EMT transcription factors in cancer development re-evaluated: Beyond EMT and MET

Goossens, Steven; Vandamme, Niels; Vlierberghe, Pieter Van; Berx, Geert

doi:10.1016/j.bbcan.2017.06.006

Cited by 245 publications

(233 citation statements)

References 103 publications

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“…It promotes cancer metastasis, contributes to tumor heterogeneity and also confers therapeutic resistance. The EMT‐TFs (transcription factors) not only induce the morphology change from epithelial to mesenchymal but also make mesenchymal cells more resistant to radiotherapy and chemotherapy . RAS‐ERK and RAS‐AKT signaling transmit signals from a vast variety of inputs to support cancer proliferation, survival and metastasis .…”

Section: Resultsmentioning

confidence: 99%

“…The EMT-TFs (transcription factors) not only induce the morphology change from epithelial to mesenchymal but also make mesenchymal cells more resistant to radiotherapy and chemotherapy. 11 RAS-ERK and RAS-AKT signaling transmit signals from a vast variety of inputs to support cancer proliferation, survival and metastasis. 12 P53 is a well-known tumor suppressor and acts as guardian of the genome for promoting cell cycle arrest, apoptosis, senescence and DNA repair.…”

Section: Aging Widely Impacts Specific Pathways Across Cancersmentioning

confidence: 99%

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Comprehensive transcriptome profiling in elderly cancer patients reveals aging‐altered immune cells and immune checkpoints

Wei

Chen

et al. 2018

Intl Journal of Cancer

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Aging is the single most significant risk factor for cancer development. However, the potential impact of aging on cancer microenvironment remains poorly understood. Here, we performed a pan-cancer transcriptome analysis to identify aging-specific molecular patterns across 18 cancer types. Strikingly, aging-specific molecular features define human cancers into two types, including the strong and weak aging-effect groups. Significant aging associated molecular signature was observed in 16 cancer types (strong aging-effect group) such as breast invasive carcinoma and acute myeloid leukemia. In such 16 cancer types, old patients showed obvious poor survival compared to young patients, but this observation was not found in the weak aging-effect cancers. Aging-associated cancer-relevant molecules significantly enriched in 23 pathways including EMT and KRAS signaling. More interestingly, in cancer microenvironment, aging significantly restrains adaptive immunity, but strikingly, increases the number of infiltrated innate immune cells. Further analysis shows that the expression of immune checkpoints including PD-1, PD-L1, PD-L2, and CTLA-4 are mostly correlated with age. In general, cancer cells in elderly patients show a more aggressive phenotype and their surrounding microenvironment is under a more immune suppression status compared with young patients. Our study provides a systematic understanding of aging-associated molecular features in pan-cancer and indicates a clinical requirement to develop aging-specific therapeutic strategies in a majority of cancer types. Furthermore, aging-altered immune cells and immune checkpoints should be considered in cancer immunotherapy. This article is protected by copyright. All rights reserved.

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Section: Resultsmentioning

confidence: 99%

Section: Aging Widely Impacts Specific Pathways Across Cancersmentioning

confidence: 99%

Comprehensive transcriptome profiling in elderly cancer patients reveals aging‐altered immune cells and immune checkpoints

Wei

Chen

et al. 2018

Intl Journal of Cancer

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“…Suramin does not significantly affect HMGA2 expression in both BTSCs ( Fig. 5B and C) and however decreases the expression of SNAIL, TWIST, and ID2, transcriptional factors associated with tumorigenesis and metastasis (66). Importantly, the decrease of these three transcriptional factors is correlated with HMGA2 expression level, suggesting that suramin binds to HMGA2 and inhibits HMGA2-DNA interactions inside these BTSCs.…”

Section: Discussionmentioning

confidence: 84%

Suramin potently inhibits binding of the mammalian high mobility group protein AT-hook 2 to DNA

