E2F1 induces miR‐224/452 expression to drive <scp>EMT</scp> through <scp>TXNIP</scp> downregulation

Knoll, Susanne; Fürst, Katharina; Kowtharapu, Bhavani S.; Schmitz, Ulf; Marquardt, Stephan; Wolkenhauer, Olaf; Martin, H; Pützer, Brigitte M.

doi:10.15252/embr.201439392

Cited by 85 publications

(76 citation statements)

References 74 publications

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“…E2F1 may enhance metastatic behavior in melanomas by directly binding with VEGFC and the corresponding receptor VEGFR-3 for transactivation (37). The oncogenic properties of E2F1 have been associated with high EMT transition (38). However, the forces that drive E2F1 gene expression in ccRCC remain unclear.…”

Section: Discussionmentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

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The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelialmesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

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“…More precisely, we aim to explore patterns (mutual exclusivity or co-occurrence), focusing on components often altered in bladder cancer and involved in growth factor signaling, cell-cycle entry, and triggering of apoptosis in response to DNA damage with the focus on the E2F pathway. It has been shown recently that the E2F pathway is not only involved in the control of proliferation but also in invasion and metastasis (22)(23)(24), justifying the study of this pathway to explore invasiveness in bladder tumors.…”

Section: Assessing Phenotypesmentioning

confidence: 99%

“…As mentioned above, mutations of PIK3CA, but also deletions of CDKN1A (p21CIP) would drastically favour proliferation (Supplementary Tables S4 and S8). Recall that RB/E2F pathway is not only involved in proliferation but also in invasion and metastasis (22)(23)(24); thus, we anticipate that highly proliferative tumors are invasive ( Supplementary Fig. S2 shows that expression of gene targets of the E2F1-3 transcription factors is correlated to tumor stages).…”

Section: Data Interpretation Using the Modelmentioning

confidence: 99%

A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis

et al. 2015

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Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modeling to explain patterns of genetic alterations seen in 178 patients with bladder tumors (either muscle-invasive or non-muscle-invasive). A statistical analysis on frequently altered genes identified pair associations, including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signaling, cell cycle, and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publicly. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signaling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3-activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favor invasiveness. Furthermore, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness through two main progression pathways in bladder cancer.

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“…Previous studies have found that the oncogenic activity of miR-224 is exerted by targeting the 3′-UTR of TXNIP, which suppresses its expression [18]. Here, we discovered that both the mRNA and protein expression levels of TXNIP were significantly lower in all five PC cell lines tested than in normal pancreatic cells (Fig.…”

Section: Txnip Is a Direct Target Of Mir-224 In Pdac Cellsmentioning

confidence: 57%

MicroRNA-224 Promotes Pancreatic Cancer Cell Proliferation and Migration by Targeting the TXNIP-Mediated HIF1α Pathway

Zhu

Zhou

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: MicroRNAs (miRNAs) have been shown to participate in the development of pancreatic ductal adenocarcinoma (PDAC) by modulating multiple cellular processes. Increased miR-224 expression enhances proliferation and metastasis in human cancers. This study aimed to investigate the role of miR-224 and its underlying mechanism of action in PDAC. Methods: BrdU, MTT, and cell migration assays were performed to determine cell proliferation, viability, and migration, respectively. The binding sites of miR-224 were identified using a luciferase reporter system, whereas protein expression of target genes was determined by immunoblotting and immunofluorescence analyses. A BALB/c nude mouse xenograft model was used to evaluate the role of miR-224 in vivo. Results: We demonstrated that miR-224 expression was enhanced in PDAC cells and tissues, and was related to migration and proliferation. Noticeably, miR-224 overexpression promoted the proliferation, migration, and metastasis of Panc1 cells, while miR-224 inhibition had the reverse effect on PDAC cells. Moreover, we found that thioredoxin-interacting protein (TXNIP) is a target of miR-224. The results also indicated that miR-224 inversely regulated TXNIP by binding directly to its 3′-untranslated region, which resulted in the activation of hypoxia-inducible factor 1α (HIF1α). Further, either TXNIP re-expression or HIF1α depletion abolished the effects of miR-224 on the proliferation and migration of PDAC cells in vitro and in vivo. Regarding the relationship of TXNIP and HIF1α, we found that TXNIP mediated the nuclear export of HIF1α and its degradation by forming a complex with HIF1α. Conclusion: The miR-224-TXNIP-HIF1α axis may be useful in developing novel therapies for PDAC.

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E2F1 induces miR‐224/452 expression to drive EMT through TXNIP downregulation

Cited by 85 publications

References 74 publications

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis

MicroRNA-224 Promotes Pancreatic Cancer Cell Proliferation and Migration by Targeting the TXNIP-Mediated HIF1α Pathway

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