IGF2BP1 promotes mesenchymal cell properties and migration of tumor-derived cells by enhancing the expression of LEF1 and SNAI2 (SLUG)

Zirkel, Anne; Lederer, Marcell; Stöhr, Nadine; Pazaitis, Nikolaos; Hüttelmaier, Stefan

doi:10.1093/nar/gkt410

Cited by 60 publications

(62 citation statements)

References 50 publications

(108 reference statements)

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“…Several reports have indicated that LEF1 induces EMT in PCa cells (18, 37, 38). Here we sought to determine whether miR-34a, via LEF1, regulates EMT, migration and invasion of PCa cells.…”

Section: Resultsmentioning

confidence: 99%

LEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a

Liang

Daniels

et al. 2015

Molecular Cancer Research

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The microRNA-34a (miR-34a), a tumor suppressive microRNA (miRNA), is implicated in epithelial-mesenchymal transition (EMT) and cancer stem cells. Lymphoid enhancer-binding factor-1 (LEF1) is a key transcription factor in the Wnt signaling pathway, and has been suggested to be involved in regulation of cell proliferation and invasion. Here, the molecular mechanism of miR-34a and LEF1 in cooperatively regulating prostate cancer (PCa) cell invasion is described. Molecular profiling analysis of miRNA levels in PCa cells revealed a negative correlation between miR-34a and LEF1 expression, and the downregulation of LEF1 by miR-34a was confirmed by luciferase assays. Further, miR-34a specifically repressed LEF1 expression through direct binding to its 3′-untranslated (3′-UTR) regions. miR-34a modulated the levels of LEF1 to regulate EMT in PCa cells. Functionally, miR-34a negatively correlated with the migration and invasion of PCa cells through LEF1. An analysis of miR-34a expression levels in matched human tumor and benign tissues demonstrated consistent and statistically significant downregulation of miR-34a in primary PCa specimens. These data strongly suggest that miR-34a/LEF1 regulation of EMT plays an important role in PCa migration and invasion. Implications The miR-34a/LEF1 axis represents a potential molecular target for novel therapeutic strategies in PCa.

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“…Several reports have indicated that LEF1 induces EMT in PCa cells (18, 37, 38). Here we sought to determine whether miR-34a, via LEF1, regulates EMT, migration and invasion of PCa cells.…”

Section: Resultsmentioning

confidence: 99%

LEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a

Liang

Daniels

et al. 2015

Molecular Cancer Research

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“…Similarly, we found a substantial decrease in expression of IGF2BP2 after wounding in transgenic mice, providing a possibility that IGF2BP2 could maintain skin tissue homoeostasis by promoting the migration of keratinocyte. Many studies illustrated that IGF2BPs may enhance the formation of lamellipodia, enforce intrinsic polarization and thus promote cell migration in tumor cell dissemination . The function of IGF2BP1 is well known to promote cell migration, but the exact function of IGF2BP2 is still not clear and needs to be fully elucidated in cutaneous wound healing.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA Let‐7b inhibits keratinocyte migration in cutaneous wound healing by targeting IGF2BP2

Zhong

Hou³

et al. 2017

Experimental Dermatology

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Wound healing is a complex process which involves proliferation and migration of keratinocyte for closure of epidermal injuries. A member of microRNA family, let-7b, has been expressed in mammalian skin, but its exact role in keratinocyte migration is still not in knowledge. Here, we showed that let-7b regulates keratinocyte migration by targeting the insulin-like growth factor IGF2BP2. Overexpression of let-7b led to reduced HaCaT cell migration, while knockdown of let-7b resulted in enhanced migration. Furthermore, let-7b was decreased during wound healing in wild-type mice, which led us to construct the transgenic mice with overexpression of let-7b in skin. The re-epithelialization of epidermis of let-7b transgenic mice was reduced during wound healing. Using bioinformatics prediction software and a reporter gene assay, we found that IGF2BP2 was a target of let-7b, which contributes to keratinocyte migration. Introduction of an expression vector of IGF2BP2 also rescued let-7b-induced migration deficiency, which confirms that IGF2BP2 is an important target for let-7b regulation. Our findings suggest that let-7b significantly delayed the re-epithelialization possibly due to reduction of keratinocyte migration and restraints IGF2BP2 during skin wound healing.

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“…Briefly, cells were co-transfected with a SNAI2 -promoter containing luciferase promoter construct (kindly provided by S. Hüttelmaier; (30) together with a plasmid expressing Renilla luciferase (pRL-TK, Promega) and either an empty control vector (pSG5) or KLF10 expression vector. Firefly luciferase activity was normalized to Renilla luciferase activity to control for transfection efficiency.…”

Section: Methodsmentioning

confidence: 99%

Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism

et al. 2017

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TGFβ-SMAD signaling exerts a contextual effect that suppresses malignant growth early in epithelial tumorigenesis but promotes metastasis at later stages. Longstanding challenges in resolving this functional dichotomy may uncover new strategies to treat advanced carcinomas. The Krüppel-like transcription factor KLF10 is a pivotal effector of TGFβ/SMAD signaling that mediates anti-proliferative effects of TGFβ. In this study, we show how KLF10 opposes the pro-metastatic effects of TGFβ by limiting its ability to induce epithelial-to-mesenchymal transition (EMT). KLF10 depletion accentuated induction of EMT as assessed by multiple metrics. KLF10 occupied GC-rich sequences in the promoter region of the EMT-promoting transcription factor SLUG/SNAI2, repressing its transcription by recruiting HDAC1 and licensing the removal of activating histone acetylation marks. In clinical specimens of lung adenocarcinoma, low KLF10 expression associated with decreased patient survival, consistent with a pivotal role for KLF10 in distinguishing the anti-proliferative versus pro-metastatic functions of TGFβ. Our results establish that KLF10 functions to suppress TGFβ-induced EMT, establishing a molecular basis for the dichotomy of TGFβ function during tumor progression.

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IGF2BP1 promotes mesenchymal cell properties and migration of tumor-derived cells by enhancing the expression of LEF1 and SNAI2 (SLUG)

Cited by 60 publications

References 50 publications

LEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a

LEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a

MicroRNA Let‐7b inhibits keratinocyte migration in cutaneous wound healing by targeting IGF2BP2

Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism

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