Bryan

Battista

et al. 2019

Preprint

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The mammalian high mobility group protein AT-hook 2 (HMGA2) is a multi-functional DNAbinding protein which plays important roles in tumorigenesis and adipogenesis. Previous results showed that HMGA2 is a potential therapeutic target of anticancer and anti-obesity drugs by inhibiting its DNA-binding activities. Here we report the development of a miniaturized, automated AlphaScreen high throughput screening (HTS) assay to identify inhibitors targeting HMGA2-DNA interactions. After screening the LOPAC1280 compound library, we discovered that suramin, a negatively charged antiparasitic drug potently inhibits the HMGA2-DNA interaction. Our results also show that the inhibition is through suramin binding to the AT-hooks of HMGA2, therefore blocking its DNA binding capacity. Furthermore, we demonstrate that suramin can induce brain tumor stem cells differentiation into cells with neurite-like structures, a process triggered by disrupting HMGA2-DNA interactions. Since suramin has strong antitumor and anti-metastasis activities, our discovery suggests that HMGA2 and HMGA2-like proteins may be the cellular target of this century-old drug.The mammalian high mobility group protein AT-hook 2 (HMGA2) is a multi-functional nuclear protein associated with epithelial-to-mesenchymal transition (EMT) during embryonic development (1). Early studies showed that HMGA2 is related to preadipocyte proliferation and obesity (2-4). For example, Hmga2 knockout mice were severely deficient in fat cells and developed pygmy phenotype (5). The disruption of Hmga2 gene dramatically reduced obesity of leptin-deficient mice (Lep ob /Lep ob ) (2). These results suggest that HMGA2 is a potential target for the treatment of obesity. HMGA2 is also linked to oncogenesis. Its over and/or aberrant expression leads to the formation of a variety of tumors including benign tumors, such as lipomas (6), uterine leiomyomas (7), and fibroadenomas (8), and malignant tumors, such as lung cancer (9,10), breast cancer (11,12), prostate cancer (13), leukemia (14), and melanoma (15-18).Intriguingly, HMGA2 expression level always correlates with the degree of malignancy, metastasis, and a poor prognosis (19,20), suggesting that this protein is also a therapeutic target of anti-cancer and anti-metastasis drugs (21,22). Furthermore, HMGA2 is associated with neural and hematopoietic stem cell youth (23,24), human height (25), and human intelligence (26).HMGA2 is a small DNA-binding protein consisting of three "AT-hook" DNA binding motifs and a highly acidic C-terminal motif (27). These three "AT-hooks" contain a unique palindromic sequence, PGRGP, each side surrounded by one or two positively charged amino acids, i.e., Lysine or Arginine (28). HMGA2 is an intrinsically disordered protein (IDP (29)). When it binds to AT-rich DNA sequences, the "AT-hook" DNA binding motifs adopt defined structures (30).This disordered-to-ordered conformational transition allows HMGA2 to adapt to different ATrich DNA sequences and to participate in different nuclear activities, such as tra...

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“…These TFs directly regulates genes involved in cell adhesion, polarity and cytoskeleton reorganization [16]. Overexpression of these TFs in epithelial cells induces either partial or complete changes from an epithelial to mesenchymal morphology, associated with increased motility, invasive capacity and resistance to chemotherapy [17][18][19]. In normal conditions, the epithelial cells maintains adherent junctions, where E-cadherin forms a complex with βcatenin in the cell membrane [3,20].…”

Section: Introductionmentioning

confidence: 99%

Leptin promotes expression of EMT-related transcription factors and invasion in a Src and FAK-dependent pathway in MCF10A mammary epithelial cells

Olea-Flores

Zuñiga-Eulogio

Tacuba-Saavedra

et al. 2019

Preprint

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Leptin is one of the main adipokines secreted in breast tissue, and has been associated with epithelial-mesenchymal transition (EMT) and tumor progression in breast cancer. Leptin promotes EMT, cell migration and invasion in epithelial breast cells, leading to tumor progression. However, the molecular mechanism that underlies these events is not fully understood; however, the activation of different signaling pathways appears to be essential. In this sense, the effect of leptin on the activation of kinases like Src and FAK, which regulate signaling pathways that activate the EMT program, has not been completely described. Therefore, we investigated the involvement of these kinases using an in vitro model for leptin-induced EMT process in the non-tumorigenic MCF10A cell line. To this end, MCF10A cells were stimulated with leptin, and Src and FAK activation was assessed. Specific events occurring during EMT were also evaluated in the presence or absence of the kinases's chemical inhibitors PP2 and PF-573228. For instance, we tested the expression and subcellular localization of the EMT--catenin, by western blot and immunofluorescence. We also evaluated the secretion and activation of matrix metalloproteases (MMP-2 and MMP-9) by gelatin zymography. Invasiveness properties of leptin-stimulated cells were determined by invadopodia formation assays, and by the transwell chamber method. Our results showed that leptin promotes EMT through Src and FAK activation, which leads to the secretion and activation of MMP-2 and MMP-9, invadopodia formation and cell invasion in MCF10A cells. In conclusion, our data suggest that -catenin, the secretion of MMP-2, MMP-9, the invadopodia formation and invasion in MCF10A cells in a Src and FAK-dependent manner.

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EMT transcription factors in cancer development re-evaluated: Beyond EMT and MET

Cited by 245 publications

References 103 publications

Comprehensive transcriptome profiling in elderly cancer patients reveals aging‐altered immune cells and immune checkpoints

Comprehensive transcriptome profiling in elderly cancer patients reveals aging‐altered immune cells and immune checkpoints

Suramin potently inhibits binding of the mammalian high mobility group protein AT-hook 2 to DNA

Leptin promotes expression of EMT-related transcription factors and invasion in a Src and FAK-dependent pathway in MCF10A mammary epithelial cells

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