRNAs in the mouse prostate tissues collected at the prostatic inter-epithelial neoplasia (PIN) stage from Transgenic adenocarcinoma of the mouse (TRAMP)/Akt1+/+ versus TRAMP/Akt1–/– mice, and at the advanced stage from TRAMP/Akt1+/+ mice treated with triciribine (Akt inhibitor) versus DMSO-treated control. Our analysis demonstrates that in the early stage, Akt1 in the TRAMP prostate tumors express a set of miRNAs responsible for regulating cancer cell survival, proliferation, and tumor growth, whereas, in the advanced stages, a different set of miRNAs that promote EMT and cancer metastasis is expressed. Our study has identified novel Akt-regulated signature microRNAs in the early and advanced PCa and demonstrates their differential effects on PCa growth and metastasis.

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“…miR-384 has suppressive effects on tumor cell proliferation through the direct inhibition of IRS1 expression (Lai et al, 2016), and contributes to aberrant Runx expression in prostate tumors (Farina et al, 2016). In addition, several studies have demonstrated a relationship between miR-384 and the CNS.…”

Section: Discussionmentioning

confidence: 99%

MiR-384 Regulates the Th17/Treg Ratio during Experimental Autoimmune Encephalomyelitis Pathogenesis

Han

Zhang

et al. 2017

Front. Cell. Neurosci.

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Specific miRNAs are involved in the pathogenesis of multiple sclerosis (MS), during which IL-17-producing CD4+ T helper (Th17) cells accumulate in the central nervous system (CNS). In this study, we identified levels of miR-384 as significantly increased in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Over-expression of miR-384 in vivo led to severe EAE, characterized by exacerbated demyelination, and increased inflammatory cell infiltration of the spinal cord; inhibition of miR-384 reversed these changes. Both the percentage of Th17, and ratio of Th17/regulatory T (Treg), cells were elevated in miR-384-transfected EAE mice, which was consistent with the observed upregulation of expression of IL-17 and the Th17 lineage-specific transcription factor, RORγt. Importantly, transfer of miR-384 overexpressing naïve T cells from wild-type (WT) to Rag1−/− mice, which are deficient in functional autologous T and B cells, led to aggravated EAE pathogenesis, while an miR-384 inhibited group was protected from EAE. Moreover, miR-384 promoted differentiation of naïve T cells into Th17 cells in vitro. Furthermore, target prediction and dual luciferase reporter assays demonstrated that suppressor of cytokine signaling 3 (SOCS3), a gene encoding protein with an established role in Th17 differentiation, was a direct target of miR-384. Our results demonstrate an important role for miR-384 in regulation of the Th17/Treg ratio during the pathogenesis of EAE, indicating that this molecule may have potential as a biomarker and/or therapeutic target in MS.

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A microRNA/Runx1/Runx2 network regulates prostate tumor progression from onset to adenocarcinoma in TRAMP mice

Cited by 28 publications

References 60 publications

Loss of RUNX1 is associated with aggressive lung adenocarcinomas

Loss of RUNX1 is associated with aggressive lung adenocarcinomas

Modulation in the microRNA repertoire is responsible for the stage-specific effects of Akt suppression on murine neuroendocrine prostate cancer

MiR-384 Regulates the Th17/Treg Ratio during Experimental Autoimmune Encephalomyelitis Pathogenesis

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